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Young RJ, Kirkham A, Savage J, Gaskell C, Johnson S, Dockrell DH, Bower M, Westwell S, Bowman C, Leahy M, Woll P, Billingham L. Selumetinib in Combination with Anti Retroviral Therapy in HIV-associated Kaposi sarcoma (SCART): an open-label, multicentre, phase I/II trial. BMC Cancer 2025; 25:505. [PMID: 40108492 PMCID: PMC11921695 DOI: 10.1186/s12885-025-13890-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 03/10/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Kaposi sarcoma (KS) is the commonest HIV-associated malignancy. It is caused by co-infection with Kaposi sarcoma herpesvirus (KSHV), which upregulates the MAPK pathway. The aim of the SCART trial was to identify a safe dose for the MEK inhibitor selumetinib in combination with antiretroviral therapy (ART) and to establish evidence of the combination's efficacy. METHODS SCART was a prospective, single arm, open-label, multi-centre, phase I/II trial, recruiting from four UK centres. Eligible patients were HIV positive, established on an ART regimen ≥ 3 months, had HIV viral load ≤ 200/ml, and had histologically confirmed KS with progressive disease. Phase I primary outcomes were occurrence of dose limiting toxicity (DLT) to determine the maximum tolerated dose/recommended phase II dose (RP2D), and pharmacokinetic assessments of selumetinib and N-desmethyl metabolite. Phase II primary outcome was occurrence of objective response (OR) as defined by AIDS Clinical Trials Group (ACTG) criteria. RESULTS Between 15-Jun-2012 and 25-Sep-2018, 19 patients were recruited; three did not start treatment and were not included in the final analysis. Ten eligible patients were treated in phase I and an additional six in phase II. There was one DLT at the 75 mg bd dose, which was deemed to be the RP2D. Of those patients receiving the RP2D (six within phase I, six within phase II), one achieved a partial response (OR 8.3%, 90% confidence interval: 0.4, 33.9). Further to the DLT, two serious adverse reactions, one unrelated serious adverse event (AE), and six non-serious grade 3 AEs were reported, together with 360 AEs graded 1 or 2. No detrimental impact on ART drug levels or HIV viral load were observed, with improvements in CD4 count and evidence of response in Angiopoietin-2 demonstrated. CONCLUSIONS SCART was closed early due to slow recruitment, partly due to the rarity of KS because of improvements in HIV care, but also due to patients' concerns about experiencing non-serious toxicity additional to those from ART. Although we cannot recommend the use of 75 mg bd selumetinib with ART in patients with HIV-associated KS, studies exploring selumetinib in combination with other agents including anti-angiogenic agents and/or immune checkpoint inhibitors are warranted. TRIAL REGISTRATION ISRCTN24921472.
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Affiliation(s)
- Robin J Young
- University of Sheffield, Sheffield, UK.
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
| | - Amanda Kirkham
- Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham, Birmingham, UK
| | - Joshua Savage
- Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham, Birmingham, UK
| | - Charlotte Gaskell
- Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham, Birmingham, UK
| | - Sarah Johnson
- Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham, Birmingham, UK
| | - David H Dockrell
- Institute for Regeneration and Repair, Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | - Mark Bower
- National Centre for HIV Malignancy, Chelsea & Westminster Hospital, London, UK
| | - Sarah Westwell
- Brighton and Sussex University Hospitals NHS Trust, Brighton, UK
| | - Christine Bowman
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | | | - Penella Woll
- University of Sheffield, Sheffield, UK
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Lucinda Billingham
- Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham, Birmingham, UK
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Lurain K, Ramaswami R, Ekwede I, Eulo V, Goyal G, Menon M, Odeny TA, Sharon E, Wagner MJ, Wang CC(J, Bhardwaj N, Friedlander PA, Abdul-Hay M, Castro EMC, Labo N, Marshall VA, Miley W, Moore K, Roshan R, Whitby D, Kask AS, Kaiser J, Han E, Wright A, Yarchoan R, Fling SP, Uldrick TS. Cancer Immunotherapy Trials Network 12: Pembrolizumab in HIV-Associated Kaposi Sarcoma. J Clin Oncol 2025; 43:432-442. [PMID: 39356983 PMCID: PMC11779594 DOI: 10.1200/jco.24.00640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 06/21/2024] [Accepted: 08/12/2024] [Indexed: 10/04/2024] Open
Abstract
PURPOSE Cancer Immunotherapy Trials Network 12 demonstrated safety of pembrolizumab in treating advanced cancer in people with HIV. Here, we report results of the Kaposi sarcoma (KS) cohort. METHODS In this multicenter phase I trial, we enrolled participants with HIV-associated KS on antiretroviral therapy with CD4+ ≥50 cells/μL and HIV plasma RNA <200 copies/mL. Pembrolizumab 200 mg intravenously was administered once every 3 weeks for up to 35 cycles. The primary end point was safety, and the secondary end point was KS response by modified AIDS Clinical Trials Group Criteria. RESULTS Thirty-two cisgender men enrolled with baseline median CD4+ T-cell count of 274 cells/µL. All but nine participants had received previous systemic KS therapy. Participants received a median of 11 cycles of pembrolizumab (range, 1-35). Sixty-six percent had grade ≥1 treatment-emergent adverse events, including one death from polyclonal KS herpesvirus-related B-cell lymphoproliferation. Thirty-one percent had ≥one immune-mediated AEs (imAEs) with 25% requiring systemic steroids. In 29 participants with evaluable KS, the overall response rate (ORR) was 62.1% (95% CI, 42.3 to 79.3) and did not differ by CD4+ T-cell count. ORR in the eight participants with evaluable disease without previous KS therapy was 87.5% (95% CI, 47.3 to 99.7). Median duration of response (DOR) was not reached, and the Kaplan-Meier estimate of DOR of ≥12 months was 92.3% (95% CI, 56.6 to 98.8). Median progression-free survival was 28.2 months (95% CI, 4.2 to noncalculable). CONCLUSION Pembrolizumab yielded a high rate of durable responses in HIV-associated KS. imAEs were successfully managed with standard guidelines.
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MESH Headings
- Humans
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/adverse effects
- Male
- Middle Aged
- Sarcoma, Kaposi/drug therapy
- Sarcoma, Kaposi/immunology
- Sarcoma, Kaposi/virology
- Sarcoma, Kaposi/mortality
- Adult
- HIV Infections/drug therapy
- HIV Infections/complications
- HIV Infections/immunology
- Antineoplastic Agents, Immunological/therapeutic use
- Antineoplastic Agents, Immunological/adverse effects
- AIDS-Related Opportunistic Infections/drug therapy
- AIDS-Related Opportunistic Infections/immunology
- Immune Checkpoint Inhibitors/adverse effects
- Immune Checkpoint Inhibitors/therapeutic use
- Aged
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Affiliation(s)
- Kathryn Lurain
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Ramya Ramaswami
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Irene Ekwede
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Vanessa Eulo
- University of Alabama at Birmingham, Birmingham, AL, USA
| | - Gaurav Goyal
- University of Alabama at Birmingham, Birmingham, AL, USA
| | - Manoj Menon
- Fred Hutchinson Cancer Center and University of Washington, Seattle, WA, USA
| | - Thomas A. Odeny
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Elad Sharon
- Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Dana-Farber Cancer Institute, Boston, MA, USA
| | - Michael J. Wagner
- Fred Hutchinson Cancer Center and University of Washington, Seattle, WA, USA
- Dana-Farber Cancer Institute, Boston, MA, USA
| | | | - Nina Bhardwaj
- Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA
| | | | - Maher Abdul-Hay
- Laura and Isaac Perlmutter Cancer Center at NYU Langone Health, New York, NY, USA
| | - Elena M. Cornejo Castro
- Viral Oncology Section, AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Nazzarena Labo
- Viral Oncology Section, AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Vickie Ann Marshall
- Viral Oncology Section, AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Wendell Miley
- Viral Oncology Section, AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Kyle Moore
- Viral Oncology Section, AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Romin Roshan
- Viral Oncology Section, AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Denise Whitby
- Viral Oncology Section, AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Angela Shaulov Kask
- Fred Hutchinson Cancer Center and University of Washington, Seattle, WA, USA
| | - Judith Kaiser
- Fred Hutchinson Cancer Center and University of Washington, Seattle, WA, USA
| | - Emma Han
- Cytel (Shanghai) Co. Ltd, Shanghai, China
| | - Anna Wright
- Fred Hutchinson Cancer Center and University of Washington, Seattle, WA, USA
| | - Robert Yarchoan
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Steven P. Fling
- Fred Hutchinson Cancer Center and University of Washington, Seattle, WA, USA
| | - Thomas S. Uldrick
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Fred Hutchinson Cancer Center and University of Washington, Seattle, WA, USA
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Losay VA, Damania B. Unraveling the Kaposi Sarcoma-Associated Herpesvirus (KSHV) Lifecycle: An Overview of Latency, Lytic Replication, and KSHV-Associated Diseases. Viruses 2025; 17:177. [PMID: 40006930 PMCID: PMC11860327 DOI: 10.3390/v17020177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/18/2025] [Accepted: 01/23/2025] [Indexed: 02/27/2025] Open
Abstract
Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic gammaherpesvirus and the etiological agent of several diseases. These include the malignancies Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD), as well as the inflammatory disorder KSHV inflammatory cytokine syndrome (KICS). The KSHV lifecycle is characterized by two phases: a default latent phase and a lytic replication cycle. During latency, the virus persists as an episome within host cells, expressing a limited subset of viral genes to evade immune surveillance while promoting cellular transformation. The lytic phase, triggered by various stimuli, results in the expression of the full viral genome, production of infectious virions, and modulation of the tumor microenvironment. Both phases of the KSHV lifecycle play crucial roles in driving viral pathogenesis, influencing oncogenesis and immune evasion. This review dives into the intricate world of the KSHV lifecycle, focusing on the molecular mechanisms that drive its latent and lytic phases, their roles in disease progression, and current therapeutic strategies.
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Affiliation(s)
- Victor A. Losay
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA;
- Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Blossom Damania
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA;
- Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA
- Department of Microbiology & Immunology, University of North Carolina, Chapel Hill, NC 27599, USA
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Banerjee A, Dass D, Mukherjee S, Kaul M, Harshithkumar R, Bagchi P, Mukherjee A. The 'Oma's of the Gammas-Cancerogenesis by γ-Herpesviruses. Viruses 2024; 16:1928. [PMID: 39772235 PMCID: PMC11680331 DOI: 10.3390/v16121928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 12/10/2024] [Accepted: 12/11/2024] [Indexed: 01/03/2025] Open
Abstract
Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), which are the only members of the gamma(γ) herpesviruses, are oncogenic viruses that significantly contribute to the development of various human cancers, such as Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's lymphoma, Kaposi's sarcoma, and primary effusion lymphoma. Oncogenesis triggered by γ-herpesviruses involves complex interactions between viral genetics, host cellular mechanisms, and immune evasion strategies. At the genetic level, crucial viral oncogenes participate in the disruption of cell signaling, leading to uncontrolled proliferation and inhibition of apoptosis. These viral proteins can modulate several cellular pathways, including the NF-κB and JAK/STAT pathways, which play essential roles in cell survival and inflammation. Epigenetic modifications further contribute to EBV- and KSHV-mediated cancerogenesis. Both EBV and KSHV manipulate host cell DNA methylation, histone modification, and chromatin remodeling, the interplay of which contribute to the elevation of oncogene expression and the silencing of the tumor suppressor genes. Immune factors also play a pivotal role in the development of cancer. The γ-herpesviruses have evolved intricate immune evasion strategies, including the manipulation of the major histocompatibility complex (MHC) and the release of cytokines, allowing infected cells to evade immune detection and destruction. In addition, a compromised immune system, such as in HIV/AIDS patients, significantly increases the risk of cancers associated with EBV and KSHV. This review aims to provide a comprehensive overview of the genetic, epigenetic, and immune mechanisms by which γ-herpesviruses drive cancerogenesis, highlighting key molecular pathways and potential therapeutic targets.
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Affiliation(s)
- Anwesha Banerjee
- Division of Virology, ICMR-National Institute of Translational Virology and AIDS Research, Pune 411026, MH, India; (A.B.); (D.D.); (S.M.); (M.K.); (R.H.)
| | - Debashree Dass
- Division of Virology, ICMR-National Institute of Translational Virology and AIDS Research, Pune 411026, MH, India; (A.B.); (D.D.); (S.M.); (M.K.); (R.H.)
| | - Soumik Mukherjee
- Division of Virology, ICMR-National Institute of Translational Virology and AIDS Research, Pune 411026, MH, India; (A.B.); (D.D.); (S.M.); (M.K.); (R.H.)
| | - Mollina Kaul
- Division of Virology, ICMR-National Institute of Translational Virology and AIDS Research, Pune 411026, MH, India; (A.B.); (D.D.); (S.M.); (M.K.); (R.H.)
| | - R. Harshithkumar
- Division of Virology, ICMR-National Institute of Translational Virology and AIDS Research, Pune 411026, MH, India; (A.B.); (D.D.); (S.M.); (M.K.); (R.H.)
| | - Parikshit Bagchi
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Anupam Mukherjee
- Division of Virology, ICMR-National Institute of Translational Virology and AIDS Research, Pune 411026, MH, India; (A.B.); (D.D.); (S.M.); (M.K.); (R.H.)
