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Giusti V, Miserocchi G, Sbanchi G, Pannella M, Hattinger CM, Cesari M, Fantoni L, Guerrieri AN, Bellotti C, De Vita A, Spadazzi C, Donati DM, Torsello M, Lucarelli E, Ibrahim T, Mercatali L. Xenografting Human Musculoskeletal Sarcomas in Mice, Chick Embryo, and Zebrafish: How to Boost Translational Research. Biomedicines 2024; 12:1921. [PMID: 39200384 PMCID: PMC11352184 DOI: 10.3390/biomedicines12081921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 08/08/2024] [Accepted: 08/14/2024] [Indexed: 09/02/2024] Open
Abstract
Musculoskeletal sarcomas pose major challenges to researchers and clinicians due to their rarity and heterogeneity. Xenografting human cells or tumor fragments in rodents is a mainstay for the generation of cancer models and for the preclinical trial of novel drugs. Lately, though, technical, intrinsic and ethical concerns together with stricter regulations have significantly curbed the employment of murine patient-derived xenografts (mPDX). In alternatives to murine PDXs, researchers have focused on embryonal systems such as chorioallantoic membrane (CAM) and zebrafish embryos. These systems are time- and cost-effective hosts for tumor fragments and near-patient cells. The CAM of the chick embryo represents a unique vascularized environment to host xenografts with high engraftment rates, allowing for ease of visualization and molecular detection of metastatic cells. Thanks to the transparency of the larvae, zebrafish allow for the tracking of tumor development and metastatization, enabling high-throughput drug screening. This review will focus on xenograft models of musculoskeletal sarcomas to highlight the intrinsic and technically distinctive features of the different hosts, and how they can be exploited to elucidate biological mechanisms beneath the different phases of the tumor's natural history and in drug development. Ultimately, the review suggests the combination of different models as an advantageous approach to boost basic and translational research.
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Affiliation(s)
- Veronica Giusti
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
| | - Giacomo Miserocchi
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (G.M.); (A.D.V.); (C.S.)
| | - Giulia Sbanchi
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
| | - Micaela Pannella
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
| | - Claudia Maria Hattinger
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
| | - Marilena Cesari
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
| | - Leonardo Fantoni
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy
| | - Ania Naila Guerrieri
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
| | - Chiara Bellotti
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
| | - Alessandro De Vita
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (G.M.); (A.D.V.); (C.S.)
| | - Chiara Spadazzi
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (G.M.); (A.D.V.); (C.S.)
| | - Davide Maria Donati
- Orthopaedic Oncology Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy;
| | - Monica Torsello
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
| | - Enrico Lucarelli
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
| | - Toni Ibrahim
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
| | - Laura Mercatali
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
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Liu XX, Han YH, Kuang BH, Lin GH, Wang BC. Novel-fosfamide monotherapy or in combination with doxorubicin versus doxorubicin alone in patients with advanced soft tissue sarcoma: A pooled analysis of randomized clinical trials. Medicine (Baltimore) 2023; 102:e34902. [PMID: 37603507 PMCID: PMC10443742 DOI: 10.1097/md.0000000000034902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 08/03/2023] [Indexed: 08/23/2023] Open
Abstract
BACKGROUND Novel-fosfamides (NFOs) belong to active metabolites of ifosfamide that bypass the generation of toxic byproducts. In this analysis, we aimed to comprehensively assess the benefits and risks of NFO monotherapy or in combination with doxorubicin (DOX) versus single-drug DOX in previously untreated patients with advanced soft-tissue sarcoma (ASTS). METHODS Online PubMed, Web of Science, Embase, and Cochrane CENTRAL databases were systematically searched on April 26, 2022. Objective response rate and disease control rate were primary outcomes. Overall survival (OS), progression-free survival (PFS), and grade ≥ 3 treatment-related adverse events were secondary outcomes. RESULTS In all, 3 randomized clinical trials with a total of 1207 ASTS patients were eligible. DOX plus NFO combination therapy showed higher risk ratios of objective response rate (1.50, 95% CI 1.20-1.68, P = .0003) and disease control rate (1.15, 95% CI 1.05-1.27, P = .0030) compared with DOX monotherapy. Nevertheless, NFO-based monotherapy and combination therapy were found no improvements on OS (hazard ratio 0.93, 95% CI 0.52-1.65, P = .8050) and PFS (hazard ratio 0.88, 95% CI 0.54-1.43, P = .6088) against DOX. More incidences of grade 3 or worse anemia, thrombocytopenia, stomatitis, diarrhea, constipation, and febrile neutropenia were observed in NFO-based treatments. CONCLUSION Adding NFO to DOX as first-line therapy improved the responses in ASTS patients but did not prolong OS and PFS. Grade 3 or worse treatment-related adverse events should be treated with caution during the NFO-based therapies.
