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CAR T-Cell Immunotherapy Treating T-ALL: Challenges and Opportunities. Vaccines (Basel) 2023; 11:vaccines11010165. [PMID: 36680011 PMCID: PMC9861718 DOI: 10.3390/vaccines11010165] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 12/28/2022] [Accepted: 01/06/2023] [Indexed: 01/14/2023] Open
Abstract
T-cell acute lymphoblastic leukemia (T-ALL), a form of T-cell malignancy, is a typically aggressive hematological malignancy with high rates of disease relapse and a poor prognosis. Current guidelines do not recommend any specific treatments for these patients, and only allogeneic stem cell transplant, which is associated with potential risks and toxicities, is a curative therapy. Recent clinical trials showed that immunotherapies, including monoclonal antibodies, checkpoint inhibitors, and CAR T therapies, are successful in treating hematologic malignancies. CAR T cells, which specifically target the B-cell surface antigen CD19, have demonstrated remarkable efficacy in the treatment of B-cell acute leukemia, and some progress has been made in the treatment of other hematologic malignancies. However, the development of CAR T-cell immunotherapy targeting T-cell malignancies appears more challenging due to the potential risks of fratricide, T-cell aplasia, immunosuppression, and product contamination. In this review, we discuss the current status of and challenges related to CAR T-cell immunotherapy for T-ALL and review potential strategies to overcome these limitations.
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Mai J, Li X, Zhang G, Huang Y, Xu R, Shen Q, Lokesh GL, Thiviyanathan V, Chen L, Liu H, Zu Y, Ma X, Volk DE, Gorenstein DG, Ferrari M, Shen H. DNA Thioaptamer with Homing Specificity to Lymphoma Bone Marrow Involvement. Mol Pharm 2018; 15:1814-1825. [PMID: 29537266 PMCID: PMC6311132 DOI: 10.1021/acs.molpharmaceut.7b01169] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Selective drug accumulation in the malignant tissue is a prerequisite for effective cancer treatment. However, most drug molecules and their formulated particles are blocked en route to the destiny tissue due to the existence of multiple biological and physical barriers including the tumor microvessel endothelium. Since the endothelial cells on the surface of the microvessel wall can be modulated by inflammatory cytokines and chemokines secreted by the tumor or stromal cells, an effective drug delivery approach is to enhance interaction between the drug particles and the unique spectrum of surface proteins on the tumor endothelium. In this study, we performed in vivo screening for thioaptamers that bind to the bone marrow endothelium with specificity in a murine model of lymphoma with bone marrow involvement (BMI). The R1 thioaptamer was isolated based on its high homing potency to bones with BMI, and 40-60% less efficiency in accumulation to healthy bones. In cell culture, R1 binds to human umbilical vein endothelial cells (HUVEC) with a high affinity ( Kd ≈ 3 nM), and the binding affinity can be further enhanced when cells were treated with a mixture of lymphoma cell and bone marrow cell conditioned media. Cellular uptake of R1 is through clathrin-mediated endocytosis. Conjugating R1 on to the surface of liposomal doxorubicin nanoparticles resulted in 2-3-fold increase in drug accumulation in lymphoma BMI. Taking together, we have successfully identified a thioaptamer that preferentially binds to the endothelium of lymphoma BMI. It can serve as an affinity moiety for targeted delivery of drug particles to the disease organ.
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Affiliation(s)
- Junhua Mai
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA
| | - Xin Li
- Institute of Molecular Medicine and the Department of Nanomedicine and Biomedical Engineering, McGovern Medical School, The University of Texas Health Science Center at Houston, 1825 Hermann Pressler, Houston 77030, USA
| | - Guodong Zhang
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA
| | - Yi Huang
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA
| | - Rong Xu
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA
| | - Qi Shen
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA
| | - Ganesh L. Lokesh
- Institute of Molecular Medicine and the Department of Nanomedicine and Biomedical Engineering, McGovern Medical School, The University of Texas Health Science Center at Houston, 1825 Hermann Pressler, Houston 77030, USA
| | - Varatharasa Thiviyanathan
- Institute of Molecular Medicine and the Department of Nanomedicine and Biomedical Engineering, McGovern Medical School, The University of Texas Health Science Center at Houston, 1825 Hermann Pressler, Houston 77030, USA
| | - Lingxiao Chen
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA
- Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Haoran Liu
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA
- College of Materials Science and Opto-Electronic Technology, University of Chinese Academy of Sciences, Beijing, China
| | - Youli Zu
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas 77030, USA
| | - Xiaojing Ma
- Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York 10065, USA
| | - David E. Volk
- Institute of Molecular Medicine and the Department of Nanomedicine and Biomedical Engineering, McGovern Medical School, The University of Texas Health Science Center at Houston, 1825 Hermann Pressler, Houston 77030, USA
| | - David G. Gorenstein
- Institute of Molecular Medicine and the Department of Nanomedicine and Biomedical Engineering, McGovern Medical School, The University of Texas Health Science Center at Houston, 1825 Hermann Pressler, Houston 77030, USA
| | - Mauro Ferrari
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA
- Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA
| | - Haifa Shen
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA
- Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York 10065, USA
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3
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Sun P, Zhou X, He Y, Liu H, Wang Y, Chen Y, Li M, He Y, Li G, Li Y. Effect of trichostatin A on Burkitt's lymphoma cells: Inhibition of EPS8 activity through Phospho-Erk1/2 pathway. Biochem Biophys Res Commun 2018; 497:990-996. [PMID: 29462617 DOI: 10.1016/j.bbrc.2018.02.128] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 02/14/2018] [Indexed: 01/24/2023]
Abstract
Histone deacetylase inhibitors (HDACi) manifest great potential for treatment of Burkitt's lymphoma (BL), an aggressive B-cell lymphoma. Epidermal growth factor receptor pathway substrate 8 (EPS8) is confirmed overexpressed and associated with poor prognosis in solid tumors and leukemia. However, EPS8 expression and the relationship between EPS8 and HDACi on BL remains obscure. Here, we hypothesized that trichostatin A (TSA), a pan-HDACi, could inhibit BL cells by downregulating EPS8. We demonstrated that TSA reduced cell viability, induced apoptosis and cell arrest at G0/G1. Mechanismly, TSA attenuated EPS8 and downstream Phospho-Erk1/2 pathway. Knockdown of EPS8 resulted in a significant reduction in cellular proliferation and suppressed Phospho-Erk1/2 pathway activity, particularly when combined with TSA. Conversely, overexpression of EPS8 rescued this phenomenon. Then we showed that the combination of TSA and Epirubicin had a more significant effect when compared with TSA or Epirubicin alone. Finally, knockdown of EPS8 and TSA had a synergistic suppression effect on BALB/c nude mice. In conclusion, this study reveals that TSA affects BL cells by suppressing Phospho-Erk1/2 pathway through downregulating EPS8.
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Affiliation(s)
- Peipei Sun
- Department of Hematology, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China.
| | - Xin Zhou
- Department of Hematology, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China.
| | - Yingzhi He
- Department of Hematology, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China.
| | - Huimin Liu
- Department of Hematology, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China.
| | - Yuxin Wang
- Department of Hematology, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China.
| | - Yiran Chen
- Department of Hematology, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China.
| | - Meifang Li
- Department of Hematology, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China.
| | - Yanjie He
- Department of Hematology, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China.
| | - Guowei Li
- Department of Hematology, Huizhou Municipal Central Hospital, 41 Eling Road North, 516001, Huizhou, China.
| | - Yuhua Li
- Department of Hematology, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China.