- AcSIR—Academy of Scientific & Innovative Research, Ghaziabad 201002, UP, India
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Denaro N, Indini A, Brambilla L, Marzano AV, Garrone O, Tourlaki A. Management and Future Therapeutic Perspectives of Classic Kaposi's Sarcoma: An Evidence-Based Review. Onco Targets Ther 2024; 17:961-976. [PMID: 39530040 PMCID: PMC11552409 DOI: 10.2147/ott.s468787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 08/31/2024] [Indexed: 11/16/2024] Open
Abstract
Background Kaposi sarcoma (KS) is a cutaneous neoplasm of endothelial origin. The causative agent is the human herpes virus-8 (HHV-8) which, combined with an immune system impairment, causes cell proliferation. To date, high-quality evidence and treatment recommendations for the management of KS are confined to the acquired immune deficiency syndrome (AIDS)-related KS, while the clinical approach to the treatment of classic KS (CKS) is based on small retrospective case series and the experience of clinicians in selected referral centers. Materials and Methods A search of the English literature was conducted through PubMed/MEDLINE databases for studies regarding CKS diagnosis, staging, and treatment, published between January 1990 and September 2023. Results Overall, 122 out of 565 articles were selected. Based on the results of this literature review, we proposed indications regarding the recommended flow chart for diagnosis, staging, and follow-up of patients with CKS. We assess available evidences regarding topic, locoregional, and systemic treatments of CKS. We also provide a focus on novel treatment strategies and therapeutic approaches currently under evaluation in clinical trials. Conclusion CKS is a rare disease and its management requires a multidisciplinary assessment. Treatment in referral centers and enrolment in clinical trials might impact on outcomes.
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Affiliation(s)
- Nerina Denaro
- Medical Oncology Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Alice Indini
- Melanoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Lucia Brambilla
- Dermatology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Angelo Valerio Marzano
- Dermatology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Ornella Garrone
- Medical Oncology Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Athanasia Tourlaki
- Dermatology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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Batash R, Crimí A, Kassem R, Asali M, Ostfeld I, Biz C, Ruggieri P, Schaffer M. Classic Kaposi sarcoma: Diagnostics, treatment modalities, and genetic implications - A review of the literature. Acta Oncol 2024; 63:783-790. [PMID: 39415564 PMCID: PMC11495121 DOI: 10.2340/1651-226x.2024.40537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 09/28/2024] [Indexed: 10/18/2024]
Abstract
BACKGROUND AND PURPOSE Classic Kaposi sarcoma (CKS) is a rare vascular disease mainly found in populations of Mediterranean origin. The pathogenesis involves Human Herpes Virus 8 (HHV8) and genetic mutations such as SNP309 in the MDM2 gene. The recently discovered BPTF mutation in cells of CKS patients demonstrated higher latency-associated nuclear antigen (LANA) staining and altered vital transcriptomics, implicating a potential role in tumorigenesis. This review explores the genetic underpinnings and treatments for CKS. MATERIAL AND METHODS A comprehensive literature search was conducted from 2004 to 2024, yielding 70 relevant papers. Ongoing clinical trials investigating novel treatments such as talimogene and abemaciclib were included in the search and presented in the results. RESULTS Clinical diagnosis and treatment can be challenging as the number of studies on CKS and treatment modalities is limited. Treatment strategies vary by disease stage, with local therapies like surgical intervention and radiation therapy recommended for early stages, while systemic therapies are considered in cases of systemic disease. INTERPRETATION While advancements in CKS treatment offer hope, further studies on immunotherapy are warranted to broaden the therapeutic options, such as anti-bromodomain or BPTF-targeted therapy.
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Affiliation(s)
- Ron Batash
- Orthopedics and Orthopedic Oncology, Department of Surgery, Oncology and Gastroenterology DiSCOG, University of Padova, Padova, Italy
| | - Alberto Crimí
- Orthopedics and Orthopedic Oncology, Department of Surgery, Oncology and Gastroenterology DiSCOG, University of Padova, Padova, Italy.
| | - Riad Kassem
- Dermatology Unit, Sheba Medical Center, Ramat-gan, Israel; Tel Aviv University, Faculty of Medicine, Tel Aviv, Israel
| | - Murad Asali
- Urology department, Barziali Medical Center, Ashkelon, Israel
| | - Ishay Ostfeld
- Department of Thoracic surgeon, Baruch Padeh Medical Center, Poriya, Israel
| | - Carlo Biz
- Orthopedics and Orthopedic Oncology, Department of Surgery, Oncology and Gastroenterology DiSCOG, University of Padova, Padova, Italy
| | - Pietro Ruggieri
- Orthopedics and Orthopedic Oncology, Department of Surgery, Oncology and Gastroenterology DiSCOG, University of Padova, Padova, Italy
| | - Moshe Schaffer
- Oncology department, Barzilai Medical Center, Ashkelon, Israel; Faculty of Health Sciences, Ben Gurion University of the Negev, Israel
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Li X, Ohler ZW, Day A, Bassel L, Grosskopf A, Afsari B, Tagawa T, Custer W, Mangusan R, Lurain K, Yarchoan R, Ziegelbauer J, Ramaswami R, Krug LT. Mapping herpesvirus-driven impacts on the cellular milieu and transcriptional profile of Kaposi sarcoma in patient-derived mouse models. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.27.615429. [PMID: 39386738 PMCID: PMC11463583 DOI: 10.1101/2024.09.27.615429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Abstract
Kaposi sarcoma (KS) is defined by aberrant angiogenesis driven by Kaposi sarcoma herpesvirus (KSHV)-infected spindle cells with endothelial characteristics. KS research is hindered by rapid loss of KSHV infection upon explant culture of tumor cells. Here, we establish patient-derived KS xenografts (PDXs) upon orthotopic implantation of cutaneous KS biopsies in immunodeficient mice. KS tumors were maintained in 27/28 PDX until experimental endpoint, up to 272 days in the first passage of recipient mice. KSHV latency associated nuclear antigen (LANA)+ endothelial cell density increased by a mean 4.3-fold in 14/15 PDX analyzed by IHC at passage 1 compared to respective input biopsies, regardless of implantation variables and clinical features of patients. The Ki-67 proliferation marker colocalized with LANA more frequently in PDXs. Spatial transcriptome analysis revealed increased expression of viral transcripts from latent and lytic gene classes in the PDX. The expanded KSHV+ regions of the PDX maintained signature gene expression of KS tumors, with enrichment in pathways associated with angiogenesis and endothelium development. Cells with characteristics of tumor-associated fibroblasts derived from PDX were propagated for 15 passages. These fibroblast-like cells were permissive for de novo KSHV infection, and one lineage produced CXCL12, a cancer-promoting chemokine. Spatial analysis revealed that fibroblasts are a likely source of CXCL12 signaling to CXCR4 that was upregulated in KS regions. The reproducible expansion of KSHV-infected endothelial cells in PDX from multiple donors and recapitulation of a KS tumor gene signature supports the application of patient-derived KS mouse models for studies of pathogenesis and novel therapies.
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Affiliation(s)
- Xiaofan Li
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute; Bethesda, MD
| | - Zoë Weaver Ohler
- Center for Advanced Preclinical Research, Center for Cancer Research, National Cancer Institute; Frederick, MD
| | - Amanda Day
- Center for Advanced Preclinical Research, Center for Cancer Research, National Cancer Institute; Frederick, MD
| | - Laura Bassel
- Center for Advanced Preclinical Research, Center for Cancer Research, National Cancer Institute; Frederick, MD
| | - Anna Grosskopf
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute; Bethesda, MD
| | - Bahman Afsari
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute; Bethesda, MD
| | - Takanobu Tagawa
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute; Bethesda, MD
| | - Wendi Custer
- Center for Advanced Preclinical Research, Center for Cancer Research, National Cancer Institute; Frederick, MD
| | - Ralph Mangusan
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute; Bethesda, MD
| | - Kathryn Lurain
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute; Bethesda, MD
| | - Robert Yarchoan
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute; Bethesda, MD
| | - Joseph Ziegelbauer
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute; Bethesda, MD
| | - Ramya Ramaswami
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute; Bethesda, MD
| | - Laurie T. Krug
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute; Bethesda, MD
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Abdeljaleel F, Azar J, Ayasa LA, Rabaia D. Kaposi sarcoma-induced immune reconstitution syndrome: a case report. Ann Med Surg (Lond) 2024; 86:2242-2247. [PMID: 38576974 PMCID: PMC10990315 DOI: 10.1097/ms9.0000000000001842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 02/08/2024] [Indexed: 04/06/2024] Open
Abstract
Introduction and importance Kaposi sarcoma (KS) is an angioproliferative disease, that mostly affects HIV-infected patients with a high viral load and a low CD4 count. In rare cases, the paradoxical worsening of a pre-existing or previously unrecognized opportunistic infection occurs in a phenomenon known as immune reconstitution inflammatory response (IRIS). Case presentation The authors presented a male patient in his 30s with HIV, who developed a series of complications caused by KS following the initiation of antiretroviral therapy. Despite ongoing antiretroviral therapy (ART), chemotherapy, and supportive measures, the patient developed KS-related IRIS, characterized by rapid clinical deterioration, multiorgan failure, and ultimately succumbed to the disease. Clinical discussion To the best of our knowledge, very rare cases have been reported with KS-IRIS after the initiation of ART. Many predictors of KS-IRIS development have been identified. Patients must meet the known diagnostic criteria to be diagnosed with IRIS. The treatment of KS-IRIS depends on the stage of KS. ART alone is usually adequate in mild cutaneous KS. Chemotherapy and ART are recommended for patients with severe cutaneous and visceral KS. Conclusion HIV patients with KS undergoing ART initiation or modification should be closely monitored, particularly during the early stages and in those with extensive disease. Treating opportunistic infections before ART initiation may reduce the risk of KS-IRIS. The increasing prevalence of KS in ART-treated patients with HIV warrants further attention and highlights the need for better management strategies in this population.
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Affiliation(s)
| | - Jehad Azar
- Mayo Clinic Health System, Cleveland, Ohio
| | | | - Dima Rabaia
- Faculty of Medicine and Health Science, An-Najah National University, Nablus, Palestine
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Sato Y, Deguchi S, Norose T, Oishi T, Mitsuya K, Sugino T, Akiyama Y, Nagashima T, Urakami K, Shimoda Y, Ohshima K, Hayashi N, Yamaguchi K. An autopsy case of primary gliosarcoma with multiple extracranial metastases: pathology after administration of bevacizumab and genetic profile. NAGOYA JOURNAL OF MEDICAL SCIENCE 2023; 85:828-835. [PMID: 38155632 PMCID: PMC10751501 DOI: 10.18999/nagjms.85.4.828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 12/12/2022] [Indexed: 12/30/2023]
Abstract
Gliosarcoma (GS), a morphological variant of glioblastoma, pathologically shows a biphasic pattern with gliomatous and sarcomatous components. It has been reported that GS has much higher metastatic capacity than glioblastoma. A few reports on the pathology of the extracranial metastasis of GS have shown that metastatic lesions had a sarcomatous component alone or a mixture of gliomatous and sarcomatous ones. Therefore, it is considered that GS tends to disseminate hematogenously due to its mesenchymal sarcomatous component. Herein, we report an autopsy case of GS with multiple extracranial metastases treated by craniotomy, radiotherapy, and bevacizumab. In this case, metastatic lesions at autopsy contained a gliomatous component alone, but no sarcomatous component. In addition, the sarcomatous component disappeared from the intracranial lesion at autopsy after the administration of bevacizumab. In this report, we discuss the clinical course and pathological findings at the initial state, recurrence, and autopsy, including the results of whole-genome analysis.
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Affiliation(s)
- Yoshiki Sato
- Division of Neurosurgery, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Shoichi Deguchi
- Division of Neurosurgery, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Tomoko Norose
- Division of Diagnostic Pathology, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Takuma Oishi
- Division of Diagnostic Pathology, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Koichi Mitsuya
- Division of Neurosurgery, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Takashi Sugino
- Division of Diagnostic Pathology, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Yasuto Akiyama
- Division of Immunotherapy, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Takeshi Nagashima
- Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Nagaizumi, Japan
- SRL, Tokyo, Japan
| | - Kenichi Urakami
- Medical Genetics Division, Shizuoka Cancer Center Research Institute, Nagaizumi, Japan
| | - Yuji Shimoda
- Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Nagaizumi, Japan
- SRL, Tokyo, Japan
| | - Keiichi Ohshima
- Medical Genetics Division, Shizuoka Cancer Center Research Institute, Nagaizumi, Japan
| | - Nakamasa Hayashi
- Division of Neurosurgery, Shizuoka Cancer Center, Nagaizumi, Japan
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10
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Epeldegui M, Chang D, Lee J, Magpantay LI, Borok M, Bukuru A, Busakhala N, Godfrey C, Hosseinipour MC, Kang M, Kanyama C, Langat D, Mngqibisa R, Mwelase N, Nyirenda M, Samaneka W, Hoagland B, Campbell TB, Martínez-Maza O, Krown SE. Predictive Value of Serum Biomarkers for Response of Limited-Stage AIDS-Associated Kaposi Sarcoma to Antiretroviral Therapy With or Without Concomitant Chemotherapy in Resource-Limited Settings. J Acquir Immune Defic Syndr 2023; 94:165-173. [PMID: 37368929 PMCID: PMC10527582 DOI: 10.1097/qai.0000000000003236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 06/01/2023] [Indexed: 06/29/2023]
Abstract
BACKGROUND Guidelines for limited-stage human immunodeficiency virus-associated Kaposi sarcoma (AIDS/KS) recommend antiretroviral therapy (ART) as initial treatment. However, many such individuals show worsening KS and require additional chemotherapy. Methods to identify such patients are lacking. SETTING We studied whether serum levels of biomarkers associated with angiogenesis, systemic inflammation, and immune activation, which are elevated in HIV-infected individuals and implicated in the development of KS, could prospectively identify individuals with limited-stage AIDS-KS who would benefit from chemotherapy administered with ART. METHODS Serum specimens were obtained from participants in a randomized trial evaluating the value of adding oral etoposide chemotherapy to ART in treatment-naïve people with limited-stage AIDS-KS in resource-limited settings. Serum biomarkers of inflammation (C-reactive protein [CRP], interleukin [IL]-6, IL-8, IL-10, granulocyte colony stimulating factor, soluble tumor necrosis factor receptor-2), immune system activation (soluble IL-2 receptor alfa, C-X-C motif chemokine ligand 10/interferon gamma-induced protein 10, C-C motif ligand 2/monocyte chemoattractant protein 1), and angiogenesis (vascular endothelial growth factor, matrix metalloproteinase-2, -9, endoglin, hepatocyte growth factor) were measured at entry to determine whether baseline levels are associated with KS response. On-treatment changes in biomarker levels were determined to assess how etoposide modifies the effects of ART. RESULTS Pretreatment CRP and IL-10 were higher in those whose KS progressed, and lowest in those who had good clinical responses. Pretreatment CRP, IL-6, and soluble tumor necrosis factor receptor-2 showed significant associations with KS progression at the week-48 primary endpoint. Immediate etoposide led to lower inflammation biomarker levels compared with ART alone. Early KS progression was associated with elevated pretreatment levels of inflammation-associated biomarkers and increasing levels post-treatment. CONCLUSIONS Quantifying serum biomarkers, especially CRP, may help identify persons with AIDS-KS who would benefit from early introduction of chemotherapy in addition to ART.