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Affiliation(s)
- Xin-Xiu Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan-Hong Han
- Nursing Department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bo-Hua Kuang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guo-He Lin
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Bi-Cheng Wang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Law AMK, Rodriguez de la Fuente L, Grundy TJ, Fang G, Valdes-Mora F, Gallego-Ortega D. Advancements in 3D Cell Culture Systems for Personalizing Anti-Cancer Therapies. Front Oncol 2021; 11:782766. [PMID: 34917509 PMCID: PMC8669727 DOI: 10.3389/fonc.2021.782766] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 11/11/2021] [Indexed: 01/09/2023] Open
Abstract
Over 90% of potential anti-cancer drug candidates results in translational failures in clinical trials. The main reason for this failure can be attributed to the non-accurate pre-clinical models that are being currently used for drug development and in personalised therapies. To ensure that the assessment of drug efficacy and their mechanism of action have clinical translatability, the complexity of the tumor microenvironment needs to be properly modelled. 3D culture models are emerging as a powerful research tool that recapitulates in vivo characteristics. Technological advancements in this field show promising application in improving drug discovery, pre-clinical validation, and precision medicine. In this review, we discuss the significance of the tumor microenvironment and its impact on therapy success, the current developments of 3D culture, and the opportunities that advancements that in vitro technologies can provide to improve cancer therapeutics.
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Affiliation(s)
- Andrew M K Law
- Tumour Development Group, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Randwick, NSW, Australia
| | - Laura Rodriguez de la Fuente
- Tumour Development Group, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Randwick, NSW, Australia.,Cancer Epigenetic Biology and Therapeutics Lab, Children's Cancer Institute, Randwick, NSW, Australia
| | - Thomas J Grundy
- Life Sciences, Inventia Life Science Pty Ltd, Alexandria, NSW, Australia
| | - Guocheng Fang
- School of Biomedical Engineering, Faculty of Engineering and IT, University of Technology Sydney, Ultimo, NSW, Australia
| | - Fatima Valdes-Mora
- Cancer Epigenetic Biology and Therapeutics Lab, Children's Cancer Institute, Randwick, NSW, Australia.,School of Women's and Children's Health, Faculty of Medicine, University of New South Wales Sydney, Randwick, NSW, Australia
| | - David Gallego-Ortega
- Tumour Development Group, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Randwick, NSW, Australia.,School of Biomedical Engineering, Faculty of Engineering and IT, University of Technology Sydney, Ultimo, NSW, Australia
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Zhang M, Liu Y, Kong D. Identifying biomolecules and constructing a prognostic risk prediction model for recurrence in osteosarcoma. J Bone Oncol 2021; 26:100331. [PMID: 33376666 PMCID: PMC7758551 DOI: 10.1016/j.jbo.2020.100331] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/30/2020] [Accepted: 10/02/2020] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION Osteosarcoma is a high-morbidity bone cancer with an unsatisfactory prognosis. The aim of this study is to develop novel potential prognostic biomarkers and construct a prognostic risk prediction model for recurrence in osteosarcoma. METHODS By analyzing microarray data, univariate and multivariate Cox regression analyses were performed to screen prognostic RNA signatures and to build a prognostic model. The RNA signatures were validated using Kaplan-Meier curves. Then, we developed and validated a nomogram combining age, recurrence, metastatic, and Prognostic score (PS) models to predict the individual's overall survival at the 3- and 5-year points. Pathway enrichment of RNA was conducted based on the significant co-expressed RNAs. RESULTS A total of 319 mRNAs and 14 lncRNAs were identified in the microarray data. One lncRNA (LINC00957) and six mRNAs (METL1, CA9, B3GALT4, ALDH1A1, LAMB3, and ITGB4) were identified as RNA signatures and showed good performances in survival prediction for both the training and validation cohorts. Cox regression analysis showed that the seven RNA signatures could independently predict overall survival. Furthermore, age, recurrence, metastatic, and PS models were identified as independent prognostic factors via univariate and multivariate Cox analyses (P < 0.05) and included in the prognostic nomogram. The C-index values for the 3- and 5-year overall survival predictions of the nomogram were 0.809 and 0.740, respectively. CONCLUSIONS The current study provides the novel potential of seven RNA candidates as prognostic biomarkers. Nomograms were constructed to provide accurate and individualized survival prediction for recurrence in osteosarcoma patients.