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4
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Catalan-Dibene J, Vazquez MI, Luu VP, Nuccio SP, Karimzadeh A, Kastenschmidt JM, Villalta SA, Ushach I, Pone EJ, Casali P, Raffatellu M, Burkhardt AM, Hernandez-Ruiz M, Heller G, Hevezi PA, Zlotnik A. Identification of IL-40, a Novel B Cell-Associated Cytokine. THE JOURNAL OF IMMUNOLOGY 2017; 199:3326-3335. [PMID: 28978694 DOI: 10.4049/jimmunol.1700534] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Accepted: 08/31/2017] [Indexed: 11/19/2022]
Abstract
We describe a novel B cell-associated cytokine, encoded by an uncharacterized gene (C17orf99; chromosome 17 open reading frame 99), that is expressed in bone marrow and fetal liver and whose expression is also induced in peripheral B cells upon activation. C17orf99 is only present in mammalian genomes, and it encodes a small (∼27-kDa) secreted protein unrelated to other cytokine families, suggesting a function in mammalian immune responses. Accordingly, C17orf99 expression is induced in the mammary gland upon the onset of lactation, and a C17orf99-/- mouse exhibits reduced levels of IgA in the serum, gut, feces, and lactating mammary gland. C17orf99-/- mice have smaller and fewer Peyer's patches and lower numbers of IgA-secreting cells. The microbiome of C17orf99-/- mice exhibits altered composition, likely a consequence of the reduced levels of IgA in the gut. Although naive B cells can express C17orf99 upon activation, their production increases following culture with various cytokines, including IL-4 and TGF-β1, suggesting that differentiation can result in the expansion of C17orf99-producing B cells during some immune responses. Taken together, these observations indicate that C17orf99 encodes a novel B cell-associated cytokine, which we have called IL-40, that plays an important role in humoral immune responses and may also play a role in B cell development. Importantly, IL-40 is also expressed by human activated B cells and by several human B cell lymphomas. The latter observations suggest that it may play a role in the pathogenesis of certain human diseases.
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Affiliation(s)
- Jovani Catalan-Dibene
- Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697.,Institute for Immunology, University of California, Irvine, Irvine, CA 92697
| | - Monica I Vazquez
- Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697.,Institute for Immunology, University of California, Irvine, Irvine, CA 92697
| | - Van Phi Luu
- Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697.,Institute for Immunology, University of California, Irvine, Irvine, CA 92697
| | - Sean-Paul Nuccio
- Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA 92697; and
| | - Alborz Karimzadeh
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697
| | - Jenna M Kastenschmidt
- Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697.,Institute for Immunology, University of California, Irvine, Irvine, CA 92697
| | - S Armando Villalta
- Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697.,Institute for Immunology, University of California, Irvine, Irvine, CA 92697
| | - Irina Ushach
- Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697.,Institute for Immunology, University of California, Irvine, Irvine, CA 92697
| | - Egest J Pone
- Institute for Immunology, University of California, Irvine, Irvine, CA 92697.,Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697
| | - Paolo Casali
- Institute for Immunology, University of California, Irvine, Irvine, CA 92697.,Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697
| | - Manuela Raffatellu
- Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA 92697; and
| | - Amanda M Burkhardt
- Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697.,Institute for Immunology, University of California, Irvine, Irvine, CA 92697
| | - Marcela Hernandez-Ruiz
- Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697.,Institute for Immunology, University of California, Irvine, Irvine, CA 92697
| | - Gina Heller
- Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697.,Institute for Immunology, University of California, Irvine, Irvine, CA 92697
| | - Peter A Hevezi
- Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697.,Institute for Immunology, University of California, Irvine, Irvine, CA 92697
| | - Albert Zlotnik
- Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697; .,Institute for Immunology, University of California, Irvine, Irvine, CA 92697
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Islam S, Qi W, Morales C, Cooke L, Spier C, Weterings E, Mahadevan D. Disruption of Aneuploidy and Senescence Induced by Aurora Inhibition Promotes Intrinsic Apoptosis in Double Hit or Double Expressor Diffuse Large B-cell Lymphomas. Mol Cancer Ther 2017; 16:2083-2093. [PMID: 28615297 DOI: 10.1158/1535-7163.mct-17-0089] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 05/05/2017] [Accepted: 06/06/2017] [Indexed: 11/16/2022]
Abstract
Double hit (DH) or double expressor (DE) diffuse large B-cell lymphomas (DLBCL) are aggressive non-Hodgkin's lymphomas (NHL) with translocations and/or overexpressions of MYC and BCL-2, which are difficult to treat. Aurora kinase (AK) inhibition with alisertib in DH/DE-DLBCL induces cell death in ∼30%, while ∼70% are aneuploid and senescent cells (AASC), a mitotic escape mechanism contributing to drug resistance. These AASCs elaborated a high metabolic rate by increased AKT/mTOR and ERK/MAPK activity via BTK signaling through the chronic active B-cell receptor (BCR) pathway. Combinations of alisertib + ibrutinib or alisertib + ibrutinib + rituximab significantly reduced AASCs with enhanced intrinsic cell death. Inhibition of AK + BTK reduced phosphorylation of AKT/mTOR and ERK-1/2, upregulated phospho-H2A-X and Chk-2 (DNA damage), reduced Bcl-6, and decreased Bcl-2 and Bcl-xL and induced apoptosis by PARP cleavage. In a DE-DLBCL SCID mouse xenograft model, ibrutinib alone was inactive, while alisertib + ibrutinib was additive with a tumor growth inhibition (TGI) rate of ∼25%. However, TGI for ibrutinib + rituximab was ∼50% to 60%. In contrast, triple therapy showed a TGI rate of >90%. Kaplan-Meier survival analysis showed that 67% of mice were alive at day 89 with triple therapy versus 20% with ibrutinib + rituximab. All treatments were well tolerated with no changes in body weights. A novel triple therapy consisting of alisertib + ibrutinib + rituximab inhibits AASCs induced by AK inhibition in DH/DE-DLBCL leading to a significant antiproliferative signal, enhanced intrinsic apoptosis and may be of therapeutic potential in these lymphomas. Mol Cancer Ther; 16(10); 2083-93. ©2017 AACR.
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Affiliation(s)
- Shariful Islam
- University of Arizona Cancer Center, Cancer Biology Graduate Interdisciplinary Program, Tucson, Arizona
| | - Wenqing Qi
- West Cancer Center and University of Tennessee Health Sciences Center, Memphis, Tennessee
| | - Carla Morales
- West Cancer Center and University of Tennessee Health Sciences Center, Memphis, Tennessee
| | - Laurence Cooke
- University of Arizona Cancer Center, Department of Medicine, Tucson, Arizona
| | - Catherine Spier
- University of Arizona, Department of Pathology, Tucson, Arizona
| | - Eric Weterings
- University of Arizona, Department of Radiation Oncology, Tucson, Arizona
| | - Daruka Mahadevan
- University of Arizona Cancer Center, Department of Medicine, Tucson, Arizona.
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6
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Bharti B, Shukla S, Tripathi R, Mishra S, Kumar M, Pandey M, Mishra R. Level of PAX5 in differential diagnosis of non-Hodgkin's lymphoma. Indian J Med Res 2016; 143:S23-S31. [PMID: 27748274 PMCID: PMC5080925 DOI: 10.4103/0971-5916.191747] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background & objectives: The PAX5, a paired box transcription factor and B-cell activator protein (BSAP), activates B-cell commitment genes and represses non-B-cell lineage genes. About 14 transcript variants of PAX5 have been observed in human. Any alteration in its expression pattern leads to lymphogenesis or associated diseases and carcinogenesis in non-lymphoid tissues. Its mechanisms of function in pathophysiology of non-Hodgkin's lymphoma (NHL) are unclear. This study was intended to explore influence of PAX5 in cascade of NHL pathogenesis and diagnosis. Methods: Samples of 65 patients were evaluated by immunohistochemical staining for cellular localization of PAX5, CD19, CD3, cABL, p53, Ras and Raf and by TUNEL assay, RNA-isolation and reverse transcriptase (RT)-PCR, Western blot analysis, and lactate dehydrogenase (LDH) specific staining. Results: B-cell type NHL patients were positive for PAX5, p53, Ras, CD19, Raf and CD3. All of them showed TUNEL-positive cells. The differential expression pattern of PAX5, CD19, p53, CD3, ZAP70, HIF1α, Ras, Raf and MAPK (mitogen-activated protein kinase) at the levels of transcripts and proteins was observed. The LDH assay showed modulation of LDH4 and LDH5 isoforms in the lymph nodes of NHL patients. Interpretation & conclusions: The histological observations suggested that the patients represent diverse cases of NHL like mature B-cell type, mature T-cell type and high grade diffuse B-cell type NHL. The findings indicate that patients with NHL may also be analyzed for status of PAX5, CD19 and ZAP70, and their transcriptional and post-translational variants for the differential diagnosis of NHL and therapy.