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Affiliation(s)
- Marta Epeldegui
- Department of Obstetrics and Gynecology, University of California, Los Angeles, CA
| | - Di Chang
- Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Jeannette Lee
- Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Larry I Magpantay
- Department of Obstetrics and Gynecology, University of California, Los Angeles, CA
| | - Margaret Borok
- Unit of Internal Medicine, University of Zimbabwe Faculty of Medicine and Health Sciences, Harare, Zimbabwe
| | | | - Naftali Busakhala
- Department of Pharmacology, Moi University School of Medicine, Eldoret, Kenya
| | - Catherine Godfrey
- Office of the Global AIDS Coordinator, Department of State, Washington, DC
| | - Mina C Hosseinipour
- Department of Medicine, Division of Infectious Diseases, University of North Carolina Project, Lilongwe, Malawi
| | - Minhee Kang
- Center for Biostatistics in AIDS Research in the Department of Biostatistics, Harvard School of Public Health, Boston, MA
| | - Cecilia Kanyama
- Department of Medicine, Division of Infectious Diseases, University of North Carolina Project, Lilongwe, Malawi
| | - Deborah Langat
- Department of Research, KEMRI Walter Reed Project, Kericho, Kenya
| | - Rosie Mngqibisa
- Research Unit, Enhancing Care Foundation, Durban International Clinical Research Site, King Edward Hospital, Enhancing Care Foundation, Durban, South Africa
| | - Noluthando Mwelase
- Department of Internal Medicine, University of Witwatersrand, Johannesburg, South Africa
| | - Mulinda Nyirenda
- College of Medicine-Johns Hopkins Research Project, Blantyre, Malawi
| | - Wadzanai Samaneka
- Unit of Internal Medicine, University of Zimbabwe Faculty of Medicine and Health Sciences, Harare, Zimbabwe
| | - Brenda Hoagland
- Department of Infectious Diseases, National Institute of Infectious Diseases Evandro Chagas/Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Thomas B Campbell
- Department of Medicine, University of Colorado School of Medicine Aurora, CO; and
| | | | - Susan E Krown
- Department of Medicine, Memorial Sloan-Kettering Cancer Center (Emerita), New York, NY
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11
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Ramaswami R, Tagawa T, Mahesh G, Serquina A, Koparde V, Lurain K, Dremel S, Li X, Mungale A, Beran A, Ohler ZW, Bassel L, Warner A, Mangusan R, Widell A, Ekwede I, Krug LT, Uldrick TS, Yarchoan R, Ziegelbauer JM. Transcriptional landscape of Kaposi sarcoma tumors identifies unique immunologic signatures and key determinants of angiogenesis. J Transl Med 2023; 21:653. [PMID: 37740179 PMCID: PMC10517594 DOI: 10.1186/s12967-023-04517-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 09/09/2023] [Indexed: 09/24/2023] Open
Abstract
BACKGROUND Kaposi sarcoma (KS) is a multicentric tumor caused by Kaposi sarcoma herpesvirus (KSHV) that leads to morbidity and mortality among people with HIV worldwide. KS commonly involves the skin but can occur in the gastrointestinal tract (GI) in severe cases. METHODS RNA sequencing was used to compare the cellular and KSHV gene expression signatures of skin and GI KS lesions in 44 paired samples from 19 participants with KS alone or with concurrent KSHV-associated diseases. Analyses of KSHV expression from KS lesions identified transcriptionally active areas of the viral genome. RESULTS The transcript of an essential viral lytic gene, ORF75, was detected in 91% of KS lesions. Analyses of host genes identified 370 differentially expressed genes (DEGs) unique to skin KS and 58 DEGs unique to GI KS lesions as compared to normal tissue. Interleukin (IL)-6 and IL-10 gene expression were higher in skin lesions as compared to normal skin but not in GI KS lesions. Twenty-six cellular genes were differentially expressed in both skin and GI KS tissues: these included Fms-related tyrosine kinase 4 (FLT4), encoding an angiogenic receptor, and Stanniocalcin 1 (STC1), a secreted glycoprotein. FLT4 and STC1 were further investigated in functional studies using primary lymphatic endothelial cells (LECs). In these models, KSHV infection of LECs led to increased tubule formation that was impaired upon knock-down of STC1 or FLT4. CONCLUSIONS This study of transcriptional profiling of KS tissue provides novel insights into the characteristics and pathogenesis of this unique virus-driven neoplasm.
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Affiliation(s)
- Ramya Ramaswami
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Takanobu Tagawa
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Guruswamy Mahesh
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Anna Serquina
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Vishal Koparde
- Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Kathryn Lurain
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Sarah Dremel
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Xiaofan Li
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Ameera Mungale
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Alex Beran
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Zoe Weaver Ohler
- Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Laura Bassel
- Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Andrew Warner
- Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Ralph Mangusan
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Anaida Widell
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Irene Ekwede
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Laurie T Krug
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Thomas S Uldrick
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Robert Yarchoan
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Joseph M Ziegelbauer
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, 20892, USA.
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12
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Ahmed K, Jha S. Oncoviruses: How do they hijack their host and current treatment regimes. Biochim Biophys Acta Rev Cancer 2023; 1878:188960. [PMID: 37507056 DOI: 10.1016/j.bbcan.2023.188960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 07/05/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023]
Abstract
Viruses have the ability to modulate the cellular machinery of their host to ensure their survival. While humans encounter numerous viruses daily, only a select few can lead to disease progression. Some of these viruses can amplify cancer-related traits, particularly when coupled with factors like immunosuppression and co-carcinogens. The global burden of cancer development resulting from viral infections is approximately 12%, and it arises as an unfortunate consequence of persistent infections that cause chronic inflammation, genomic instability from viral genome integration, and dysregulation of tumor suppressor genes and host oncogenes involved in normal cell growth. This review provides an in-depth discussion of oncoviruses and their strategies for hijacking the host's cellular machinery to induce cancer. It delves into how viral oncogenes drive tumorigenesis by targeting key cell signaling pathways. Additionally, the review discusses current therapeutic approaches that have been approved or are undergoing clinical trials to combat malignancies induced by oncoviruses. Understanding the intricate interactions between viruses and host cells can lead to the development of more effective treatments for virus-induced cancers.
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Affiliation(s)
- Kainat Ahmed
- Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA
| | - Sudhakar Jha
- Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA.
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13
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Goff CB, Dasanu CA. Changing therapeutic landscape in advanced Kaposi sarcoma: Current state and future directions. J Oncol Pharm Pract 2023:10781552221148417. [PMID: 36718515 DOI: 10.1177/10781552221148417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Kaposi sarcoma is a malignant neoplasm arising from the endothelial cell lining of blood and lymphatic vessels. Herein, we discuss etiopathogenesis, clinical presentation, diagnostic criteria, updated guideline-based approach to its management and newer experimental approaches. Given its efficacy and side effect profile, pegylated doxorubicin is the currently preferred first-line therapy in advanced disease. Paclitaxel remains an alternative first-line option. At the time of relapse, patients can be retreated with the same agents as they often maintain their clinical efficacy. New therapeutic options are on the rise, with pomalidomide being approved in 2020 as a second-line therapy. Optimal control of retroviral infection in human immunodeficiency virus (HIV) positive is instrumental in preventing disease occurrence in most patients. Suppressing human herpes virus type 8 (HHV-8) infection might also play a role in controlling Kaposi sarcoma growth, yet clinical trials are lacking. Unraveling the molecular and genetic intricacies of Kaposi sarcoma's pathogenesis might allow for the emergence of novel and effective therapeutic strategies. Clinical trials are currently underway to establish potential roles for various targeted agents, immune checkpoint inhibitors (ICIs) and experimental agents in the treatment of advanced Kaposi sarcoma.
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Affiliation(s)
- Catherine B Goff
- Department of Internal Medicine, 541618Eisenhower Health, Rancho Mirage, CA, USA
| | - Constantin A Dasanu
- Lucy Curci Cancer Center, 541618Eisenhower Health, Rancho Mirage, CA, USA.,Department of Medical Oncology and Hematology, University of California in San Diego Health System, San Diego, CA, USA
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14
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Bose S, Lee T, Choi S, Fazlollahi L, Rasiej MJ, Schwartz GK, Ingham M. CDK4/6 Inhibition With Anti-PD-1 Checkpoint Blockade Induces Major Response in Aggressive Classic Kaposi Sarcoma After Previous Progression on Anti-PD-1 Alone. JCO Precis Oncol 2022; 6:e2100550. [PMID: 35820086 DOI: 10.1200/po.21.00550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Sminu Bose
- Division of Hematology and Medical Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY
| | - Tristan Lee
- Department of Medicine, Columbia University Irving Medical Center, New York, NY
| | - Shaelyn Choi
- Division of Hematology and Medical Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY
| | - Ladan Fazlollahi
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY
| | - Michael J Rasiej
- Department of Radiology, Columbia University Irving Medical Center, New York, NY
| | - Gary K Schwartz
- Division of Hematology and Medical Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY
| | - Matthew Ingham
- Division of Hematology and Medical Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY
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15
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Subramaniam A, Giani C, Napolitano A, Ravi V, Frezza AM, Jones RL. Management of Vascular Sarcoma. Surg Oncol Clin N Am 2022; 31:485-510. [PMID: 35715146 DOI: 10.1016/j.soc.2022.03.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Vascular sarcomas encompass 3 well-defined sarcoma types: hemangioendothelioma, Kaposi sarcoma, and angiosarcoma. These distinct types are exceedingly rare and very different in terms of clinical behavior, biological features, and treatment approach. Because of this rarity and heterogeneity, it is crucial that vascular sarcomas are treated in sarcoma reference centers or networks, in order to ensure optimal management. The diversity of vascular sarcomas also needs to be taken into account in the design of clinical trials, in order to produce meaningful results that can be consistently translated into everyday clinical practice.
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Affiliation(s)
- Aparna Subramaniam
- Department of Sarcoma Medical Oncology, University of Texas MD Anderson Cancer Center, 1400 Holcombe Blvd, Unit 0450, FC12.3044, Houston, TX 77030, USA
| | - Claudia Giani
- Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Via Giacomo Venezian 1, Milan 20133, Italy
| | - Andrea Napolitano
- Sarcoma Unit, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, UK
| | - Vinod Ravi
- Department of Sarcoma Medical Oncology, University of Texas MD Anderson Cancer Center, 1400 Holcombe Blvd, Unit 0450, FC12.3044, Houston, TX 77030, USA.
| | - Anna Maria Frezza
- Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Via Giacomo Venezian 1, Milan 20133, Italy
| | - Robin L Jones
- Sarcoma Unit, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, UK
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16
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Molecular Mechanisms of Kaposi Sarcoma Development. Cancers (Basel) 2022; 14:cancers14081869. [PMID: 35454776 PMCID: PMC9030761 DOI: 10.3390/cancers14081869] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/03/2022] [Accepted: 04/05/2022] [Indexed: 01/08/2023] Open
Abstract
Simple Summary There are at least four forms of Kaposi’s sarcoma (KS) with the ‘HIV’-related form being the most aggressive and can involve mucosae or visceral organs. Kaposi’s sarcoma-associated herpes virus (KSHV) is the underlying cause of this disease. It can infect endothelial and/or mesenchymal cells and establish a latent phase in host cells in which latency proteins and various non-coding RNAs (ncRNAs) play a complex role in proliferation and angiogenesis. It also undergoes periods of sporadic lytic reactivation that are key for KS progression. Complex interactions with the microenvironment with production of inflammatory cytokines and paracrine signaling is a standout feature of KS development and maintenance. KSHV impairs the immune response by various mechanisms such as the degradation of a variety of proteins involved in immune response or binding to cellular chemokines. Treatment options include classical chemotherapy, but other novel therapies are being investigated. Abstract Kaposi’s sarcoma (KS) is a heterogeneous angioproliferative tumor that generally arises in the skin. At least four forms of this disease have been described, with the ‘HIV’-related form being the most aggressive and can involve mucosae or visceral organs. Three quarters of KS cases occur in sub-Saharan Africa (SSA) as geographic variation is explained by the disparate prevalence of KS-associated herpes virus (KSHV), which is the underlying cause of this disease. It can infect endothelial and/or mesenchymal cells that consequently transdifferentiate to an intermediate state. KSHV establishes a latent phase in host cells in which latency proteins and various non-coding RNAs (ncRNAs) play a complex role in proliferation and angiogenesis. It also undergoes periods of sporadic lytic reactivation triggered by various biological signals in which lytic stage proteins modulate host cell signaling pathways and are key in KS progression. Complex interactions with the microenvironment with production of inflammatory cytokines with paracrine signaling is a standout feature of KS development and maintenance. KSHV impairs the immune response by various mechanisms such as the degradation of a variety of proteins involved in immune response or binding to cellular chemokines. Treatment options include classical chemotherapy, but other novel therapies are being investigated.