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Affiliation(s)
- Minglei Zhang
- Departments of Orthopaedics, China-Japan Union Hospital of Jilin University, No.126, Xiantai Street, Changchun, Jilin 130033, China
| | - Yang Liu
- Department of Radiological, The Second Clinical Hospital of Jilin University, NO.218, Ziqiang Street, Nanguan District, Changchun, Jilin 130000, China
| | - Daliang Kong
- Departments of Orthopaedics, China-Japan Union Hospital of Jilin University, No.126, Xiantai Street, Changchun, Jilin 130033, China
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VanCleave A, Palmer M, Fang F, Torres H, Rodezno T, Li Q, Fuglsby K, Evans C, Afeworki Y, Ross A, Rao P, Leiferman P, Zheng S, Houghton P, Tao J. Development and characterization of the novel human osteosarcoma cell line COS-33 with sustained activation of the mTOR pathway. Oncotarget 2020; 11:2597-2610. [PMID: 32676162 PMCID: PMC7343631 DOI: 10.18632/oncotarget.27611] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 05/01/2020] [Indexed: 01/04/2023] Open
Abstract
Outcomes have not improved for metastatic osteosarcoma for several decades. In part, this failure to develop better therapies stems from a lack of understanding of osteosarcoma biology, given the rarity of the disease and the high genetic heterogeneity at the time of diagnosis. We report here the successful establishment of a new human osteosarcoma cell line, COS-33, from a patient-derived xenograft and demonstrate retention of the biological features of the original tumor. We found high mTOR signaling activity in the cultured cells, which were sensitive to a small molecule inhibitor, rapamycin, a suppressor of the mTOR pathway. Suppressed mTOR signaling after treatment with rapamycin was confirmed by decreased phosphorylation of the S6 ribosomal protein. Increasing concentrations of rapamycin progressively inhibited cell proliferation in vitro. We observed significant inhibitory effects of the drug on cell migration, invasion, and colony formation in the cultured cells. Furthermore, we found that only a strong osteogenic inducer, bone morphogenetic protein-2, promoted the cells to differentiate into mature mineralizing osteoblasts, indicating that the COS-33 cell line may have impaired osteoblast differentiation. Grafted COS-33 cells exhibited features typical of osteosarcoma, such as production of osteoid and tumorigenicity in vivo. In addition, we revealed that the COS-33 cell line retained a complex karyotype, a homozygous deletion of the TP53 gene, and typical histological features from its original tumor. Our novel cellular model may provide a valuable platform for studying the etiology and molecular pathogenesis of osteosarcoma as well as for testing novel drugs for future genome-informed targeted therapy.