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Affiliation(s)
- Brij Bharti
- Department of Zoology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Sachin Shukla
- Department of Zoology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Ratnakar Tripathi
- Department of Zoology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Suman Mishra
- Department of Zoology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Mohan Kumar
- Department of Pathology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Manoj Pandey
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Rajnikant Mishra
- Department of Zoology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
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7
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Karpel-Massler G, Horst BA, Shu C, Chau L, Tsujiuchi T, Bruce JN, Canoll P, Greene LA, Angelastro JM, Siegelin MD. A Synthetic Cell-Penetrating Dominant-Negative ATF5 Peptide Exerts Anticancer Activity against a Broad Spectrum of Treatment-Resistant Cancers. Clin Cancer Res 2016; 22:4698-711. [PMID: 27126996 DOI: 10.1158/1078-0432.ccr-15-2827] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 04/09/2016] [Indexed: 12/20/2022]
Abstract
PURPOSE Despite significant progress in cancer research, many tumor entities still have an unfavorable prognosis. Activating transcription factor 5 (ATF5) is upregulated in various malignancies and promotes apoptotic resistance. We evaluated the efficacy and mechanisms of the first described synthetic cell-penetrating inhibitor of ATF5 function, CP-d/n-ATF5-S1. EXPERIMENTAL DESIGN Preclinical drug testing was performed in various treatment-resistant cancer cells and in vivo xenograft models. RESULTS CP-d/n-ATF5-S1 reduced the transcript levels of several known direct ATF5 targets. It depleted endogenous ATF5 and induced apoptosis across a broad panel of treatment-refractory cancer cell lines, sparing non-neoplastic cells. CP-d/n-ATF5-S1 promoted tumor cell apoptotic susceptibility in part by reducing expression of the deubiquitinase Usp9X and led to diminished levels of antiapoptotic Bcl-2 family members Mcl-1 and Bcl-2. In line with this, CP-d/n-ATF5-S1 synergistically enhanced tumor cell apoptosis induced by the BH3-mimetic ABT263 and the death ligand TRAIL. In vivo, CP-d/n-ATF5-S1 attenuated tumor growth as a single compound in glioblastoma, melanoma, prostate cancer, and triple receptor-negative breast cancer xenograft models. Finally, the combination treatment of CP-d/n-ATF5-S1 and ABT263 significantly reduced tumor growth in vivo more efficiently than each reagent on its own. CONCLUSIONS Our data support the idea that CP-d/n-ATF5-S1, administered as a single reagent or in combination with other drugs, holds promise as an innovative, safe, and efficient antineoplastic agent against treatment-resistant cancers. Clin Cancer Res; 22(18); 4698-711. ©2016 AACR.
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Affiliation(s)
- Georg Karpel-Massler
- Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York
| | - Basil A Horst
- Department of Dermatology, Columbia University Medical Center, New York, New York
| | - Chang Shu
- Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York
| | - Lily Chau
- Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York
| | - Takashi Tsujiuchi
- Department of Neurosurgery, Columbia University Medical Center, New York, New York
| | - Jeffrey N Bruce
- Department of Neurosurgery, Columbia University Medical Center, New York, New York
| | - Peter Canoll
- Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York
| | - Lloyd A Greene
- Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York
| | - James M Angelastro
- Department of Molecular Biosciences, University of California, Davis School of Veterinary Medicine, Davis, California.
| | - Markus D Siegelin
- Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York.
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8
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Chen D, Mao C, Zhou Y, Su Y, Liu S, Qi WQ. PF-04691502, a dual PI3K/mTOR inhibitor has potent pre-clinical activity by inducing apoptosis and G1 cell cycle arrest in aggressive B-cell non-Hodgkin lymphomas. Int J Oncol 2015; 48:253-60. [PMID: 26549638 DOI: 10.3892/ijo.2015.3231] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 10/16/2015] [Indexed: 11/05/2022] Open
Abstract
The PI3K/Akt/mTOR pathway is activated in a variety of human tumors including B-cell non-Hodgkin lymphoma (B-NHL). Targeting this pathway has been validated in solid and hematological tumors. In the present study, we demonstrated that PF-04691502, a novel PI3K/mTOR inhibitor has potent activity in a panel of aggressive B-NHL cell lines including diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). MTS analysis showed that PF-04691502 effectively inhibited cell proliferation with IC50 values ranging from 0.12 to 0.55 µM. Cells treated with PF-04691502 exhibited decreased phosphorylation of Akt and S6 ribosomal protein confirming the mechanism of action of a PI3K/mTOR inhibitor. Also, treatment of B-NHL cell lines with PF-04691502 induced apoptosis in a dose- and time-dependent manner. Moreover, PF-04691502 significantly induced G1 cell cycle arrest associated with a decrease in cyclin D1 which contributed to suppression of cell proliferation. Finally, rituximab enhanced apoptosis induced by PF-04691502. Taken together, our findings provide for the first time that PF-04691502 inhibits the constitutively activated PI3K/mTOR pathway in aggressive B-cell NHL cell lines associated with inhibition of cell cycle progression, cell proliferation and promotion of apoptosis. These findings suggest that PF-04691502 is a novel therapeutic strategy in aggressive B-cell NHL and warrants early phase clinical trial evaluation with and without rituximab.
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Affiliation(s)
- Deyu Chen
- Institute of Oncology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
| | - Chaoming Mao
- Institute of Oncology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
| | - Yuepeng Zhou
- Institute of Oncology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
| | - Yuting Su
- Institute of Oncology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
| | - Shenzha Liu
- Institute of Oncology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
| | - Wen-Qing Qi
- Institute of Oncology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
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9
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Muscaritoli M, Capria S, Iori AP, Fanelli FR. Nutritional and Metabolic Support in Haematological Malignancies and Haematopoietic Stem-Cell Transplantation. Clin Nutr 2015. [DOI: 10.1002/9781119211945.ch15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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10
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Lipchik AM, Perez M, Cui W, Parker LL. Multicolored, Tb³⁺-Based Antibody-Free Detection of Multiple Tyrosine Kinase Activities. Anal Chem 2015. [PMID: 26207839 DOI: 10.1021/acs.analchem.5b02233] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Kinase signaling is a major mechanism driving many cancers. While many inhibitors have been developed and are employed in the clinic, resistance due to crosstalk and pathway reprogramming is an emerging problem. High-throughput assays to detect multiple pathway kinases simultaneously could better model these complex relationships and enable drug development to combat this type of resistance. We developed a strategy to take advantage of time-resolved luminescence of Tb(3+)-chelated phosphotyrosine-containing peptides, which facilitated efficient energy transfer to small molecule fluorophores conjugated to the peptides to produce orthogonally colored biosensors for two different kinases. This enabled multiplexed detection with high signal-to-noise in a high-throughput-compatible format. This proof-of-concept study provides a platform that could be applied to other lanthanide metal and fluorophore combinations to achieve even greater multiplexing without the need for phosphospecific antibodies.
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Affiliation(s)
- Andrew M Lipchik
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy and Purdue Center for Cancer Research, Purdue University, 201 S. University Street, West Lafayette, Indiana 47907, United States
| | - Minervo Perez
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy and Purdue Center for Cancer Research, Purdue University, 201 S. University Street, West Lafayette, Indiana 47907, United States
| | - Wei Cui
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy and Purdue Center for Cancer Research, Purdue University, 201 S. University Street, West Lafayette, Indiana 47907, United States
| | - Laurie L Parker
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy and Purdue Center for Cancer Research, Purdue University, 201 S. University Street, West Lafayette, Indiana 47907, United States
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Huang HL, Peng CY, Lai MJ, Chen CH, Lee HY, Wang JC, Liou JP, Pan SL, Teng CM. Novel oral histone deacetylase inhibitor, MPT0E028, displays potent growth-inhibitory activity against human B-cell lymphoma in vitro and in vivo. Oncotarget 2015; 6:4976-91. [PMID: 25669976 PMCID: PMC4467128 DOI: 10.18632/oncotarget.3213] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Accepted: 12/26/2014] [Indexed: 12/16/2022] Open
Abstract
Histone deacetylase (HDAC) inhibitor has been a promising therapeutic option in cancer therapy due to its ability to induce growth arrest, differentiation, and apoptosis. In this study, we demonstrated that MPT0E028, a novel HDAC inhibitor, reduces the viability of B-cell lymphomas by inducing apoptosis and shows a more potent HDAC inhibitory effect compared to SAHA, the first HDAC inhibitor approved by the FDA. In addition to HDACs inhibition, MPT0E028 also possesses potent direct Akt targeting ability as measured by the kinome diversity screening assay. Also, MPT0E028 reduces Akt phosphorylation in B-cell lymphoma with an IC50 value lower than SAHA. Transient transfection assay revealed that both targeting HDACs and Akt contribute to the apoptosis induced by MPT0E028, with both mechanisms functioning independently. Microarray analysis also shows that MPT0E028 may regulate many oncogenes expression (e.g., TP53, MYC, STAT family). Furthermore, in vivo animal model experiments demonstrated that MPT0E028 (50-200 mg/kg, po, qd) prolongs the survival rate of mice bearing human B-cell lymphoma Ramos cells and inhibits tumor growth in BJAB xenograft model. In summary, MPT0E028 possesses strong in vitro and in vivo activity against malignant cells, representing a potential therapeutic approach for cancer therapy.