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17
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Henry DH, Maki RG. Lenalidomide and the expanding toolkit to manage Kaposi sarcoma. Clin Cancer Res 2022; 28:2485-2487. [DOI: 10.1158/1078-0432.ccr-22-0884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 03/28/2022] [Accepted: 04/04/2022] [Indexed: 11/16/2022]
Abstract
Abstract
Lenalidomide recently was shown to have clinical activity in patients with human immunodeficiency virus-associated Kaposi sarcoma. Immunomodulatory imine drugs thus provide another tool in the treatment of this challenging neoplasm.
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Affiliation(s)
- David H. Henry
- University of Pennsylvania Health System, Philadelphia, PA, United States
| | - Robert G. Maki
- University of Pennsylvania Health System, Philadelphia, PA, United States
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18
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Badalamenti G, Incorvaia L, Algeri L, Bonasera A, Dimino A, Scalia R, Cucinella A, Madonia G, Pomi FL, Galvano A, Gristina V, Toia F, Cordova A, Bazan V, Russo A. Safety and effectiveness of gemcitabine for the treatment of classic Kaposi’s sarcoma without visceral involvement. Ther Adv Med Oncol 2022; 14:17588359221086829. [PMID: 35356263 PMCID: PMC8958699 DOI: 10.1177/17588359221086829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 02/23/2022] [Indexed: 11/15/2022] Open
Abstract
Background: Classic Kaposi’s sarcoma (CKS) is a rare, multifocal, endothelial cell neoplasm that typically occurs in elderly people with previous infection by human herpes virus-8. Prospective trials are rare, and the choice of drugs relies on prospective trials performed on HIV-associated Kaposi’s sarcoma (KS). Pegylated liposomal anthracyclines and taxanes are considered the standard first- and second-line chemotherapy, respectively. Despite the indolent biologic behavior, the natural history is characterized by recurrent disease. This condition of chronic administration of cytotoxic drugs is often associated with immediate/long-term adverse events. Methods: This was an observational, retrospective study to evaluate the effectiveness and safety of gemcitabine in patients with CKS. From January 2016 to September 2021, the patients were treated with gemcitabine 1000 mg/m2 on days 1 and 8, with cycles repeated every 21 days. The treatment was administered as first or second line. Results: Twenty-seven (27) patients were included in the study. Twenty-one (21) out 27 patients (77.8%) achieved a partial response (PR), including 8 patients with major response (MR) (29.6%) and 13 patients with minor response (mR) (48.2%); 2 (7.4%) showed a complete response (CR), 3 (11.1%) a stable disease (SD), and 1 (3.7%) a progressive disease (PD). Tumor responses were generally rapid, with a median time to first response of 4 weeks (range, 3–12 weeks). Patients who responded had disease improvement with flattening of the skin lesions, decrease in the number of lesions, and substantial reduction in tumor-associated complications. Median duration of response was 19.2 months. Common adverse events were grades 1/2 thrombocytopenia, and grade 1 noninfectious fever. No patient discontinued treatment as a result of adverse events. Conclusion: Our study showed that gemcitabine is effective and well tolerated, acts rapidly on cutaneous lesions, and allows substantial symptom palliation, without dose-limiting toxicity. Gemcitabine represents a safe and effective option for the treatment of CKS.
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Affiliation(s)
- Giuseppe Badalamenti
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Lorena Incorvaia
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Via del Vespro 127, 90127 Palermo, Italy
| | - Laura Algeri
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Annalisa Bonasera
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Alessandra Dimino
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Raimondo Scalia
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Alessandra Cucinella
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Giorgio Madonia
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Federica Li Pomi
- Section of Dermatology, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Antonio Galvano
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Valerio Gristina
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Francesca Toia
- Division of Plastic and Reconstructive Surgery, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Adriana Cordova
- Division of Plastic and Reconstructive Surgery, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Viviana Bazan
- Section of Medical Oncology, Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bind.), University of Palermo, Palermo, Italy
| | - Antonio Russo
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
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19
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Poizot-Martin I, Brégigeon S, Palich R, Marcelin AG, Valantin MA, Solas C, Veyri M, Spano JP, Makinson A. Immune Reconstitution Inflammatory Syndrome Associated Kaposi Sarcoma. Cancers (Basel) 2022; 14:986. [PMID: 35205734 PMCID: PMC8869819 DOI: 10.3390/cancers14040986] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/28/2022] [Accepted: 02/09/2022] [Indexed: 02/01/2023] Open
Abstract
People living with HIV (PLWH) with advanced immunosuppression who initiate antiretroviral therapy (ART) are susceptible to the occurrence of an immune reconstitution inflammatory syndrome (IRIS). Although ART is responsible for AIDS- associated Kaposi sarcoma (KS) improvement and resolution, new onset (unmasking KS-IRIS) or sudden progression of preexisting KS (paradoxical KS-IRIS) can occur after a time delay of between a few days and 6 months after the initiation or resumption of ART, even in patients with a low degree of immunocompromise. KS-IRIS incidence varies from 2.4% to 39%, depending on study design, populations, and geographic regions. Risk factors for developing KS-IRIS include advanced KS tumor stage (T1), pre-treatment HIV viral load >5 log10 copies/mL, detectable pre-treatment plasma-KSHV, and initiation of ART alone without concurrent chemotherapy. Both paradoxical and unmasking KS-IRIS have been associated with significant morbidity and mortality, and thrombocytopenia (<100,000 platelets/mm3 at 12 weeks) has been associated with death. KS-IRIS is not to be considered as ART failure, and an ART regimen must be pursued. Systemic chemotherapy for KS in conjunction with ART is recommended and, in contrast with management of IRIS for other opportunistic infections, glucocorticoids are contra-indicated. Despite our preliminary results, the place of targeted therapies in the prevention or treatment of KS-IRIS needs further assessment.
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Affiliation(s)
- Isabelle Poizot-Martin
- Assistance Publique-Hôpitaux de Marseille (APHM), Inserm, Institut de Recherche pour le Développement (IRD), SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l’Information Médicale, ISSPAM, APHM Sainte-Marguerite, Service D’immuno-Hématologie Clinique, Aix-Marseille Université, 13009 Marseille, France
| | - Sylvie Brégigeon
- Assistance Publique-Hôpitaux de Marseille (APHM) Sainte-Marguerite, Service D’immuno-Hématologie Clinique, Aix-Marseille Université, 13009 Marseille, France;
| | - Romain Palich
- Department of Infectious Diseases, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Pierre Louis Epidemiology and Public Health Institute (iPLESP), INSERM U1136, Sorbonne University, 75013 Paris, France; (R.P.); (M.-A.V.)
| | - Anne-Geneviève Marcelin
- INSERM, Institut Pierre Louis d’Epidémiologie et de Santé Publique (iPLESP), AP-HP, Hôpital Pitié Salpêtrière, Service de Virologie, Sorbonne Université, 75013 Paris, France;
| | - Marc-Antoine Valantin
- Department of Infectious Diseases, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Pierre Louis Epidemiology and Public Health Institute (iPLESP), INSERM U1136, Sorbonne University, 75013 Paris, France; (R.P.); (M.-A.V.)
| | - Caroline Solas
- Assistance Publique-Hôpitaux de Marseille (APHM), Hôpital La Timone, Laboratoire de Pharmacocinétique et Toxicologie, INSERM 1207, IRD 190, Unité des Virus Emergents, Aix-Marseille Université, 13005 Marseille, France;
| | - Marianne Veyri
- Department of Medical Oncology, Pitié Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Institut Universitaire de Cancérologie (IUC), CLIP2 Galilée, Pierre Louis Epidemiology and Public Health Institute (iPLESP), INSERM U1136, Sorbonne Université, 75013 Paris, France; (M.V.); (J.-P.S.)
| | - Jean-Philippe Spano
- Department of Medical Oncology, Pitié Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Institut Universitaire de Cancérologie (IUC), CLIP2 Galilée, Pierre Louis Epidemiology and Public Health Institute (iPLESP), INSERM U1136, Sorbonne Université, 75013 Paris, France; (M.V.); (J.-P.S.)
| | - Alain Makinson
- Centre Hospitalier Universitaire de Montpellier, Département des Maladies Infectieuses et Tropicales, INSERM U1175/IRD UMI 233, 34000 Montpellier, France;
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20
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Abu Khalaf S, Dandachi D, Granwehr BP, Rodriguez-Barradas MC. Cancer immunotherapy in adult patients with HIV. J Investig Med 2022; 70:883-891. [PMID: 35086858 DOI: 10.1136/jim-2021-002205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/07/2021] [Indexed: 11/03/2022]
Abstract
The availability of antiretroviral therapy (ART) has increased the life expectancy of people with HIV (PWH) and reduced the incidence of AIDS-associated malignancies, yet PWH have a significantly increased incidence of malignancy and less favorable outcomes of cancer treatment compared with the general population.Immunotherapy has revolutionized cancer therapy, becoming the standard of care for various malignancy treatments. However, PWH are an underserved population with limited access to clinical trials and cancer treatment.This review of the available evidence on different classes of cancer immunotherapy in PWH is mostly based on case reports, case series, but few prospective studies and clinical trials due to the exclusion of PWH from most oncologic clinical trials. The results of the available evidence support the safety of immunotherapy in PWH. Immunotherapy has similar effectiveness in PWH, an acceptable toxicity profile, and has no clinically significant impact on HIV viral load and CD4-T cell count. In addition, there is no reported change in the incidence of opportunistic infections and other complications for PWH with well-controlled viremia.This review aims to briefly summarize the current state of immunotherapy in cancer, guide clinicians in the management of immunotherapy in cancer PWH, and encourage the inclusion of PWH in clinical trials of cancer immunotherapy.
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Affiliation(s)
- Suha Abu Khalaf
- Department of Medicine, Division of Infectious Diseases, University of Missouri System, Columbia, Missouri, USA
| | - Dima Dandachi
- Department of Medicine, Division of Infectious Diseases, University of Missouri System, Columbia, Missouri, USA
| | - Bruno P Granwehr
- Department of Medicine, Division of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Maria C Rodriguez-Barradas
- Infectious Diseases Section, Michael E DeBakey VAMC, Houston, Texas, USA.,Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
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21
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Valantin MA, Royston L, Hentzien M, Jary A, Makinson A, Veyri M, Ronot-Bregigeon S, Isnard S, Palich R, Routy JP. Therapeutic Perspectives in the Systemic Treatment of Kaposi's Sarcoma. Cancers (Basel) 2022; 14:484. [PMID: 35158752 PMCID: PMC8833559 DOI: 10.3390/cancers14030484] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/07/2022] [Accepted: 01/14/2022] [Indexed: 11/28/2022] Open
Abstract
In patients with Kaposi's sarcoma (KS), the therapeutic goal is to achieve a durable remission in the size and number of skin and visceral lesions. Although most patients show tumor regression in response to standard systemic chemotherapy regimens, alternative systemic treatments are needed for patients who develop refractory KS. Anti-angiogenic therapies represent attractive therapeutic targets in this context, due to the central role of angiogenesis in KS pathogenesis. Pomalidomide, which exhibits such anti-angiogenic activity through inhibition of VEGF, currently constitutes the most promising agent of this class and has been recently approved by the FDA. In addition, immune checkpoint blockade also represents an interesting alternative therapeutic approach through the restoration of immunity against HHV-8, the causative agent of KS, and improvement of tumor control. Although small series of cases treated successfully with these drugs have been reported, there is no marketing approval for anti-immune checkpoint antibodies for KS to date. In the present review, we will discuss potential therapeutic options for patients with recurrent or refractory KS, including systemic chemotherapies, immune checkpoint inhibitors, anti-herpesvirus agents, and anti-angiogenic drugs. Well-conducted clinical trials in this population are urgently needed to correctly address the efficacy of targeted agents and immunomodulators, while monitoring for adverse effects.
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Affiliation(s)
- Marc-Antoine Valantin
- Infectious Diseases Department, Pitié-Salpêtrière Hospital, AP-HP, Pierre Louis Epidemiology and Public Health Institute (iPLESP), INSERM U1136, Sorbonne University, 75013 Paris, France;
| | - Léna Royston
- Infectious Diseases and Immunity in Global Health Program & Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC H4A3J1, Canada; (S.I.); (J.-P.R.)