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Affiliation(s)
- Ashley VanCleave
- Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD, USA
| | - Mykayla Palmer
- Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD, USA.,SPUR Scholar Program, University of South Dakota, Sioux Falls, SD, USA
| | - Fang Fang
- Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD, USA
| | - Haydee Torres
- Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD, USA.,Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD, USA
| | - Tania Rodezno
- Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD, USA
| | - Qilin Li
- Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Kirby Fuglsby
- Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD, USA.,Department of Biomedical Engineering, University of South Dakota, Sioux Falls, SD, USA
| | - Claire Evans
- Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD, USA
| | - Yohannes Afeworki
- Functional Genomics & Bioinformatics Core Facility, Sanford Research, Sioux Falls, SD, USA
| | - Alan Ross
- Sanford Medical Genetics Laboratory of Sanford Health, Sioux Falls, SD, USA
| | - Pulivarthi Rao
- Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - Patricia Leiferman
- EGL Genetics Laboratory, Tucker, GA, USA.,Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA
| | - Siyuan Zheng
- Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Peter Houghton
- Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Jianning Tao
- Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD, USA.,Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD, USA.,Department of Biomedical Engineering, University of South Dakota, Sioux Falls, SD, USA.,Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA
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Chaicharoenaudomrung N, Kunhorm P, Noisa P. Three-dimensional cell culture systems as an in vitro platform for cancer and stem cell modeling. World J Stem Cells 2019; 11:1065-1083. [PMID: 31875869 PMCID: PMC6904866 DOI: 10.4252/wjsc.v11.i12.1065] [Citation(s) in RCA: 239] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 10/09/2019] [Accepted: 11/05/2019] [Indexed: 02/06/2023] Open
Abstract
Three-dimensional (3D) culture systems are becoming increasingly popular due to their ability to mimic tissue-like structures more effectively than the monolayer cultures. In cancer and stem cell research, the natural cell characteristics and architectures are closely mimicked by the 3D cell models. Thus, the 3D cell cultures are promising and suitable systems for various proposes, ranging from disease modeling to drug target identification as well as potential therapeutic substances that may transform our lives. This review provides a comprehensive compendium of recent advancements in culturing cells, in particular cancer and stem cells, using 3D culture techniques. The major approaches highlighted here include cell spheroids, hydrogel embedding, bioreactors, scaffolds, and bioprinting. In addition, the progress of employing 3D cell culture systems as a platform for cancer and stem cell research was addressed, and the prominent studies of 3D cell culture systems were discussed.
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Affiliation(s)
- Nipha Chaicharoenaudomrung
- Laboratory of Cell-Based Assays and Innovations, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand
| | - Phongsakorn Kunhorm
- Laboratory of Cell-Based Assays and Innovations, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand
| | - Parinya Noisa
- Laboratory of Cell-Based Assays and Innovations, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand
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IPSE, a urogenital parasite-derived immunomodulatory protein, ameliorates ifosfamide-induced hemorrhagic cystitis through downregulation of pro-inflammatory pathways. Sci Rep 2019; 9:1586. [PMID: 30733505 PMCID: PMC6367514 DOI: 10.1038/s41598-018-38274-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 12/18/2018] [Indexed: 12/15/2022] Open
Abstract
Ifosfamide and other oxazaphosphorines can result in hemorrhagic cystitis, a constellation of complications caused by acrolein metabolites. We previously showed that a single dose of IPSE (Interleukin-4-inducing principle from Schistosoma eggs), a schistosome-derived host modulatory protein, can ameliorate ifosfamide-related cystitis; however, the mechanisms underlying this urotoxicity and its prevention are not fully understood. To provide insights into IPSE’s protective mechanism, we undertook transcriptional profiling of bladders from ifosfamide-treated mice, with or without pretreatment with IPSE or IPSE-NLS (a mutant of IPSE lacking nuclear localization sequence). Ifosfamide treatment upregulated a range of proinflammatory genes. The IL-1β-TNFα-IL-6 proinflammatory cascade via NFκB and STAT3 pathways was identified as the key driver of inflammation. The NRF2-mediated oxidative stress response pathway, which regulates heme homoeostasis and expression of antioxidant enzymes, was highly activated. Anti-inflammatory cascades, namely Wnt, Hedgehog and PPAR pathways, were downregulated. IPSE drove significant downregulation of major proinflammatory pathways including the IL-1β-TNFα-IL-6 pathways, interferon signaling, and reduction in oxidative stress. IPSE-NLS reduced inflammation but not oxidative stress. Taken together, we have identified signatures of acute-phase inflammation and oxidative stress in ifosfamide-injured bladder, which are reversed by pretreatment with IPSE. This work revealed several pathways that could be therapeutically targeted to prevent ifosfamide-induced hemorrhagic cystitis.