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Affiliation(s)
- Han-Li Huang
- 1 Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chieh-Yu Peng
- 2 Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
- 3 School of Pharmacy, China Medical University, Taichung, Taiwan
| | - Mei-Jung Lai
- 4 Center for Translational Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chun-Han Chen
- 1 Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hsueh-Yun Lee
- 5 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Jing-Chi Wang
- 6 The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Jing-Ping Liou
- 5 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Shiow-Lin Pan
- 6 The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Che-Ming Teng
- 1 Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan
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12
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Yu X, Long YC, Shen HM. Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy. Autophagy 2015; 11:1711-28. [PMID: 26018563 PMCID: PMC4824607 DOI: 10.1080/15548627.2015.1043076] [Citation(s) in RCA: 148] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Revised: 04/11/2015] [Accepted: 04/14/2015] [Indexed: 02/06/2023] Open
Abstract
Autophagy is an evolutionarily conserved and exquisitely regulated self-eating cellular process with important biological functions. Phosphatidylinositol 3-kinases (PtdIns3Ks) and phosphoinositide 3-kinases (PI3Ks) are involved in the autophagic process. Here we aim to recapitulate how 3 classes of these lipid kinases differentially regulate autophagy. Generally, activation of the class I PI3K suppresses autophagy, via the well-established PI3K-AKT-MTOR (mechanistic target of rapamycin) complex 1 (MTORC1) pathway. In contrast, the class III PtdIns3K catalytic subunit PIK3C3/Vps34 forms a protein complex with BECN1 and PIK3R4 and produces phosphatidylinositol 3-phosphate (PtdIns3P), which is required for the initiation and progression of autophagy. The class II enzyme emerged only recently as an alternative source of PtdIns3P and autophagic initiator. However, the orthodox paradigm is challenged by findings that the PIK3CB catalytic subunit of class I PI3K acts as a positive regulator of autophagy, and PIK3C3 was thought to be an amino acid sensor for MTOR, which curbs autophagy. At present, a number of PtdIns3K and PI3K inhibitors, including specific PIK3C3 inhibitors, have been developed for suppression of autophagy and for clinical applications in autophagy-related human diseases.
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Affiliation(s)
- Xinlei Yu
- a Department of Biochemistry; Yong Loo Lin School of Medicine, National University of Singapore ; Singapore
| | - Yun Chau Long
- a Department of Biochemistry; Yong Loo Lin School of Medicine, National University of Singapore ; Singapore
| | - Han-Ming Shen
- b Department of Physiology; Yong Loo Lin School of Medicine, National University of Singapore ; Singapore
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Abstract
INTRODUCTION Bortezomib , the first proteasome inhibitor (PI) to be evaluated in humans, is approved in the USA and Europe for the treatment of patients with multiple myeloma, and in the USA for patients with relapsed mantle cell lymphoma (MCL). AREAS COVERED This review examines the role of bortezomib in the therapy of non-Hodgkin's lymphoma (NHL). Bortezomib may be particularly effective against the NF-κB-dependent activated B-cell subtype of diffuse large B-cell lymphoma. The combination of bortezomib with rituximab and dexamethasone represents a standard approach for the treatment of Waldenström's macroglobulinemia, and that with bendamustine and rituximab has demonstrated excellent efficacy in follicular lymphoma. Combinations with other novel agents, such as inhibitors of cyclin-dependent kinases or histone deacetylases, also hold substantial promise in NHL. Unmet needs in NHL, competitor compounds, chemistry, pharmacokinetics, pharmacodynamics and safety and tolerability of bortezomib are also discussed. EXPERT OPINION The success of bortezomib in MCL has validated the proteasome as a therapeutic target in NHL. Rational combinations, for example, with Bruton's tyrosine kinase inhibitors or BH3-mimetics, may hold the key to optimizing the therapeutic potential of PIs in NHL. Future trials are likely to involve newer agents with improved pharmacodynamic (e.g., carfilzomib, marizomib) or pharmacokinetic (e.g., ixazomib, oprozomib) properties.
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Affiliation(s)
- Prithviraj Bose
- Virginia Commonwealth University, Massey Cancer Center, Richmond, VA, USA
- Virginia Commonwealth University, Department of Internal Medicine, Richmond, VA, USA
| | - Michael S. Batalo
- Virginia Commonwealth University, Department of Internal Medicine, Richmond, VA, USA
| | - Beata Holkova
- Virginia Commonwealth University, Massey Cancer Center, Richmond, VA, USA
- Virginia Commonwealth University, Department of Internal Medicine, Richmond, VA, USA
| | - Steven Grant
- Virginia Commonwealth University, Massey Cancer Center, Richmond, VA, USA
- Virginia Commonwealth University, Department of Internal Medicine, Richmond, VA, USA
- Virginia Commonwealth University, Department of Microbiology and Immunology, Richmond, VA, USA
- Virginia Commonwealth University, Department of Biochemistry and Molecular Biology, Richmond, VA, USA
- Virginia Commonwealth University, Department of Human and Molecular Genetics, Richmond, VA, USA
- Virginia Commonwealth University, Institute for Molecular Medicine, 401 College Street, P.O. Box 980035, Richmond, VA 23298, USA Tel: +1 804 828 5211
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Endosonography for the Diagnosis of Malignant Lymphoma Presenting With Mediastinal Lymphadenopathy. J Bronchology Interv Pulmonol 2014; 21:298-305. [DOI: 10.1097/lbr.0000000000000093] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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15
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Tarella C, Gueli A, Delaini F, Rossi A, Barbui AM, Gritti G, Boschini C, Caracciolo D, Bruna R, Ruella M, Gottardi D, Passera R, Rambaldi A. Rate of primary refractory disease in B and T-cell non-Hodgkin's lymphoma: correlation with long-term survival. PLoS One 2014; 9:e106745. [PMID: 25255081 PMCID: PMC4177839 DOI: 10.1371/journal.pone.0106745] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Accepted: 08/01/2014] [Indexed: 01/27/2023] Open
Abstract
Background Primary refractory disease is a main challenge in the management of non-Hodgkin’s Lymphoma (NHL). This survey was performed to define the rate of refractory disease to first-line therapy in B and T-cell NHL subtypes and the long-term survival of primary refractory compared to primary responsive patients. Methods Medical records were reviewed of 3,106 patients who had undergone primary treatment for NHL between 1982 and 2012, at the Hematology Centers of Torino and Bergamo, Italy. Primary treatment included CHOP or CHOP-like regimens (63.2%), intensive therapy with autograft (16.9%), or other therapies (19.9%). Among B-cell NHL, 1,356 (47.8%) received first-line chemotherapy with rituximab. Refractory disease was defined as stable/progressive disease, or transient response with disease progression within six months. Results Overall, 690 (22.2%) patients showed primary refractory disease, with a higher incidence amongst T-cell compared to B-cell NHL (41.9% vs. 20.5%, respectively, p<0.001). Several other clinico-pathological factors at presentation were variably associated with refractory disease, including histological aggressive disease, unfavorable clinical presentation, Bone Marrow involvement, low lymphocyte/monocyte ration and male gender. Amongst B-cell NHL, the addition of rituximab was associated with a marked reduction of refractory disease (13.6% vs. 26.7% for non-supplemented chemotherapy, p<0.001). Overall, primary responsive patients had a median survival of 19.8 years, compared to 1.3 yr. for refractory patients. A prolonged survival was consistently observed in all primary responsive patients regardless of the histology. The long life expectancy of primary responsive patients was documented in both series managed before and after 2.000. Response to first line therapy resulted by far the most predictive factor for long-term outcome (HR for primary refractory disease: 16.52, p<0.001). Conclusion Chemosensitivity to primary treatment is crucial for the long-term survival in NHL. This supports the necessity of studies aimed to early identify refractory disease and to develop different treatment strategies for responsive and refractory patients.