- Division of Infectious Diseases, Geneva University Hospitals, 1205 Geneva, Switzerland
| | - Maxime Hentzien
- Service de Médecine Interne, Maladies Infectieuses, Immunologie Clinique, CHU Robert Debré, 51090 Reims, France;
| | - Aude Jary
- Service de Virologie, Pitié-Salpêtrière Hospital, AP-HP, Pierre Louis Epidemiology and Public Health Institute (iPLESP), INSERM U1136, Sorbonne University, 75013 Paris, France;
| | - Alain Makinson
- Infectious Diseases Department, INSERM U1175, University Hospital of Montpellier, 34000 Montpellier, France;
| | - Marianne Veyri
- Service d’Oncologie Médicale, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, AP-HP, Pierre Louis Epidemiology and Public Health Institute (iPLESP), INSERM, Sorbonne University, 75013 Paris, France;
| | - Sylvie Ronot-Bregigeon
- Service d’Immuno-Hématologie Clinique, Hôpital Sainte-Marguerite, Aix Marseille Université, 13009 Marseille, France;
| | - Stéphane Isnard
- Infectious Diseases and Immunity in Global Health Program & Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC H4A3J1, Canada; (S.I.); (J.-P.R.)
| | - Romain Palich
- Infectious Diseases Department, Pitié-Salpêtrière Hospital, AP-HP, Pierre Louis Epidemiology and Public Health Institute (iPLESP), INSERM U1136, Sorbonne University, 75013 Paris, France;
| | - Jean-Pierre Routy
- Infectious Diseases and Immunity in Global Health Program & Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC H4A3J1, Canada; (S.I.); (J.-P.R.)
- Division of Hematology, McGill University Health Centre, Montréal, QC H4A3J1, Canada
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22
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Ramaswami R, Lurain K, Yarchoan R. Oncologic Treatment of HIV-Associated Kaposi Sarcoma 40 Years on. J Clin Oncol 2022; 40:294-306. [PMID: 34890242 PMCID: PMC8769148 DOI: 10.1200/jco.21.02040] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
The observation in 1981 of the emergence of Kaposi sarcoma (KS) among young men who had sex with men was one of the first harbingers of the HIV epidemic. With advances in HIV care, the incidence of HIV-associated KS (HIV+KS) has decreased over time in the United States. However, it remains a persistent malignancy among some HIV-infected populations and is one of the most common tumors in sub-Saharan Africa. Because of the relapsing and remitting nature of this cancer, patients with HIV+KS can experience significant, long-term, morbidity. Patients with severe HIV+KS may also have concurrent lymphoproliferative syndromes, malignancies, and/or infections that can contribute to mortality. Several chemotherapy agents were explored in clinical trials for HIV+KS during the early stage of the epidemic. As HIV+KS emerges with CD4 lymphopenia and immunodysregulation, T-cell-sparing options are important to consider. Here, we explore the pathogenesis of HIV+KS and the current evidence for immunotherapy and therapies that potentially target KS pathogenesis. This review provides the current landscape of therapies for HIV+KS and highlights management issues for patients with HIV and cancer.
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Affiliation(s)
- Ramya Ramaswami
- HIV and AIDS Malignancy Branch, Center for Cancer Research, NCI, Bethesda, MD,Ramya Ramaswami, MBBS, MPH, HIV and AIDS Malignancy Branch, Center for Cancer Research, 10 Center Drive, 6N106, Bethesda, MD 20892; e-mail:
| | - Kathryn Lurain
- HIV and AIDS Malignancy Branch, Center for Cancer Research, NCI, Bethesda, MD
| | - Robert Yarchoan
- HIV and AIDS Malignancy Branch, Center for Cancer Research, NCI, Bethesda, MD
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23
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Naimo E, Zischke J, Schulz TF. Recent Advances in Developing Treatments of Kaposi's Sarcoma Herpesvirus-Related Diseases. Viruses 2021; 13:1797. [PMID: 34578378 PMCID: PMC8473310 DOI: 10.3390/v13091797] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/30/2021] [Accepted: 09/01/2021] [Indexed: 12/27/2022] Open
Abstract
Kaposi-sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV-8) is the causative agent of several malignancies, including Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). Active KSHV replication has also been associated with a pathological condition called KSHV inflammatory cytokine syndrome (KICS), and KSHV may play a role in rare cases of post-transplant polyclonal lymphoproliferative disorders. Several commonly used herpesviral DNA polymerase inhibitors are active against KSHV in tissue culture. Unfortunately, they are not always efficacious against KSHV-induced diseases. To improve the outcome for the patients, new therapeutics need to be developed, including treatment strategies that target either viral proteins or cellular pathways involved in tumor growth and/or supporting the viral life cycle. In this review, we summarize the most commonly established treatments against KSHV-related diseases and review recent developments and promising new compounds that are currently under investigation or on the way to clinical use.
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Affiliation(s)
- Eleonora Naimo
- Institute of Virology, Hannover Medical School, 30625 Hannover, Germany; (E.N.); (J.Z.)
- German Centre for Infection Research, Hannover-Braunschweig Site, 38023 Braunschweig, Germany
| | - Jasmin Zischke
- Institute of Virology, Hannover Medical School, 30625 Hannover, Germany; (E.N.); (J.Z.)
- German Centre for Infection Research, Hannover-Braunschweig Site, 38023 Braunschweig, Germany
| | - Thomas F. Schulz
- Institute of Virology, Hannover Medical School, 30625 Hannover, Germany; (E.N.); (J.Z.)
- German Centre for Infection Research, Hannover-Braunschweig Site, 38023 Braunschweig, Germany
- Cluster of Excellence 2155 RESIST, Institute of Virology, Hannover Medical School, 30625 Hannover, Germany
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24
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Garcia A, Nelson K, Patel V. Emerging therapies for rare cutaneous cancers: A systematic review. Cancer Treat Rev 2021; 100:102266. [PMID: 34418780 DOI: 10.1016/j.ctrv.2021.102266] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 08/09/2021] [Accepted: 08/10/2021] [Indexed: 12/23/2022]
Abstract
BACKGROUND Rare cutaneous cancers require early management given their aggressive nature; however, few therapeutic options exist for managing these rare cancers. OBJECTIVE To identify emerging therapies for extramammary Paget's disease, Merkel cell carcinoma, sebaceous gland carcinoma, microcystic adnexal carcinoma, Kaposi sarcoma and cutaneous angiosarcoma. METHODS A systematic review was conducted using PubMed database from October 2010 to October 2020. Published clinical trials and case reports/series were included if they involved primarily a targeted agent rather than classic cytotoxic chemotherapy or photosensitizing medication. Active clinical trials were evaluated using ClinicalTrials.gov, the Japanese University Hospitals Clinical Information Network, and the ISRCTN registry. Quality of evidence for each study was rated using the Oxford Centre for Evidence-Based Medicine Level of Evidence Rating Scale. RESULTS There are several emerging therapies for rare cutaneous cancers with many clinical trials actively recruiting. PD-1 receptor inhibitors were the most investigated treatment, targeting several cancers. Merkel cell carcinoma and Kaposi sarcoma had the most clinical trials while microcystic adnexal carcinoma and sebaceous gland carcinoma had the least. The main limitation was a lack of key findings from clinical trials still in progress. CONCLUSIONS Emerging therapies exist for rare cutaneous cancers; results of ongoing studies will provide more robust evidence in the future.
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Affiliation(s)
- Andrew Garcia
- The George Washington University School of Medicine and Health Sciences, Washington, DC, United States.
| | - Kamaria Nelson
- Department of Dermatology, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
| | - Vishal Patel
- Department of Dermatology, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
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25
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Venkateswaran N, Ramos JC, Cohen AK, Alvarez OP, Cohen NK, Galor A, Karp CL. Spotlight on ocular Kaposi’s sarcoma: an update on the presentation, diagnosis, and management options. EXPERT REVIEW OF OPHTHALMOLOGY 2021; 16:477-489. [DOI: 10.1080/17469899.2021.1962294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
| | - Juan C. Ramos
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Adam K. Cohen
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Osmel P. Alvarez
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Noah K. Cohen
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Anat Galor
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Surgical Services, Miami Veterans Affairs Hospital, Miami, FL, USA
| | - Carol L. Karp
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
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26
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Martínez-Trufero J, Cruz Jurado J, Gómez-Mateo MC, Bernabeu D, Floría LJ, Lavernia J, Sebio A, García Del Muro X, Álvarez R, Correa R, Hernández-León CN, Marquina G, Hindi N, Redondo A, Martínez V, Asencio JM, Mata C, Valverde Morales CM, Martin-Broto J. Uncommon and peculiar soft tissue sarcomas: Multidisciplinary review and practical recommendations for diagnosis and treatment. Spanish group for Sarcoma research (GEIS - GROUP). Part I. Cancer Treat Rev 2021; 99:102259. [PMID: 34311246 DOI: 10.1016/j.ctrv.2021.102259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 07/03/2021] [Accepted: 07/06/2021] [Indexed: 12/22/2022]
Affiliation(s)
| | - Josefina Cruz Jurado
- Hospital Universitario Canarias, Medical Oncology Department, Santa Cruz de Tenerife, Spain
| | | | - Daniel Bernabeu
- Hospital Universitario La Paz, Radiology Department, Madrid, Spain
| | - Luis Javier Floría
- Hospital Universitario Miguel Servet, Orthopedic and Traumatology Department, Zaragoza, Spain
| | - Javier Lavernia
- Instituto Valenciano de Oncología, Medical Oncology Department, Valencia, Spain
| | - Ana Sebio
- Hospital Universitario Santa Creu i Sant Pau, Medical Oncology Department, Barcelona, Spain
| | | | - Rosa Álvarez
- Hospital Universitario Gregorio Marañón, Medical Oncology Department, Madrid, Spain
| | - Raquel Correa
- Hospital Virgen de la Victoria, Radiation Oncology Department, Malaga, Spain
| | | | - Gloria Marquina
- Hospital Universitario Clínico San Carlos, Medical Oncology Department, Madrid, Spain
| | - Nadia Hindi
- University Hospital "Fundacion Jimenez Diaz" Madrid, Medical Oncology Department, Madrid, Research Institute FJD-UAM, Madrid (Spain), TBsarc, CITIUS III, Seville, Spain
| | - Andrés Redondo
- Hospital Universitario La Paz, Medical Oncology Department, Madrid, Spain
| | - Virginia Martínez
- Hospital Universitario La Paz, Medical Oncology Department, Madrid, Spain
| | | | - Cristina Mata
- Hospital Universitario Gregorio Marañón, Pediatric and Adolescent Hemato-oncology Department, Madrid, Spain
| | | | - Javier Martin-Broto
- University Hospital "Fundacion Jimenez Diaz" Madrid, Medical Oncology Department, Madrid, Research Institute FJD-UAM, Madrid (Spain), TBsarc, CITIUS III, Seville, Spain
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27
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Clinicopathologic Correlation of Kaposi Sarcoma Involving the Ocular Adnexa: Immunophenotyping of Diagnostic and Therapeutic Targets. Ophthalmic Plast Reconstr Surg 2021; 36:185-190. [PMID: 31743287 DOI: 10.1097/iop.0000000000001506] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE To describe the clinicopathologic characteristics and the expression of diagnostic/treatment targets in ocular adnexal Kaposi Sarcoma. METHODS We conducted a clinical-pathologic retrospective case series. Immunohistochemical staining for cluster of differentiation 31 (CD31), human herpesvirus-8 (HHV8), platelet-derived growth factor receptor alpha (PDGFR-A), vascular endothelial growth factor receptor-1 (VEGF), tyrosine-protein kinase Kit (c-Kit), and programmed cell death protein 1 (PD-1) were performed. Percentage of positive tumor cells was recorded for PD-1; staining intensity and distribution (H-score) were determined for the remaining stains. A Friedman non-parametric ANOVA analysis evaluated the staining. RESULTS The study cohort included 13 patients (age 25 to 95 years; mean 46): 7 lesions were in the eyelid, 5 in the conjunctiva, and 1 in the cornea. Nine of 11 lesions (82%) were in human immunodeficiency syndrome-positive patients (human immunodeficiency syndrome status was unknown in 2 cases). Staging included 6 plaques and 7 nodules. The mean H-scores of CD31, HHV8, c-Kit, VEGF, and PDGF-A were 8.00, 8.23, 2.77, 11.54, and 10.31, respectively. Mean PD-1 staining was 6.46%. The Friedman non-parametric ANOVA analysis showed VEGF, PDGF-A, CD31, and HHV8 differed significantly, and all differed significantly from c-Kit. Programmed cell death protein 1 staining was not significant with any clinical variable. CONCLUSIONS Cluster of differentiation 31 and HHV8 are helpful diagnostic adjuncts for ocular adnexal Kaposi Sarcoma. Platelet-derived growth factor receptor alpha and VEGF are promising treatment targets. Programmed cell death protein 1/PD-L1 and c-Kit are targets that are useful in several tumors; their roles in ocular adnexal Kaposi Sarcoma warrant further studies.
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28
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Indrastiti RK, Wardhany II, Soegyanto AI. Oral manifestations of HIV: Can they be an indicator of disease severity? (A systematic review). Oral Dis 2020; 26 Suppl 1:133-136. [PMID: 32862546 DOI: 10.1111/odi.13394] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVE To review the existing research literature on the paradigm that the oral lesions could be an indicator of the disease severity with the objective of documenting the current status of research, highlighting its major findings. MATERIAL AND METHODS Publications were identified through a careful search, of which a majority focused on oral lesions as an indicator for HIV progression. A PubMed journal search of 10 years OF period publication (2009-2019) for "oral lesion, oral manifestation, indicator, HIV and HIV-associated" was performed and analysed. Various research methods were included within the study criteria including clinical study, clinical trial, comparative study and randomised control trial. RESULTS A total 33 studies were obtained and analysed, including cohort study, cross-sectional study, case-control study, clinical trial, retrospective observational analysis study, prospective observational study and randomised control trial. The most common oral lesions found in the studies were Kaposi sarcoma (KS), followed by oral candidiasis, periodontitis, necrotising ulcerative gingivitis (NUG), necrotising ulcerative periodontitis (NUP) and oral hairy leucoplakia (OHL). The early diagnosis and accurate treatment plan were very important to indicate the disease severity related to HIV infection. CONCLUSION Oral lesions reported in 39% articles and could be an indicator of HIV disease severity due to its effects on decreased cluster-differentiated (CD4+) T-cell count and increased viral load.