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BO-1055, a novel DNA cross-linking agent with remarkable low myelotoxicity shows potent activity in sarcoma models. Oncotarget 2018; 7:43062-43075. [PMID: 27248664 PMCID: PMC5190008 DOI: 10.18632/oncotarget.9657] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Accepted: 05/14/2016] [Indexed: 02/04/2023] Open
Abstract
DNA damaging agents cause rapid shrinkage of tumors and form the basis of chemotherapy for sarcomas despite significant toxicities. Drugs having superior efficacy and wider therapeutic windows are needed to improve patient outcomes. We used cell proliferation and apoptosis assays in sarcoma cell lines and benign cells; γ-H2AX expression, comet assay, immunoblot analyses and drug combination studies in vitro and in patient derived xenograft (PDX) models. BO-1055 caused apoptosis and cell death in a concentration and time dependent manner in sarcoma cell lines. BO-1055 had potent activity (submicromolar IC50) against Ewing sarcoma and rhabdomyosarcoma, intermediate activity in DSRCT (IC50 = 2-3μM) and very weak activity in osteosarcoma (IC50 >10μM) cell lines. BO-1055 exhibited a wide therapeutic window compared to other DNA damaging drugs. BO-1055 induced more DNA double strand breaks and γH2AX expression in cancer cells compared to benign cells. BO-1055 showed inhibition of tumor growth in A673 xenografts and caused tumor regression in cyclophosphamide resistant patient-derived Ewing sarcoma xenografts and A204 xenografts. Combination of BO-1055 and irinotecan demonstrated synergism in Ewing sarcoma PDX models. Potent activity on sarcoma cells and its relative lack of toxicity presents a strong rationale for further development of BO-1055 as a therapeutic agent.
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Skarbek C, Delahousse J, Pioche-Durieu C, Baconnais S, Deroussent A, Renevret P, Rivard M, Desmaele D, Martens T, Le Cam E, Couvreur P, Paci A. Poly-isoprenylated ifosfamide analogs: Preactivated antitumor agents as free formulation or nanoassemblies. Int J Pharm 2017; 532:748-756. [PMID: 28546071 DOI: 10.1016/j.ijpharm.2017.05.044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 05/19/2017] [Accepted: 05/20/2017] [Indexed: 01/28/2023]
Abstract
Oxazaphosphorines including cyclophosphamide, trofosfamide and ifosfamide (IFO) belong to the alkylating agent class and are indicated in the treatment of numerous cancers. However, IFO is subject to limiting side-effects in high-dose protocols. To circumvent IFO drawbacks in clinical practices, preactivated IFO analogs were designed to by-pass the toxic metabolic pathway. Among these IFO analogs, some of them showed the ability to self-assemble due to the use of a poly-isoprenyloxy chain as preactivating moiety. We present here, the in vitro activity of the nanoassembly formulations of preactivated IFO derivatives with a C-4 geranyloxy, farnesyloxy and squalenoxy substituent on a large panel of tumor cell lines. The chemical and colloidal stabilities of the geranyloxy-IFO (G-IFO), farnesyloxy-IFO (F-IFO) and squalenoxy-IFO (SQ-IFO) NAs were further evaluated in comparison to their free formulation. Finally, pharmacokinetic parameters and maximal tolerated dose of the most potent preactivated IFO analog (G-IFO) were determined and compared to IFO, paving the way to in vivo studies.
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Affiliation(s)
- Charles Skarbek
- Vectorologie des anticancéreux et des acides nucléiques, UMR 8203, CNRS, Université Paris-Sud, Gustave Roussy, Université Paris-Saclay, 94805 Villejuif, France
| | - Julia Delahousse
- Vectorologie des anticancéreux et des acides nucléiques, UMR 8203, CNRS, Université Paris-Sud, Gustave Roussy, Université Paris-Saclay, 94805 Villejuif, France; Service de Pharmacologie, Département de Biologie et Pathologie médicales, Gustave Roussy, 94805 Villejuif, France
| | - Catherine Pioche-Durieu
- Signalisations, Noyaux et Innovations en Cancérologie, UMR 8126, CNRS, Université Paris-Sud, Gustave Roussy, Université Paris-Saclay, 94805 Villejuif, France
| | - Sonia Baconnais
- Signalisations, Noyaux et Innovations en Cancérologie, UMR 8126, CNRS, Université Paris-Sud, Gustave Roussy, Université Paris-Saclay, 94805 Villejuif, France
| | - Alain Deroussent
- Vectorologie des anticancéreux et des acides nucléiques, UMR 8203, CNRS, Université Paris-Sud, Gustave Roussy, Université Paris-Saclay, 94805 Villejuif, France
| | - Patrice Renevret
- Institut de Chimie et des Matériaux Paris Est Créteil (ICMPE), UMR 7182, CNRS, Université Paris Est (UPEC), 94320 Thiais, France