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Affiliation(s)
- Corrado Tarella
- Department of Biotechnology and Life Sciences, University of Torino, Torino, Italy
- Hematology and Cell Therapy Division, Mauriziano Hospital, Torino, Italy
- * E-mail:
| | - Angela Gueli
- Department of Biotechnology and Life Sciences, University of Torino, Torino, Italy
- Hematology and Cell Therapy Division, Mauriziano Hospital, Torino, Italy
| | - Federica Delaini
- Hematology and Bone Marrow Transplant Units, A. O. Papa Giovanni XXIII, Bergamo, Italy
| | - Andrea Rossi
- Hematology and Bone Marrow Transplant Units, A. O. Papa Giovanni XXIII, Bergamo, Italy
| | - Anna Maria Barbui
- Hematology and Bone Marrow Transplant Units, A. O. Papa Giovanni XXIII, Bergamo, Italy
| | - Giuseppe Gritti
- Hematology and Bone Marrow Transplant Units, A. O. Papa Giovanni XXIII, Bergamo, Italy
| | - Cristina Boschini
- Hematology and Bone Marrow Transplant Units, A. O. Papa Giovanni XXIII, Bergamo, Italy
| | - Daniele Caracciolo
- Department of Biotechnology and Life Sciences, University of Torino, Torino, Italy
- Division of Hematology I, A. O. Città della Salute, Torino, Italy
| | - Riccardo Bruna
- Department of Biotechnology and Life Sciences, University of Torino, Torino, Italy
- Hematology and Cell Therapy Division, Mauriziano Hospital, Torino, Italy
| | - Marco Ruella
- Department of Biotechnology and Life Sciences, University of Torino, Torino, Italy
- Hematology and Cell Therapy Division, Mauriziano Hospital, Torino, Italy
| | - Daniela Gottardi
- Department of Biotechnology and Life Sciences, University of Torino, Torino, Italy
- Hematology and Cell Therapy Division, Mauriziano Hospital, Torino, Italy
| | - Roberto Passera
- Division of Nuclear Medicine, University of Torino, Torino, Italy
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Hayden RE, Kussaibati R, Cronin LM, Pratt G, Roberts C, Drayson MT, Bunce CM. Bezafibrate and medroxyprogesterone acetate target resting and CD40L-stimulated primary marginal zone lymphoma and show promise in indolent B-cell non-Hodgkin lymphomas. Leuk Lymphoma 2014; 56:1079-87. [DOI: 10.3109/10428194.2014.939962] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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17
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Hong JY, Hong ME, Choi MK, Kim YS, Chang W, Maeng CH, Park S, Lee SJ, Do IG, Jo JS, Jung SH, Kim SJ, Ko YH, Kim WS. The impact of activated p-AKT expression on clinical outcomes in diffuse large B-cell lymphoma: a clinicopathological study of 262 cases. Ann Oncol 2014; 25:182-8. [PMID: 24356628 DOI: 10.1093/annonc/mdt530] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Oncogenic phosphatidylinositol-3-kinase/serine-threonine kinase (PI3K/AKT) pathway plays a critical role in cell proliferation and growth. Phosphorylated AKT (p-AKT) has been reported to be abnormally overexpressed and to have poor prognostic impact in solid tumors. PATIENTS AND METHODS To define the clinical implications of p-AKT expression in diffuse large B-cell lymphoma (DLBCL), we calculated arbitrary units (AUs) by multiplying the intensity and the proportion of p-AKT expression and investigated the impact of p-AKT expression on clinical outcomes. We assessed 262 patients with DLBCL. Based on a cutoff value of the upper limit of the third quartile of AUs, 56 patients were classified as high p-AKT and the remaining 206 patients were classified as low p-AKT. RESULTS The high p-AKT group was closely associated with more advanced stage (stage III-IV, P = 0.02), two or more extranodal involvement (P = 0.03), lactic dehydrogenase elevation (P = 0.03), higher International Prognostic Index risk groups (high intermediate/high, P = 0.02), and the presence of B-symptoms (P = 0.01). The high p-AKT group showed substantially worse overall survival (OS) (median OS, 115.0 months versus not reached, P = 0.004) and progression-free survival (PFS) (median PFS, 25.5 versus 105.8 months, P = 0.019) compared with the low p-AKT group. Multivariate analysis revealed that high p-AKT expression retained its significant poor prognostic impact for OS (hazard ratio 1.7; 95% confidence interval, 1.0-2.7; P = 0.031). The subgroup with high p-AKT expression and concurrent Epstein-Barr virus positivity showed worst prognosis with the median OS and PFS of 15.2 and 7.4 months. CONCLUSION DLBCL patients with high p-AKT expression showed distinct clinical features and followed a more rapidly deteriorating clinical course with worse OS and PFS. Thus, a more effective treatment option should be developed for this subset of DLBCL patients, and targeting PI3K/AKT pathway may be a promising therapeutic strategy.
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Affiliation(s)
- J Y Hong
- Division of Hematology-Oncology, Department of Medicine and
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18
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Oki Y, Buglio D, Fanale M, Fayad L, Copeland A, Romaguera J, Kwak LW, Pro B, de Castro Faria S, Neelapu S, Fowler N, Hagemeister F, Zhang J, Zhou S, Feng L, Younes A. Phase I study of panobinostat plus everolimus in patients with relapsed or refractory lymphoma. Clin Cancer Res 2013; 19:6882-90. [PMID: 24097867 DOI: 10.1158/1078-0432.ccr-13-1906] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE To evaluate the safety and efficacy of panobinostat plus everolimus in patients with relapsed Hodgkin and non-Hodgkin lymphoma. The concept was supported by the single-agent clinical activity of histone deacetylase inhibitors and mTOR inhibitors, and on the in vitro mechanism-based synergistic antiproliferative activity. EXPERIMENTAL DESIGN This was a phase I study in patients with relapsed or refractory Hodgkin and non-Hodgkin lymphoma using panobinostat orally on Monday/Wednesday/Friday and everolimus orally daily. Toxicity and responses were assessed in dose-escalation cohort followed by expansion cohort at maximum-tolerated dose. Exploratory analysis of serum cytokine levels was performed. RESULTS Thirty patients were enrolled onto four dose levels. The dose-limiting toxicity was thrombocytopenia. The maximal tolerated dose was panobinostat 20 mg and everolimus 10 mg. Grade 3/4 toxicity included thrombocytopenia (64%), neutropenia (47%), anemia (20%), infection (10%), fatigue (7%), and dyspnea (7%). A total of 10 patients (33%; indolent lymphoma, T-cell lymphoma, mantle cell lymphoma, and Hodgkin lymphoma) achieved objective responses. In patients with Hodgkin lymphoma (n = 14), the overall response rate was 43% with complete response rate of 15%. In patients with Hodgkin lymphoma, multiple serum cytokine levels decreased significantly after treatment with this combination therapy. Of note, clinical responses were associated with a decrease in serum interleukin-5 levels (day 8, P = 0.013, and day 15, P = 0.021). CONCLUSIONS Our data suggest that the combination therapy is active but with significant thrombocytopenia. Future studies should explore alternate scheduling and different compounds that target the same pathways to improve the tolerability of this novel combination.
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Affiliation(s)
- Yasuhiro Oki
- Authors' Affiliations: Departments of Lymphoma/Myeloma, Diagnostic Imaging, and Biostatistics, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas
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Puvvada S, Kendrick S, Rimsza L. Molecular classification, pathway addiction, and therapeutic targeting in diffuse large B cell lymphoma. Cancer Genet 2013; 206:257-65. [PMID: 24080457 DOI: 10.1016/j.cancergen.2013.07.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Revised: 07/22/2013] [Accepted: 07/24/2013] [Indexed: 11/16/2022]
Abstract
The rapid emergence of molecularly based techniques to detect changes in the genetic landscape of diffuse large B cell lymphoma (DLBCL), including gene expression, DNA and RNA sequencing, and epigenetic profiling, has significantly influenced the understanding and therapeutic targeting of DLBCL. In this review, we briefly discuss the new methods used in the study of DLBCL. We describe the influence of the generated data on DLBCL classification and the identification of new entities and altered cell survival strategies, with a focus on the renewed interest in some classic oncogenic pathways that are currently targeted for new therapy. Finally, we examine the molecular genomic studies that revealed the importance of the tumor microenvironment in the pathogenesis of DLBCL.