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Affiliation(s)
- Ratna Kumala Indrastiti
- Department of Oral Medicine, Faculty of Dentistry, Universitas Indonesia, Jakarta, Indonesia
| | - Indriasti I Wardhany
- Department of Oral Medicine, Faculty of Dentistry, Universitas Indonesia, Jakarta, Indonesia
| | - Anandina I Soegyanto
- Department of Oral Medicine, Faculty of Dentistry, Universitas Indonesia, Jakarta, Indonesia
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29
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Reid E, Suneja G, Ambinder RF, Ard K, Baiocchi R, Barta SK, Carchman E, Cohen A, Crysler OV, Gupta N, Gustafson C, Hall A, Johung KL, Klopp A, LaCasce AS, Lin C, Mehta A, Menon MP, Morgan D, Nathwani N, Noy A, Ratner L, Rizza S, Rudek MA, Sanchez J, Taylor J, Tomlinson B, Wang CCJ, Yendamuri S, Dwyer MA, Freedman-Cass DA. AIDS-Related Kaposi Sarcoma, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2020; 17:171-189. [PMID: 30787130 DOI: 10.6004/jnccn.2019.0008] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
As treatment of HIV has improved, people living with HIV (PLWH) have experienced a decreased risk of AIDS and AIDS-defining cancers (non-Hodgkin's lymphoma, Kaposi sarcoma, and cervical cancer), but the risk of Kaposi sarcoma in PLWH is still elevated about 500-fold compared with the general population in the United States. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AIDS-Related Kaposi Sarcoma provide diagnosis, treatment, and surveillance recommendations for PLWH who develop limited cutaneous Kaposi sarcoma and for those with advanced cutaneous, oral, visceral, or nodal disease.
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Affiliation(s)
| | | | | | - Kevin Ard
- 4Massachusetts General Hospital Cancer Center
| | - Robert Baiocchi
- 5The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | | | | | - Adam Cohen
- 8Huntsman Cancer Institute at the University of Utah
| | | | | | - Chelsea Gustafson
- 11Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | - Ann Klopp
- 13The University of Texas MD Anderson Cancer Center
| | | | - Chi Lin
- 15Fred & Pamela Buffett Cancer Center
| | - Amitkumar Mehta
- 16University of Alabama at Birmingham Comprehensive Cancer Center
| | - Manoj P Menon
- 17Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
| | | | | | - Ariela Noy
- 20Memorial Sloan Kettering Cancer Center
| | - Lee Ratner
- 21Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | | | | | | | - Jeff Taylor
- 24HIV + Aging Research Project - Palm Springs
| | - Benjamin Tomlinson
- 25Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
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- 28National Comprehensive Cancer Network
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30
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Eason AB, Sin SH, Shah M, Yuan H, Phillips DJ, Droste M, Shamshiev A, Dittmer DP. DLX1008 (brolucizumab), a single-chain anti-VEGF-A antibody fragment with low picomolar affinity, leads to tumor involution in an in vivo model of Kaposi Sarcoma. PLoS One 2020; 15:e0233116. [PMID: 32407363 PMCID: PMC7224538 DOI: 10.1371/journal.pone.0233116] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 04/28/2020] [Indexed: 12/17/2022] Open
Abstract
Kaposi Sarcoma (KS) is among the most angiogenic cancers in humans and an AIDS-defining condition. KS-associated herpesvirus (KSHV) is necessary for KS development, as is vascular endothelial growth factor (VEGF-A). DLX1008 is a novel anti-VEGF-A antibody single-chain variable fragment (scFv) with low picomolar affinity for VEGF-A. In vivo imaging techniques were used to establish the efficacy of DLX1008 and to establish the mechanism of action; this included non-invasive imaging by ultrasound and optical fluorescence, verified by post-mortem histochemistry. The results showed that DLX1008 was efficacious in a KS mouse model. The NSG mouse xenografts suffered massive internal necrosis or involution, consistent with a lack of blood supply. We found that imaging by ultrasound was superior to external caliper measurements in the validation of the angiogenesis inhibitor DLX1008. Further development of DLX1008 against VEGF-dependent sarcomas is warranted.
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Affiliation(s)
- Anthony B. Eason
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America
| | - Sang-Hoon Sin
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America
| | - Mohsin Shah
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America
| | - Hong Yuan
- Biomedical Research Imaging Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America
| | | | | | | | - Dirk P. Dittmer
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America
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Münz C. Tumor Microenvironment Conditioning by Abortive Lytic Replication of Oncogenic γ-Herpesviruses. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1225:127-135. [PMID: 32030652 DOI: 10.1007/978-3-030-35727-6_9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Epstein Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) constitute the human γ-herpesviruses and two of the seven human tumor viruses. In addition to their viral oncogenes that primarily belong to the latent infection programs of these viruses, they encode proteins that condition the microenvironment. Many of these are early lytic gene products and are only expressed in a subset of infected cells of the tumor mass. In this chapter I will describe their function and the evidence that targeting them in addition to the latent oncogenes could be beneficial for the treatment of EBV- and KSHV-associated malignancies.
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Affiliation(s)
- Christian Münz
- Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
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33
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Uldrick TS, Gonçalves PH, Abdul-Hay M, Claeys AJ, Emu B, Ernstoff MS, Fling SP, Fong L, Kaiser JC, Lacroix AM, Lee SY, Lundgren LM, Lurain K, Parsons CH, Peeramsetti S, Ramaswami R, Sharon E, Sznol M, Wang CCJ, Yarchoan R, Cheever MA. Assessment of the Safety of Pembrolizumab in Patients With HIV and Advanced Cancer-A Phase 1 Study. JAMA Oncol 2019; 5:1332-1339. [PMID: 31154457 DOI: 10.1001/jamaoncol.2019.2244] [Citation(s) in RCA: 174] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Importance Anti-PD-1 (anti-programmed cell death 1) and anti-PD-L1 (anti-programmed cell death ligand 1) regimens are preferred therapies for many cancers, including cancers associated with HIV. However, patients with HIV were excluded from most registered trials. Objective The primary objective was to evaluate the safety of pembrolizumab in people with HIV and advanced cancer; the secondary objective was to evaluate tumor responses. Design, Setting, and Participants Open-label, nonrandomized, phase 1 multicenter study conducted at 7 Cancer Immunotherapy Trials Network sites. Patients with HIV and advanced cancer as well as a CD4 count greater than or equal to 100 cells/μL, antiretroviral therapy (ART) for 4 or more weeks, and an HIV viral load of less than 200 copies/mL were eligible. Exclusion criteria included uncontrolled hepatitis B or C infection, active immunosuppressive therapy, or a history of autoimmune disease requiring systemic therapy. Interventions Pembrolizumab, 200 mg, administered intravenously every 3 weeks for up to 35 doses in 3 CD4 count-defined cohorts. Participants continued ART. Main Outcomes and Measures Safety and tolerability were assessed using current NCI Common Terminology Criteria for Adverse Events. Immune-related adverse events grade 2 or higher were considered immune-related events of clinical interest (irECI). Tumor responses were evaluated using standard tumor-specific criteria. Results Thirty participants (28 men and 2 women; median [range] age, 57 [39-77] years) were enrolled from April 2016 through March 2018; 6 had Kaposi sarcoma (KS), 5 had non-Hodgkin lymphoma (NHL), and 19 had non-AIDS-defining cancers. Safety was observed over 183 cycles of treatment with pembrolizumab. Most treatment-emergent adverse events at least possibly attributed to pembrolizumab were grade 1 or 2 (n = 22), and 20% (n = 6) were grade 3. The irECI included hypothyroidism (6 participants), pneumonitis (3 participants), rash (2 participants), an elevated aminotransferase/alanine aminotransferase level (1 participant), and a musculoskeletal event (1 participant). One participant with pretreatment KS herpesvirus (KSHV) viremia developed a polyclonal KSHV-associated B-cell lymphoproliferation and died. HIV was controlled in all participants. Increases in CD4 count were not statistically significant (median increase, 19 cells/μL; P = .18). Best tumor responses included complete response (lung, 1 patient), partial response (NHL, 2 patients), stable disease for 24 weeks or more (KS, 2 patients), stable disease for less than 24 weeks (15 patients), and progressive disease (8 patients); 2 patients were not evaluable. Conclusions and Relevance Pembrolizumab has acceptable safety in patients with cancer, HIV treated with ART, and a CD4+ T-cell count of greater than 100 cells/μL but may be associated with KSHV-associated B-cell lymphoproliferation. Clinical benefit was noted in lung cancer, NHL, and KS. Anti-PD-1 therapy is appropriate for US Food and Drug Administration-approved indications and clinical trials in this population. Trial Registration ClinicalTrials.gov identifier: NCT02595866.
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Affiliation(s)
- Thomas S Uldrick
- Fred Hutchinson Cancer Research Center, Cancer Immunotherapy Trials Network, Seattle, Washington.,HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Priscila H Gonçalves
- HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.,Northwell Health Cancer Institute, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Lake Success, New York
| | - Maher Abdul-Hay
- Laura and Isaac Perlmutter Cancer Center at NYU Langone, New York, New York
| | - Alisa J Claeys
- Fred Hutchinson Cancer Research Center, Cancer Immunotherapy Trials Network, Seattle, Washington
| | | | | | - Steven P Fling
- Fred Hutchinson Cancer Research Center, Cancer Immunotherapy Trials Network, Seattle, Washington
| | - Lawrence Fong
- University of California San Francisco, San Francisco
| | - Judith C Kaiser
- Fred Hutchinson Cancer Research Center, Cancer Immunotherapy Trials Network, Seattle, Washington
| | - Andreanne M Lacroix
- Fred Hutchinson Cancer Research Center, Cancer Immunotherapy Trials Network, Seattle, Washington
| | - Steve Y Lee
- Laura and Isaac Perlmutter Cancer Center at NYU Langone, New York, New York
| | - Lisa M Lundgren
- Fred Hutchinson Cancer Research Center, Cancer Immunotherapy Trials Network, Seattle, Washington
| | - Kathryn Lurain
- HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Christopher H Parsons
- Louisiana State University Health Science Center, New Orleans.,Pardee Center for Infectious Diseases, University of North Carolina Health Care, Hendersonville
| | | | - Ramya Ramaswami
- HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Elad Sharon
- HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | | | | | - Robert Yarchoan
- HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Martin A Cheever
- Fred Hutchinson Cancer Research Center, Cancer Immunotherapy Trials Network, Seattle, Washington
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Ramaswami R, Uldrick TS, Polizzotto MN, Wyvill KM, Goncalves P, Widell A, Lurain K, Steinberg SM, Figg WD, Tosato G, Whitby D, Yarchoan R. A Pilot Study of Liposomal Doxorubicin Combined with Bevacizumab followed by Bevacizumab Monotherapy in Patients with Advanced Kaposi Sarcoma. Clin Cancer Res 2019; 25:4238-4247. [PMID: 30979736 PMCID: PMC6635024 DOI: 10.1158/1078-0432.ccr-18-3528] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 01/11/2019] [Accepted: 04/08/2019] [Indexed: 12/21/2022]
Abstract
PURPOSE VEGF-A is important in the pathogenesis of Kaposi sarcoma, and bevacizumab has a response rate of 31%. We explored the combination of bevacizumab with liposomal doxorubicin in patients with Kaposi sarcoma. PATIENTS AND METHODS Patients with Kaposi sarcoma requiring systemic therapy were enrolled in one of two cohorts. Cohort 1 included patients with human immunodeficiency virus (HIV)-negative Kaposi sarcoma or with HIV-associated Kaposi sarcoma who would not be expected to respond to antiretroviral therapy (ART) alone (i.e., either stable or progressive Kaposi sarcoma on ART). Cohort 2 included all other patients with HIV-associated Kaposi sarcoma. Patients were treated with six cycles of liposomal doxorubicin with bevacizumab every 3 weeks followed by up to 11 cycles of bevacizumab alone. RESULTS Sixteen patients were enrolled: 10 (two HIV negative) in cohort 1 and six in cohort 2. Fourteen patients had advanced disease (AIDS Clinical Trials Group T1). Overall response rate (complete and partial responses) was 56% [80% confidence interval (CI), 38%-74%] for all patients and were similar in the two cohorts. Median progression-free survival was 6.9 months (95% CI, 4.5 months-not estimable). Grade 3 and 4 adverse events attributed to therapy included hypertension (n = 5), neutropenia (n = 6), gastrointestinal hemorrhage (n = 1), and cerebral ischemia (n = 1). There was a significant decrease in VEGF-A levels from baseline to the end of six cycles of combination therapy. CONCLUSIONS Pegylated liposomal doxorubicin in combination with bevacizumab has activity in advanced Kaposi sarcoma, but it is unclear whether the combination yields better outcomes than liposomal doxorubicin used alone.