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Affiliation(s)
- Soham Puvvada
- Department of Medicine, Division of Hematology-Oncology, University of Arizona, Tucson, AZ, USA.
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20
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Anti-tumor activity of obinutuzumab and rituximab in a follicular lymphoma 3D model. Blood Cancer J 2013; 3:e131. [PMID: 23933705 PMCID: PMC3763386 DOI: 10.1038/bcj.2013.32] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Revised: 07/03/2013] [Accepted: 07/15/2013] [Indexed: 11/23/2022] Open
Abstract
Follicular lymphomas (FLs) account for 35–40% of all adult lymphomas. Treatment typically involves chemotherapy combined with the anti-CD20 monoclonal antibody (MAb) rituximab (RTX). The development of the type II anti-CD20 MAb obinutuzumab (GA101) aims to further improve treatment. Here, using FL cells we show that RTX and GA101 display a similar activity on RL cells cultured in 2D. However, 2D culture cannot mimic tumor spatial organization and conventional 2D models may not reflect the effects of antibodies as they occur in vivo. Thus, we created a non-Hodgkin's lymphoma (NHL) 3D culture system, termed multicellular aggregates of lymphoma cells (MALC), and used it to compare RTX and GA101 activity. Our results show that both antibodies display greater activity towards FL cells in 3D culture compared with 2D culture. Moreover, we observed that in the 3D model GA101 was more effective than RTX both in inhibiting MALC growth through induction of (lysosomal) cell death and senescence and in inhibiting intracellular signaling pathways, such as mammalian target of rapamycin, Akt, PLCgamma (Phospholipase C gamma) and Syk. Altogether, our study demonstrates that spatial organization strongly influences the response to antibody treatment, supporting the use of 3D models for the testing of therapeutic agents in NHL.
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An integrated computational/experimental model of lymphoma growth. PLoS Comput Biol 2013; 9:e1003008. [PMID: 23555235 PMCID: PMC3610621 DOI: 10.1371/journal.pcbi.1003008] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Accepted: 02/13/2013] [Indexed: 12/27/2022] Open
Abstract
Non-Hodgkin's lymphoma is a disseminated, highly malignant cancer, with resistance to drug treatment based on molecular- and tissue-scale characteristics that are intricately linked. A critical element of molecular resistance has been traced to the loss of functionality in proteins such as the tumor suppressor p53. We investigate the tissue-scale physiologic effects of this loss by integrating in vivo and immunohistological data with computational modeling to study the spatiotemporal physical dynamics of lymphoma growth. We compare between drug-sensitive Eμ-myc Arf-/- and drug-resistant Eμ-myc p53-/- lymphoma cell tumors grown in live mice. Initial values for the model parameters are obtained in part by extracting values from the cellular-scale from whole-tumor histological staining of the tumor-infiltrated inguinal lymph node in vivo. We compare model-predicted tumor growth with that observed from intravital microscopy and macroscopic imaging in vivo, finding that the model is able to accurately predict lymphoma growth. A critical physical mechanism underlying drug-resistant phenotypes may be that the Eμ-myc p53-/- cells seem to pack more closely within the tumor than the Eμ-myc Arf-/- cells, thus possibly exacerbating diffusion gradients of oxygen, leading to cell quiescence and hence resistance to cell-cycle specific drugs. Tighter cell packing could also maintain steeper gradients of drug and lead to insufficient toxicity. The transport phenomena within the lymphoma may thus contribute in nontrivial, complex ways to the difference in drug sensitivity between Eμ-myc Arf-/- and Eμ-myc p53-/- tumors, beyond what might be solely expected from loss of functionality at the molecular scale. We conclude that computational modeling tightly integrated with experimental data gives insight into the dynamics of Non-Hodgkin's lymphoma and provides a platform to generate confirmable predictions of tumor growth. Non-Hodgkin's lymphoma is a cancer that develops from white blood cells called lymphocytes in the immune system, whose role is to fight disease throughout the body. This cancer can spread throughout the whole body and be very lethal – in the US, one third of patients will die from this disease within five years of diagnosis. Chemotherapy is a usual treatment for lymphoma, but the cancer can become highly resistant to it. One reason is that a critical gene called p53 can become mutated and help the cancer to survive. In this work we investigate how cells with this mutation affect the cancer growth by performing experiments in mice and using a computer model. By inputting the model parameters based on data from the experiments, we are able to accurately predict the growth of the tumor as compared to tumor measurements in living mice. We conclude that computational modeling integrated with experimental data gives insight into the dynamics of Non-Hodgkin's lymphoma, and provides a platform to generate confirmable predictions of tumor growth.
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Lipchik AM, Parker LL. Time-resolved luminescence detection of spleen tyrosine kinase activity through terbium sensitization. Anal Chem 2013; 85:2582-8. [PMID: 23414415 DOI: 10.1021/ac3023422] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Disruption of regulatory protein phosphorylation can lead to disease and is particularly prevalent in cancers. Inhibitors that target deregulated kinases are therefore a major focus of chemotherapeutic development. Achieving sensitivity and specificity in high-throughput compatible kinase assays is key to successful inhibitor development. Here, we describe the application of time-resolved luminescence detection to the direct sensing of spleen tyrosine kinase (Syk) activity and inhibition using a novel peptide substrate. Chelation and luminescence sensitization of Tb(3+) allowed the direct detection of peptide phosphorylation without any antibodies or other labeling reagents. Characterizing the Tb(3+) coordination properties of the phosphorylated vs unphosphorylated form of the peptide revealed that an inner-sphere water was displaced upon phosphorylation, which likely was responsible for both enhancing the luminescence intensity and also extending the lifetime, which enabled gating of the luminescence signal to improve the dynamic range. Furthermore, a shift in the optimal absorbance maximum for excitation was observed, from 275 nm (for the unphosphorylated tyrosine peptide) to 266 nm (for the phosphorylated tyrosine peptide). Accordingly, time-resolved measurements with excitation at 266 nm via a monochromator enabled a 16-fold improvement in base signal-to-noise for distinguishing phosphopeptide from unphosphorylated peptide. This led to a high degree of sensitivity and quantitative reproducibility, demonstrating the amenability of this method to both research laboratory and high-throughput applications.
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Affiliation(s)
- Andrew M Lipchik
- Department of Medicinal Chemistry and Molecular Pharmacology and Purdue Center for Cancer Research, Purdue University, 201 S. University Street, West Lafayette, Indiana 47907, United States
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Mahadevan D, Unger JM, Spier CM, Persky DO, Young F, LeBlanc M, Fisher RI, Miller TP. Phase 2 trial of combined cisplatin, etoposide, gemcitabine, and methylprednisolone (PEGS) in peripheral T-cell non-Hodgkin lymphoma: Southwest Oncology Group Study S0350. Cancer 2013; 119:371-9. [PMID: 22833464 PMCID: PMC3485430 DOI: 10.1002/cncr.27733] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2012] [Revised: 06/04/2012] [Accepted: 06/06/2012] [Indexed: 12/28/2022]
Abstract
BACKGROUND Patients with peripheral T-cell lymphomas (PTCLs) have inferior progression-free survival (PFS) and overall survival (OS) compared with patients who have aggressive B-cell non-Hodgkin lymphoma. Because PTCLs over express multidrug resistance gene 1/P-glycoprotein (MDR-1/P-gp), we devised platinum, etoposide, gemcitabine, and methylprednisolone (PEGS) with agents that are not substrates of the efflux pump. Gemcitabine was included because of its excellent single-agent activity in PTCL. METHODS Patients who had PTCL with stage II bulky disease, stage III or IV disease with extra-nodal, nodal, and transformed cutaneous presentations were eligible. Patients received intravenous cisplatin 25 mg/m(2) on days 1 through 4, etoposide 40 mg/m(2) on days 1 through 4, gemcitabine 1000 mg/m(2) on day 1, and methylprednisolone 250 mg on days 1 through 4 of a 21-day cycle for 6 cycles. RESULTS In total, 34 patients were enrolled, 33 were eligible, and 79% were newly diagnosed. Histologic types were PTCL not otherwise specified (n = 15), anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (n = 4), angioimmunoblastic T-cell lymphoma (n = 6), or other T-cell non-Hodgkin lymphomas (n = 8). Adverse events included 1 grade 5 infection with grade 3 or 4 neutropenia and 9 grade 4 hematologic toxicities. The overall response rate was 39% (47% in PTCL not otherwise specified, 33% in angioimmunoblastic T-cell lymphoma, 25% in ALK-negative and 38% in other T-cell non-Hodgkin lymphomas). The PFS rate at 2 years was 12% (95% confidence interval, 0.1%-31%), and the median PFS was 7 months. The OS rate at 2 years was 30% (95% confidence interval, 8%-54%), and the median OS was 17 months. Immunohistochemical analysis of P-gp expression revealed strong positivity in a subset of lymphoma cells (n = 6) and tumor endothelium (n = 25). CONCLUSIONS Overall, PEGS was well tolerated, but OS was not considered promising given the design-specified targets. These results may serve as a benchmark for future comparisons for non-CHOP regimens.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
- Adult
- Aged
- Aged, 80 and over
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Cisplatin/administration & dosage
- Deoxycytidine/administration & dosage
- Deoxycytidine/analogs & derivatives
- Disease-Free Survival
- Etoposide/administration & dosage
- Female
- Humans
- Kaplan-Meier Estimate
- Lymphoma, T-Cell, Peripheral/drug therapy
- Lymphoma, T-Cell, Peripheral/metabolism
- Lymphoma, T-Cell, Peripheral/mortality
- Lymphoma, T-Cell, Peripheral/pathology
- Male
- Methylprednisolone/administration & dosage
- Middle Aged
- Neoplasm Staging
- Treatment Outcome
- Young Adult
- Gemcitabine
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Affiliation(s)
- Daruka Mahadevan
- Section of Hematology, University of Arizona/Arizona Cancer Center, Tucson, Arizona 85724, USA.