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Affiliation(s)
- Ramya Ramaswami
- HIV & AIDS Malignancy Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
| | - Thomas S Uldrick
- HIV & AIDS Malignancy Branch, Center for Cancer Research, NCI, Bethesda, Maryland
| | - Mark N Polizzotto
- HIV & AIDS Malignancy Branch, Center for Cancer Research, NCI, Bethesda, Maryland
| | - Kathleen M Wyvill
- HIV & AIDS Malignancy Branch, Center for Cancer Research, NCI, Bethesda, Maryland
| | - Priscila Goncalves
- HIV & AIDS Malignancy Branch, Center for Cancer Research, NCI, Bethesda, Maryland
| | - Anaida Widell
- HIV & AIDS Malignancy Branch, Center for Cancer Research, NCI, Bethesda, Maryland
| | - Kathryn Lurain
- HIV & AIDS Malignancy Branch, Center for Cancer Research, NCI, Bethesda, Maryland
| | - Seth M Steinberg
- Biostatistics and Data Management Section, Center for Cancer Research, NCI, Bethesda, Maryland
| | - William Douglas Figg
- Molecular Pharmacology Branch, Center for Cancer Research, NCI, Bethesda, Maryland
| | - Giovanna Tosato
- Laboratory of Cellular Oncology, Center for Cancer Research, NCI, Bethesda, Maryland
| | - Denise Whitby
- Viral Oncology Section, AIDS and Cancer Virus Program, Leidos-Biomedical, Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Robert Yarchoan
- HIV & AIDS Malignancy Branch, Center for Cancer Research, NCI, Bethesda, Maryland
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Rivera-Soto R, Damania B. Modulation of Angiogenic Processes by the Human Gammaherpesviruses, Epstein-Barr Virus and Kaposi's Sarcoma-Associated Herpesvirus. Front Microbiol 2019; 10:1544. [PMID: 31354653 PMCID: PMC6640166 DOI: 10.3389/fmicb.2019.01544] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 06/20/2019] [Indexed: 12/25/2022] Open
Abstract
Angiogenesis is the biological process by which new blood vessels are formed from pre-existing vessels. It is considered one of the classic hallmarks of cancer, as pathological angiogenesis provides oxygen and essential nutrients to growing tumors. Two of the seven known human oncoviruses, Epstein–Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), belong to the Gammaherpesvirinae subfamily. Both viruses are associated with several malignancies including lymphomas, nasopharyngeal carcinomas, and Kaposi’s sarcoma. The viral genomes code for a plethora of viral factors, including proteins and non-coding RNAs, some of which have been shown to deregulate angiogenic pathways and promote tumor growth. In this review, we discuss the ability of both viruses to modulate the pro-angiogenic process.
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Affiliation(s)
- Ricardo Rivera-Soto
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Blossom Damania
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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Abstract
Kaposi sarcoma (KS) is an angioproliferative mesenchymal neoplasm caused by Kaposi sarcoma-related herpesvirus. This review outlines our current understanding of the epidemiology, pathogenesis, clinical presentation, and staging for this disease. Recent research has informed a more comprehensive understanding of the epidemiology of KS in the post-antiretroviral therapy era, and highlights the continued need to better characterize the African endemic subtype. Advances in clinical oncology, including checkpoint inhibitors and new skin-directed therapies, have translated into exciting new developments for the future of KS treatment options.
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He M, Cheng F, da Silva SR, Tan B, Sorel O, Gruffaz M, Li T, Gao SJ. Molecular Biology of KSHV in Relation to HIV/AIDS-Associated Oncogenesis. Cancer Treat Res 2019; 177:23-62. [PMID: 30523620 DOI: 10.1007/978-3-030-03502-0_2] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Discovered in 1994, Kaposi's sarcoma-associated herpesvirus (KSHV) has been associated with four human malignancies including Kaposi's sarcoma, primary effusion lymphoma, a subset of multicentric Castleman's disease, and KSHV inflammatory cytokine syndrome. These malignancies mostly occur in immunocompromised patients including patients with acquired immunodeficiency syndrome and often cause significant mortality because of the lack of effective therapies. Significant progresses have been made to understand the molecular basis of KSHV infection and KSHV-induced oncogenesis in the last two decades. This chapter provides an update on the recent advancements focusing on the molecular events of KSHV primary infection, the mechanisms regulating KSHV life cycle, innate and adaptive immunity, mechanism of KSHV-induced tumorigenesis and inflammation, and metabolic reprogramming in KSHV infection and KSHV-transformed cells.
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Affiliation(s)
- Meilan He
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Fan Cheng
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Suzane Ramos da Silva
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Brandon Tan
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Océane Sorel
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Marion Gruffaz
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Tingting Li
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Shou-Jiang Gao
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, USA.
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Abstract
Kaposi sarcoma (KS) is a mesenchymal tumour caused by KS-associated herpesvirus and is an AIDS-defining illness. Despite a decline in incidence since the introduction of combination anti-retroviral therapy, KS remains the most common cancer in people living with HIV in sub-Saharan Africa, where it causes significant morbidity and mortality. This review reflects on recent epidemiological data as well as current management, unmet needs and future perspectives in the treatment of HIV-associated KS with particular emphasis on the potential role of immune checkpoint inhibitors.
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Affiliation(s)
- Alessia Dalla Pria
- Imperial College London, London, UK
- Chelsea and Westminster Hospital, London, UK
| | - David J. Pinato
- Imperial College London, London, UK
- Chelsea and Westminster Hospital, London, UK
| | | | - Mark Bower
- Imperial College London, London, UK
- Chelsea and Westminster Hospital, London, UK
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Lebbe C, Garbe C, Stratigos AJ, Harwood C, Peris K, Marmol VD, Malvehy J, Zalaudek I, Hoeller C, Dummer R, Forsea AM, Kandolf-Sekulovic L, Olah J, Arenberger P, Bylaite-Bucinskiene M, Vieira R, Middleton M, Levy A, Eggermont AM, Battistella M, Spano JP, Grob JJ, Pages C. Diagnosis and treatment of Kaposi's sarcoma: European consensus-based interdisciplinary guideline (EDF/EADO/EORTC). Eur J Cancer 2019; 114:117-127. [DOI: 10.1016/j.ejca.2018.12.036] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 12/27/2018] [Indexed: 01/28/2023]
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Abstract
Kaposi sarcoma (KS) gained public attention as an AIDS-defining malignancy; its appearance on the skin was a highly stigmatizing sign of HIV infection during the height of the AIDS epidemic. The widespread introduction of effective antiretrovirals to control HIV by restoring immunocompetence reduced the prevalence of AIDS-related KS, although KS does occur in individuals with well-controlled HIV infection. KS also presents in individuals without HIV infection in older men (classic KS), in sub-Saharan Africa (endemic KS) and in transplant recipients (iatrogenic KS). The aetiologic agent of KS is KS herpesvirus (KSHV; also known as human herpesvirus-8), and viral proteins can induce KS-associated cellular changes that enable the virus to evade the host immune system and allow the infected cell to survive and proliferate despite viral infection. Currently, most cases of KS occur in sub-Saharan Africa, where KSHV infection is prevalent owing to transmission by saliva in childhood compounded by the ongoing AIDS epidemic. Treatment for early AIDS-related KS in previously untreated patients should start with the control of HIV with antiretrovirals, which frequently results in KS regression. In advanced-stage KS, chemotherapy with pegylated liposomal doxorubicin or paclitaxel is the most common treatment, although it is seldom curative. In sub-Saharan Africa, KS continues to have a poor prognosis. Newer treatments for KS based on the mechanisms of its pathogenesis are being explored.
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Affiliation(s)
- Ethel Cesarman
- Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
| | - Blossom Damania
- Department of Microbiology and Immunology, Lineberger Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | | | - Jeffrey Martin
- Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
| | - Mark Bower
- National Centre for HIV Malignancy, Chelsea & Westminster Hospital, London, UK
| | - Denise Whitby
- Leidos Biomedical Research, AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
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Dittmer DP, Damania B. Kaposi's Sarcoma-Associated Herpesvirus (KSHV)-Associated Disease in the AIDS Patient: An Update. Cancer Treat Res 2019; 177:63-80. [PMID: 30523621 PMCID: PMC7201581 DOI: 10.1007/978-3-030-03502-0_3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/01/2023]
Abstract
In this book chapter, we review the current knowledge of the biology and pathogenesis of Kaposi's sarcomaassociated herpesvirus (KSHV). We describe the lifecycle of KSHV, the cancers associated with this virus, as well as current treatment modalities.
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Affiliation(s)
- Dirk P Dittmer
- Department of Microbiology & Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, CB #7295, NC, 27599, Chapel Hill, USA
| | - Blossom Damania
- Department of Microbiology & Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, CB #7295, NC, 27599, Chapel Hill, USA.
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Haley CT, Mui UN, Vangipuram R, Rady PL, Tyring SK. Human oncoviruses: Mucocutaneous manifestations, pathogenesis, therapeutics, and prevention: Papillomaviruses and Merkel cell polyomavirus. J Am Acad Dermatol 2018; 81:1-21. [PMID: 30502418 DOI: 10.1016/j.jaad.2018.09.062] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 09/09/2018] [Accepted: 09/10/2018] [Indexed: 12/18/2022]
Abstract
In 1964, the first human oncovirus, Epstein-Barr virus, was identified in Burkitt lymphoma cells. Since then, 6 other human oncoviruses have been identified: human papillomavirus, Merkel cell polyomavirus, hepatitis B and C viruses, human T-cell lymphotropic virus-1, and human herpesvirus-8. These viruses are causally linked to 12% of all cancers, many of which have mucocutaneous manifestations. In addition, oncoviruses are associated with multiple benign mucocutaneous diseases. Research regarding the pathogenic mechanisms of oncoviruses and virus-specific treatment and prevention is rapidly evolving. Preventative vaccines for human papillomavirus and hepatitis B virus are already available. This review discusses the mucocutaneous manifestations, pathogenesis, diagnosis, treatment, and prevention of oncovirus-related diseases. The first article in this continuing medical education series focuses on diseases associated with human papillomavirus and Merkel cell polyomavirus, while the second article in the series focuses on diseases associated with hepatitis B and C viruses, human T-cell lymphotropic virus-1, human herpesvirus-8, and Epstein-Barr virus.
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Affiliation(s)
| | | | - Ramya Vangipuram
- Center for Clinical Studies, Webster, Texas; Department of Dermatology, University of Texas Health Science Center at Houston, Houston, Texas
| | - Peter L Rady
- Department of Dermatology, University of Texas Health Science Center at Houston, Houston, Texas
| | - Stephen K Tyring
- Center for Clinical Studies, Webster, Texas; Department of Dermatology, University of Texas Health Science Center at Houston, Houston, Texas
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KSHV-induced ligand mediated activation of PDGF receptor-alpha drives Kaposi's sarcomagenesis. PLoS Pathog 2018; 14:e1007175. [PMID: 29985958 PMCID: PMC6053240 DOI: 10.1371/journal.ppat.1007175] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 07/19/2018] [Accepted: 06/22/2018] [Indexed: 12/20/2022] Open
Abstract
Kaposi’s sarcoma (KS) herpesvirus (KSHV) causes KS, an angiogenic AIDS-associated spindle-cell neoplasm, by activating host oncogenic signaling cascades through autocrine and paracrine mechanisms. Tyrosine kinase receptor (RTK) proteomic arrays, identified PDGF receptor-alpha (PDGFRA) as the predominantly-activated RTK in KSHV-induced mouse KS-tumors. We show that: 1) KSHV lytic replication and the vGPCR can activate PDGFRA through upregulation of its ligands PDGFA/B, which increase c-myc, VEGF and KSHV gene expression in infected cells 2) KSHV infected spindle cells of most AIDS-KS lesions display robust phospho-PDGFRA staining 3) blocking PDGFRA-signaling with N-acetyl-cysteine, RTK-inhibitors Imatinib and Sunitinib, or dominant-negative PDGFRA inhibits tumorigenesis 4) PDGFRA D842V activating-mutation confers resistance to Imatinib in mouse-KS tumorigenesis. Our data show that KSHV usurps sarcomagenic PDGFRA signaling to drive KS. This and the fact that PDGFRA drives non-viral sarcomas highlights the importance for KSHV-induced ligand-mediated activation of PDGFRA in KS sarcomagenesis and shows that this oncogenic axis could be successfully blocked to impede KS tumor growth. Signaling mimicry is a key mechanism whereby oncoviruses can usurp host-regulatory pathways leading to acquisition of tissue-specific cancer hallmarks. A critical question in the KS field is the identification of this host pathways activated by KSHV that could provide novel insights on KSHV-pathobiology, elucidating new druggable pathways. Here we show that KSHV lytic replication as well as the KSHV-oncogene vGPCR activates PDGFRA signaling through upregulation of its ligands PDGFA/B, and that blocking of PDGFRA signaling is anti-tumorigenic. This indicates that approaches that fully and stably inhibit PDGFR-signaling could lead to successful treatments for KS, validating this receptor-ligand signaling-axis as a therapeutic target.