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Karanikas M, Machairiotis N, Zarogoulidis P, Stylianaki A, Corcoutsakis N, Mitrakas A, Touzopoulos P, Lyratzopoulos N, Kouklakis G, Spanoudakis M, Polychronidis A. Non-Hodgkin lymphoma and GIST: molecular pathways and clinical expressions. Onco Targets Ther 2012; 5:433-8. [PMID: 23251094 PMCID: PMC3525048 DOI: 10.2147/ott.s38645] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
We report the case of a 64-year-old woman with a gastrointestinal stromal tumor and a diffuse large cell lymphoma. For this case, we conducted a literature review in an attempt to correlate these two neoplasms on a molecular basis. Diffuse large cell lymphoma is a subtype of non-Hodgkin lymphomas. The etiologic factor of these lymphomas is considered to be the mutations or allelic losses of the TP53 tumor suppressor gene and the overexpression of the bcl-2 oncogene. Gastrointestinal stromal tumors are mesenchymal tumors, which are typically defined by the expression of c-KIT (CD117) and CD34 genes in the tumor cells. Although there are references to dispersants in the literature about patients with both non-Hodgkin lymphoma and gastrointestinal stromal tumors, there is no common molecular pathway between these two diseases. In conclusion, there is no indication that these two neoplasms are relevant on a molecular basis.
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Affiliation(s)
- Michael Karanikas
- 1st University Surgery Department, University General Hospital of Alexandroupolis, Alexandroupolis, Greece
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Datta S, Chatterjee S, Policegoudra RS, Gogoi HK, Singh L. Hepatitis viruses and non-Hodgkin’s lymphoma: A review. World J Virol 2012; 1:162-73. [PMID: 24175222 PMCID: PMC3782277 DOI: 10.5501/wjv.v1.i6.162] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2011] [Revised: 06/06/2012] [Accepted: 11/07/2012] [Indexed: 02/05/2023] Open
Abstract
Non-Hodgkin’s lymphoma (NHL) is among the haematological malignancies with high prevalence worldwide, causing estimated 355 900 new cases and 191 400 deaths in 2008. High prevalence of NHL is documented in economically more developed areas while low prevalence is observed in less developed areas of the globe. A wide array of environmental factors have been reported to be either directly involved or in modifying the risk of NHL development. In addition to these factors, a number of infectious agents, chiefly viruses have also been implicated in the development of NHL. This article reviews the available literature to discuss the role of hepatitis viruses in NHL development, possible mechanisms of lymphomagenesis and also identify the areas in which further research is required to better understand this disease. A brief discussion on the clinical aspects such as classification, staging, treatment approaches have also been included in this article.
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Affiliation(s)
- Sibnarayan Datta
- Sibnarayan Datta, Soumya Chatterjee, Rudragoud S Policegoudra, Hemant K Gogoi, Lokendra Singh, Biotechnology Division, Defence Research Laboratory, Tezpur, Assam, PIN-784001, India
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Alisertib (MLN8237) an investigational agent suppresses Aurora A and B activity, inhibits proliferation, promotes endo-reduplication and induces apoptosis in T-NHL cell lines supporting its importance in PTCL treatment. Leuk Res 2012; 37:434-9. [PMID: 23153524 DOI: 10.1016/j.leukres.2012.10.017] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2012] [Revised: 10/15/2012] [Accepted: 10/21/2012] [Indexed: 11/20/2022]
Abstract
Peripheral T-cell lymphomas (PTCL) are a diverse group of rare non-Hodgkin lymphomas (NHL) that carry a poor prognosis and are in need of effective therapies. Alisertib (MLN8237) an investigational agent that inhibits Aurora A Ser/Thr kinase has shown activity in PTCL patients. Here we demonstrate that aurora A and B are highly expressed in T-cell lymphoma cell lines. In PTCL patient samples aurora A was positive in 3 of 24 samples and co-expressed with aurora B. Aurora B was positive in tumor cells in 22 of 32 samples. Of the subtypes of PTCL, aurora B was over-expressed in PTCL (NOS) [73%], T-NHL [100%], ALCL (Alk-Neg) [100%] and AITL [100%]. Treatment with MLN8237 inhibited PTCL cell proliferation in CRL-2396 and TIB-48 cells with an IC50 of 80-100nM. MLN8237 induced endo-reduplication in a dose and time dependent manner in PTCL cell lines leading to apoptosis demonstrated by flow cytometry and PARP-cleavage at concentrations achieved in early phase clinical trials. Moreover, inhibition of HisH3 and aurora A phosphorylation was dose dependent and strongly correlated with endo-reduplication. The data provide a sound rationale for aurora inhibition in PTCL as a therapeutic modality and warrants clinical trial evaluation.
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Diffuse large B cell lymphoma: molecular targeted therapy. Int J Hematol 2012; 96:552-61. [DOI: 10.1007/s12185-012-1198-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2012] [Revised: 09/28/2012] [Accepted: 09/30/2012] [Indexed: 12/15/2022]
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Inhibition of proliferation and survival of diffuse large B-cell lymphoma cells by a small-molecule inhibitor of the ubiquitin-conjugating enzyme Ubc13-Uev1A. Blood 2012; 120:1668-77. [PMID: 22791293 DOI: 10.1182/blood-2012-02-406074] [Citation(s) in RCA: 104] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma, remains a partially curable disease. Genetic alterations affecting components of NF-κB signaling pathways occur frequently in DLBCL. Almost all activated B cell-like (ABC) DLBCL, which is the least curable group among the 3 major subtypes of this malignancy, and a substantial fraction of germinal center B cell-like (GCB) DLBCL exhibit constitutive NF-κB pathway activity. It has been demonstrated that ABC-DLBCL cells require such activity for proliferation and survival. Therefore, inhibition of NF-κB activation in DLBCL may provide an efficient and targeted therapy. In screening for small-molecule compounds that may inhibit NF-κB activation in DLBCL cells, we identified a compound, NSC697923, which inhibits the activity of the ubiquitin-conjugating (E2) enzyme Ubc13-Uev1A. NSC697923 impedes the formation of the Ubc13 and ubiquitin thioester conjugate and suppresses constitutive NF-κB activity in ABC-DLBCL cells. Importantly, NSC697923 inhibits the proliferation and survival of ABC-DLBCL cells and GCB-DLBCL cells, suggesting the Ubc13-Uev1A may be crucial for DLBCL growth. Consistently, knockdown of Ubc13 expression also inhibited DLBCL cell survival. The results of the present study indicate that Ubc13-Uev1A may represent a potential therapeutic target in DLBCL. In addition, compound NSC697923 may be exploited for the development of DLBCL therapeutic agents.