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Xu Y, Rong X, Hu W, Huang X, Li Y, Zheng D, Cai Z, Zuo Z, Tang Y. Bevacizumab Monotherapy Reduces Radiation-induced Brain Necrosis in Nasopharyngeal Carcinoma Patients: A Randomized Controlled Trial. Int J Radiat Oncol Biol Phys 2018; 101:1087-1095. [PMID: 29885994 DOI: 10.1016/j.ijrobp.2018.04.068] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 03/20/2018] [Accepted: 04/23/2018] [Indexed: 11/30/2022]
Abstract
PURPOSE Studies have shown that addition of bevacizumab to corticosteroids improves outcome against radiation-induced brain necrosis (RN). Here, we aimed to evaluate the effectiveness and safety of bevacizumab monotherapy on RN in nasopharyngeal carcinoma (NPC) patients. METHODS AND MATERIALS In this multicenter open-label study, patients with RN were randomly assigned (1:1) into a bevacizumab group (5 mg/kg intravenously every 2 weeks, for 4 cycles) or a corticosteroid group (methylprednisolone 500 mg/day intravenously for 3 consecutive days and then gradually tapered, followed by 10 mg/day oral prednisone, for 2 months in total). Magnetic resonance imaging (MRI) was performed pre- and post-treatment to define the radiographic response. The primary outcome was a 2-month response rate as determined by MRI and clinical symptoms. All of the patients were followed up with for 6 months. The trial was registered at www.clinicaltrials.gov (NCT01621880). RESULTS Of 121 patients screened, 112 patients met the entry criteria. Thirty-eight (65.5%) patients in the bevacizumab group showed response, which was significantly higher than that in the corticosteroid group (65.5% vs 31.5%, P < .001). The mean percentage decrease in RN volume seen on T1 post-gadolinium and T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI was 25.5% and 51.8%, respectively, in the bevacizumab group, versus 5.0% and 19.3%, respectively, in the corticosteroid group. Moreover, 36 patients (62.1%) on bevacizumab and 23 patients (42.6%) on corticosteroids demonstrated clinical improvement (P = .039). During the 6-month follow up, fourteen patients on bevacizumab and 13 patients on corticosteroids showed RN recurrence. The most frequent adverse event in the bevacizumab group was hypertension (20.6%). CONCLUSIONS Our study indicate that compared with corticosteroids, bevacizumab offers improved symptomatic relief and radiographic response.
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Affiliation(s)
- Yongteng Xu
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiaoming Rong
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Weihan Hu
- Department of Radiation Oncology, Cancer Center of Sun Yat-sen University, Guangzhou, China
| | - Xiaolong Huang
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yi Li
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Dong Zheng
- Department of Neurology, Guangzhou Brain Hospital, Guangzhou, China
| | - Zhaoxi Cai
- Department of Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhiyi Zuo
- Department of Anesthesiology, University of Virginia, Charlottesville, Virginia
| | - Yamei Tang
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Guangdong Province Key Laboratary of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Gaungzhou, China.
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Khan JA, Maki RG, Ravi V. Pathologic Angiogenesis of Malignant Vascular Sarcomas: Implications for Treatment. J Clin Oncol 2018; 36:194-201. [DOI: 10.1200/jco.2017.74.9812] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Angiosarcoma, epithelioid hemangioendothelioma, and Kaposi sarcoma are classified according to the line of differentiation that these neoplastic cells most closely resemble: the endothelial cell. Although these malignant vascular sarcomas demonstrate immunohistochemical and ultrastructural features typical of this lineage, they vary dramatically in presentation and behavior, reflecting oncologic mechanisms unique to each. Antineoplastic therapies offer significant benefit, but because of the rarity of these cancers, novel therapies are slow to develop, and treatment options for these cancers remain limited. Antiangiogenic approaches that have shown benefit in other malignancies have not fully realized their promise in vascular tumors, suggesting that these tumors do not depend entirely on either angiogenic growth factors or on neighboring endothelia that are affected by these agents. Nonetheless, translational studies have begun to unravel these distinct pathologies, identifying novel translocation products, targets of oncogenic virulence factors, and genomic mutations that hijack angiogenic signaling and drive malignant growth. Concurrently, an elaborate and highly regulated model of angiogenesis and lymphangiogenesis involving vascular endothelial growth factor–receptor tyrosine kinase and TGF-β and Notch pathways has emerged that informs treatment of these tumors as well as cancer in general. This review summarizes the literature on malignant vascular sarcomas in the context of current models of angiogenesis and, in light of recent clinical trial data, could help clinician-scientists generate novel therapeutic approaches.
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Affiliation(s)
- Jalal A. Khan
- Jalal A. Khan, Mount Sinai Hospital, New York City; Robert G. Maki, Monter Cancer Center, Northwell Health, and Cold Spring Harbor Laboratory, Lake Success, NY; and Vinod Ravi, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Robert G. Maki
- Jalal A. Khan, Mount Sinai Hospital, New York City; Robert G. Maki, Monter Cancer Center, Northwell Health, and Cold Spring Harbor Laboratory, Lake Success, NY; and Vinod Ravi, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Vinod Ravi
- Jalal A. Khan, Mount Sinai Hospital, New York City; Robert G. Maki, Monter Cancer Center, Northwell Health, and Cold Spring Harbor Laboratory, Lake Success, NY; and Vinod Ravi, University of Texas MD Anderson Cancer Center, Houston, TX
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Abstract
: The search for the etiologic agent for Kaposi sarcoma led to the discovery of Kaposi sarcoma-associated herpesvirus (KSHV) in 1994. KSHV, also called human herpesvirus-8, has since been shown to be the etiologic agent for several other tumors and diseases, including primary effusion lymphoma (PEL), an extracavitary variant of PEL, KSHV-associated diffuse large B-cell lymphoma, a form of multicentric Castleman disease, and KSHV inflammatory cytokine syndrome. KSHV encodes several genes that interfere with innate and specific immunity, thwart apoptosis, enhance cell proliferation and cytokine production, and promote angiogenesis, and these play important roles in disease pathogenesis. HIV is an important cofactor in Kaposi sarcoma pathogenesis, and widespread use of antiretroviral therapy has reduced Kaposi sarcoma incidence. However, Kaposi sarcoma remains the second most frequent tumor arising in HIV-infected patients in the United States and is particularly common in sub-Saharan Africa. KSHV prevalence varies substantially in different populations. KSHV is secreted in saliva, and public health measures to reduce its spread may help reduce the incidence of KSHV-associated diseases. Although there have been advances in the treatment of Kaposi sarcoma, KSHV-multicentric Castleman disease, and PEL, improved therapies are needed, especially those that are appropriate for Kaposi sarcoma in resource-poor regions.
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Abstract
PURPOSE OF REVIEW This review discusses the pathogenesis and recent advances in the management of Kaposi sarcoma herpesvirus (KSHV)-associated diseases. RECENT FINDINGS KSHV, a gammaherpesvirus, causes several tumors and related diseases, including Kaposi sarcoma, a form of multicentric Castleman disease (KSHV-MCD), and primary effusion lymphoma. These most often develop in patients infected with human immunodeficiency virus (HIV). KSHV inflammatory cytokine syndrome (KICS) is a newly described syndrome with high mortality that has inflammatory symptoms-like MCD but not the pathologic lymph node findings. KSHV-associated diseases are often associated with dysregulated human interleukin-6, and KSHV encodes a viral interleukin-6, both of which contribute to disease pathogenesis. Treatment of HIV is important in HIV-infected patients. Strategies to prevent KSHV infection may reduce the incidence of these tumors. Pomalidomide, an immunomodulatory agent, has activity in Kaposi sarcoma. Rituximab is active in KSHV-MCD but can cause Kaposi sarcoma exacerbation; rituximab plus liposomal doxorubicin is useful to treat KSHV-MCD patients with concurrent Kaposi sarcoma. SUMMARY KSHV is the etiological agents of all forms of Kaposi sarcoma and several other diseases. Strategies employing immunomodulatory agents, cytokine inhibition, and targeting of KSHV-infected cells are areas of active research.
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Abstract
Kaposi sarcoma (KS) is the most common neoplasm of people living with HIV today. In Sub-Saharan Africa, KS is among the most common cancers in men, overall. Not only HIV-positive individuals present with KS; any immune compromised person infected with KS-associated herpesvirus (KSHV) or human herpesvirus 8 is at risk: the elderly, children in KSHV-endemic areas, and transplant recipients. KS diagnosis is based on detection of the viral protein latency-associated nuclear antigen (LANA) in the biopsy, but not all cases of KS are the same or will respond to the same therapy. Standard KS therapy has not changed in 20 years, but newer modalities are on the horizon and will be discussed.
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Uldrick TS, Gonçalves PH, Wyvill KM, Peer CJ, Bernstein W, Aleman K, Polizzotto MN, Venzon D, Steinberg SM, Marshall V, Whitby D, Little RF, Wright JJ, Rudek MA, Figg WD, Yarchoan R. A Phase Ib Study of Sorafenib (BAY 43-9006) in Patients with Kaposi Sarcoma. Oncologist 2017; 22:505-e49. [PMID: 28341759 PMCID: PMC5423501 DOI: 10.1634/theoncologist.2016-0486] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 12/16/2016] [Indexed: 12/17/2022] Open
Abstract
LESSONS LEARNED Oral targeted agents are desirable for treatment of Kaposi sarcoma (KS); however, in patients with HIV, drug-drug interactions must be considered. In this study to treat KS, sorafenib was poorly tolerated at doses less than those approved by the U.S. Food and Drug Administration for hepatocellular carcinoma and other cancers, and showed only modest activity.Sorafenib's metabolism occurs via the CYP3A4 pathway, which is inhibited by ritonavir, a commonly used antiretroviral agent used by most patients in this study. Strong CYP3A4 inhibition by ritonavir may contribute to the observed sorafenib toxicity.Alternate antiretroviral agents without predicted interactions are preferred for co-administration in patients with HIV and cancers for which sorafenib is indicated. BACKGROUND We conducted a phase Ib study of sorafenib, a vascular epithelial growth factor receptor (VEGFR), c-kit, and platelet derived growth factor receptor (PDGFR)-targeted treatment in Kaposi sarcoma (KS). We evaluated drug-drug interactions between sorafenib and ritonavir, an HIV medication with strong CYP3A4 inhibitory activity. METHODS Two cohorts were enrolled: HIV-related KS on ritonavir (Cohort R) and HIV-related or classical KS not receiving ritonavir (Cohort NR). Sorafenib dose level 1 in cohort R (R1) was 200 mg daily and 200 mg every 12 hours in cohort NR (NR1). Steady-state pharmacokinetics were evaluated at cycle 1, day 8. KS responses and correlative factors were assessed. RESULTS Ten patients (nine HIV+) were enrolled: R1 (eight), NR1 (two). Median CD4+ count (HIV+) was 500 cells/µL. Dose-limiting toxicities (DLTs) were grade 3 elevated lipase (R1), grade 4 thrombocytopenia (R1), and grade 3 hand-foot syndrome (NR1). Two of seven evaluable patients had a partial response (PR; 29%; 95% CI 4%-71%). Steady-state area under the curve of the dosing interval (AUCTAU) of sorafenib was not significantly affected by ritonavir; however, a trend for decreased AUCTAU of the CYP3A4 metabolite sorafenib-N-oxide (3.8-fold decrease; p = .08) suggests other metabolites may be increased. CONCLUSION Sorafenib was poorly tolerated, and anti-KS activity was modest. Strong CYP3A4 inhibitors may contribute to sorafenib toxicity, and ritonavir has previously been shown to be a CYP3A4 inhibitor. Alternate antiretroviral agents without predicted interactions should be used when possible for concurrent administration with sorafenib. The Oncologist 2017;22:505-e49.
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Affiliation(s)
- Thomas S Uldrick
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA
| | - Priscila H Gonçalves
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA
| | - Kathleen M Wyvill
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA
| | - Cody J Peer
- Clinical Pharmacology Program, National Cancer Institute, Bethesda, Maryland, USA
| | - Wendy Bernstein
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA
| | - Karen Aleman
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA
| | - Mark N Polizzotto
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA
| | - David Venzon
- Biostatistics and Data Management Section at the Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Seth M Steinberg
- Biostatistics and Data Management Section at the Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Vickie Marshall
- Viral Oncology Section, AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Denise Whitby
- Viral Oncology Section, AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Richard F Little
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA
| | - John J Wright
- Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA
| | - Michelle A Rudek
- Analytical Pharmacology Core, Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - William D Figg
- Clinical Pharmacology Program, National Cancer Institute, Bethesda, Maryland, USA
| | - Robert Yarchoan
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA
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Wagner MJ, Ravi V, Menter DG, Sood AK. Endothelial cell malignancies: new insights from the laboratory and clinic. NPJ Precis Oncol 2017; 1:11. [PMID: 29872699 PMCID: PMC5859470 DOI: 10.1038/s41698-017-0013-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 02/13/2017] [Indexed: 12/14/2022] Open
Abstract
Endothelial cell malignancies are rare in the Western world and range from intermediate grade hemangioendothelioma to Kaposi sarcoma to aggressive high-grade angiosarcoma that metastasize early and have a high rate of mortality. These malignancies are associated with dysregulation of normal endothelial cell signaling pathways, including the vascular endothelial growth factor, angiopoietin, and Notch pathways. Discoveries over the past two decades related to mechanisms of angiogenesis have led to the development of many drugs that intuitively would be promising therapeutic candidates for these endothelial-derived tumors. However, clinical efficacy of such drugs has been limited. New insights into the mechanisms that lead to dysregulated angiogenesis such as mutation or amplification in known angiogenesis related genes, viral infection, and chromosomal translocations have improved our understanding of the pathogenesis of endothelial malignancies and how they evade anti-angiogenesis drugs. In this review, we describe the major molecular alterations in endothelial cell malignancies and consider emerging opportunities for improving therapeutic efficacy against these rare but deadly tumors.
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Affiliation(s)
- Michael J Wagner
- 1Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 USA
| | - Vinod Ravi
- 2Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 USA
| | - David G Menter
- 3Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 USA
| | - Anil K Sood
- 4Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 USA.,5Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 USA.,6Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 USA
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