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Affiliation(s)
- Emily J Guerard
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
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Mahadevan D, Stejskal A, Cooke LS, Manziello A, Morales C, Persky DO, Fisher RI, Miller TP, Qi W. Aurora A inhibitor (MLN8237) plus vincristine plus rituximab is synthetic lethal and a potential curative therapy in aggressive B-cell non-Hodgkin lymphoma. Clin Cancer Res 2012; 18:2210-9. [PMID: 22374334 DOI: 10.1158/1078-0432.ccr-11-2413] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
PURPOSE Aurora A and B are oncogenic serine/threonine kinases that regulate mitosis. Overexpression of Auroras promotes resistance to microtubule-targeted agents. We investigated mechanistic synergy by inhibiting the mitotic spindle apparatus in the presence of MLN8237 [M], an Aurora A inhibitor with either vincristine [MV] or docetaxel [MD] in aggressive B-cell non-Hodgkin lymphoma (B-NHL). The addition of rituximab [R] to MV or MD was evaluated for synthetic lethality. EXPERIMENTAL DESIGN Aggressive B-NHL cell subtypes were evaluated in vitro and in vivo for target modulation and anti-NHL activity with single agents, doublets, and triplets by analyzing cell proliferation, apoptosis, tumor growth, survival, and mechanisms of response/relapse by gene expression profiling with protein validation. RESULTS MV is synergistic whereas MD is additive for cell proliferation inhibition in B-NHL cell culture models. Addition of rituximab to MV is superior to MD, but both significantly induce apoptosis compared with doublet therapy. Mouse xenograft models of mantle cell lymphoma showed modest single-agent activity for MLN8237, rituximab, docetaxel, and vincristine with tumor growth inhibition (TGI) of approximately 10% to 15%. Of the doublets, MV caused tumor regression, whereas TGI was observed with MD (approximately 55%-60%) and MR (approximately 25%-50%), respectively. Although MV caused tumor regression, mice relapsed 20 days after stopping therapy. In contrast, MVR was curative, whereas MDR led to TGI of approximately 85%. Proliferation cell nuclear antigen, Aurora B, cyclin B1, cyclin D1, and Bcl-2 proteins of harvested tumors confirmed response and resistance to therapy. CONCLUSIONS Addition of rituximab to MV is a novel therapeutic strategy for aggressive B-NHL and warrants clinical trial evaluation.
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Affiliation(s)
- Daruka Mahadevan
- Arizona Cancer Center, the University of Arizona, Tucson, Arizona 85724, USA.
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Winer ES, Ingham RR, Castillo JJ. PCI-32765: a novel Bruton's tyrosine kinase inhibitor for the treatment of lymphoid malignancies. Expert Opin Investig Drugs 2012; 21:355-61. [PMID: 22300471 DOI: 10.1517/13543784.2012.656199] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION There has been a significant paradigm shift in the manner in which lymphoid malignancies are treated and managed. Treatment has been moving away from conventional chemotherapy and towards targeted therapy. The success of new classes of agents such as monoclonal antibodies, proteasome inhibitors and immunomodulatory derivatives has sparked further searches for novel pathways to inhibit. The Bruton's tyrosine kinase (Btk) pathway is a downstream mediator of the B-cell receptor (BCR) pathway, which is crucial in B-cell production and maintenance, and a potential therapeutic target. AREAS COVERED This review will summarize the current knowledge of the Btk pathway and its role in lymphoid malignancies. It will also discuss the present data about PCI-32765 in both the preclinical and clinical setting. EXPERT OPINION PCI-32765 is an oral irreversible Btk inhibitor with high potency and both preclinical and clinical activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL). Phase I studies have demonstrated that it is well tolerated and has an excellent safety profile. Further studies are ongoing as a single agent and in combination with other targeted and conventional therapies. PCI-32765 is a very promising targeted therapy, and the data from these trials will ultimately decide its future role and success.
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Affiliation(s)
- Eric S Winer
- Division of Hematology/Oncology, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA.
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Blanc V, Bousseau A, Caron A, Carrez C, Lutz RJ, Lambert JM. SAR3419: an anti-CD19-Maytansinoid Immunoconjugate for the treatment of B-cell malignancies. Clin Cancer Res 2012; 17:6448-58. [PMID: 22003072 DOI: 10.1158/1078-0432.ccr-11-0485] [Citation(s) in RCA: 136] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
SAR3419 is a novel anti-CD19 humanized monoclonal antibody conjugated to a maytansine derivate through a cleavable linker for the treatment of B-cell malignancies. SAR3419 combines the strengths of a high-potency tubulin inhibitor and the exquisite B-cell selectivity of an anti-CD19 antibody. The internalization and processing of SAR3419, following its binding at the surface of CD19-positive human lymphoma cell lines and xenograft models, release active metabolites that trigger cell-cycle arrest and apoptosis, leading to cell death and tumor regression. SAR3419 has also been shown to be active in different lymphoma xenograft models, including aggressive diffuse large B-cell lymphoma, resulting in complete regressions and tumor-free survival. In these models, the activity of SAR3419 compared favorably with rituximab and lymphoma standard of care chemotherapy. Two phase I trials with 2 different schedules of SAR3419 as a single agent were conducted in refractory/relapsed B-cell non-Hodgkin lymphoma. Activity was reported in both schedules, in heavily pretreated patients of both follicular and diffuse large B-cell lymphoma subtypes, with a notable lack of significant hematological toxicity, validating SAR3419 as an effective antibody-drug conjugate and opening opportunities in the future. Numerous B-cell-specific anti-CD19 biologics are available to treat B-cell non-Hodgkin lymphoma, and early phase I results obtained with SAR3419 suggest that it is a promising candidate for further development in this disease. In addition, thanks to the broad expression of CD19, SAR3419 may provide treatment options for B-cell leukemias that are often CD20-negative.
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Affiliation(s)
- Veronique Blanc
- Oncology Business Division, Sanofi, Vitry sur Seine, France.
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Zhang X, Zhao L, Chen C, Yan J, Zhou C, Yue G, Tian L, Zhang M. The effect of lentivirus-mediated expression of tumor necrosis factor related apoptosis-inducing ligand and shRNA against Bcl-2 on the growth of lymphoma cells. Leuk Lymphoma 2011; 53:710-7. [PMID: 21988644 DOI: 10.3109/10428194.2011.631158] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
It has been well established that tumor necrosis factor related apoptosis-inducing ligand (TRAIL) effectively induces apoptosis in tumor cells. However, tumor resistance to TRAIL, especially of hematological tumor cells, has become a major problem in the potential use of TRAIL in clinical practice. Among many factors that contribute to TRAIL resistance, overexpression of Bcl-2 is commonly seen in many kinds of tumors, particularly in lymphoma. In this study, we developed a lentivirus system that encodes recombinant human TRAIL cDNA for overexpression and Bcl-2 shRNA for down-regulation of Bcl-2 (lenti-TRAIL-shBcl-2) simultaneously. The efficiency of recombinant lentiviruses infecting different lymphoma cell lines was assessed by flow cytometric analysis and fluorescence microscopy. Reverse transcription polymerase chain reaction and Western blot assay were carried out to evaluate the expression of TRAIL and Bcl-2 in lymphoma cells after infection. We also examined the growth inhibition effect of recombinant lentivirus on lymphoma cell proliferation by CCK-8 (Cell Counting Kit-8) assay and its effect on bystander cells by flow cytometric analysis. The results showed that lymphoma cells were effectively infected by recombinant lentivirus and that TRAIL was exogenously expressed and Bcl-2 expression was down-regulated in lymphoma cells simultaneously. Results of this study demonstrated that lenti-TRAIL-shBcl-2 induced apoptosis in bystander cells as well as infected lymphoma cells and inhibited the growth of lymphoma cells.
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Affiliation(s)
- Xudong Zhang
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, P R China
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Beckjord EB, Arora NK, Bellizzi K, Hamilton AS, Rowland JH. Sexual Well-Being Among Survivors of Non-Hodgkin Lymphoma. Oncol Nurs Forum 2011; 38:E351-9. [DOI: 10.1188/11.onf.e351-e359] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Affiliation(s)
- Richard I. Fisher
- James P. Wilmot Cancer Center, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY
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