| | - Michael Rivard
- Institut de Chimie et des Matériaux Paris Est Créteil (ICMPE), UMR 7182, CNRS, Université Paris Est (UPEC), 94320 Thiais, France
| | - Didier Desmaele
- Institut Galien Paris-Sud, UMR 8612, CNRS, Université Paris-Saclay, Faculté de Pharmacie, 92296, Châtenay-Malabry, France
| | - Thierry Martens
- Institut de Chimie et des Matériaux Paris Est Créteil (ICMPE), UMR 7182, CNRS, Université Paris Est (UPEC), 94320 Thiais, France
| | - Eric Le Cam
- Signalisations, Noyaux et Innovations en Cancérologie, UMR 8126, CNRS, Université Paris-Sud, Gustave Roussy, Université Paris-Saclay, 94805 Villejuif, France
| | - Patrick Couvreur
- Institut Galien Paris-Sud, UMR 8612, CNRS, Université Paris-Saclay, Faculté de Pharmacie, 92296, Châtenay-Malabry, France
| | - Angelo Paci
- Vectorologie des anticancéreux et des acides nucléiques, UMR 8203, CNRS, Université Paris-Sud, Gustave Roussy, Université Paris-Saclay, 94805 Villejuif, France; Service de Pharmacologie, Département de Biologie et Pathologie médicales, Gustave Roussy, 94805 Villejuif, France; Département de Pharmacocinétique & Pharmacie Clinique, Université Paris-Sud, Université Paris-Saclay, Faculté de Pharmacie, 92296 Châtenay-Malabry, France.
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10
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Verjans ET, Doijen J, Luyten W, Landuyt B, Schoofs L. Three-dimensional cell culture models for anticancer drug screening: Worth the effort? J Cell Physiol 2017; 233:2993-3003. [PMID: 28618001 DOI: 10.1002/jcp.26052] [Citation(s) in RCA: 136] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 06/13/2017] [Indexed: 12/11/2022]
Abstract
High attrition of new oncology drug candidates in clinical trials is partially caused by the poor predictive capacity of artificial monolayer cell culture assays early in drug discovery. Monolayer assays do not take the natural three-dimensional (3D) microenvironment of cells into account. As a result, false positive compounds often enter clinical trials, leading to high dropout rates and a waste of time and money. Over the past 2 decades, tissue engineers and cell biologists have developed a broad range of 3D in vitro culturing tools that better represent in vivo cell biology. These tools preserve the 3D architecture of cells and can be used to predict toxicity of and resistance against antitumor agents. Recent progress in tissue engineering further improves 3D models by taking into account the tumor microenvironment, which is important for metastatic progression and vascularization. However, the widespread implementation of 3D cell cultures into cell-based research programs has been limited by various factors, including their cost and reproducibility. In addition, different 3D cell culture techniques often produce spheroids of different size and shape, which can strongly influence drug efficacy and toxicity. Hence, it is imperative to morphometrically characterize multicellular spheroids to avoid generalizations among different spheroid types. Standardized 3D culturing procedures could further reduce data variability and enhance biological relevance. Here, we critically evaluate the benefits and challenges inherent to growing cells in 3D, along with an overview of the techniques used to form spheroids. This is done with a specific focus on antitumor drug screening.
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Affiliation(s)
- Eddy-Tim Verjans
- Department of Biology, Division of Neurobiology and Animal Physiology, KU Leuven, Leuven, Belgium
| | - Jordi Doijen
- Department of Biology, Division of Neurobiology and Animal Physiology, KU Leuven, Leuven, Belgium
| | - Walter Luyten
- Department of Biology, Division of Neurobiology and Animal Physiology, KU Leuven, Leuven, Belgium
| | - Bart Landuyt
- Department of Biology, Division of Neurobiology and Animal Physiology, KU Leuven, Leuven, Belgium
| | - Liliane Schoofs
- Department of Biology, Division of Neurobiology and Animal Physiology, KU Leuven, Leuven, Belgium
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11
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Jalal SI, Lavin P, Lo G, Lebel F, Einhorn L. Carboplatin and Etoposide With or Without Palifosfamide in Untreated Extensive-Stage Small-Cell Lung Cancer: A Multicenter, Adaptive, Randomized Phase III Study (MATISSE). J Clin Oncol 2017; 35:2619-2623. [PMID: 28605291 DOI: 10.1200/jco.2016.71.7454] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Purpose To evaluate the efficacy of the addition of palifosfamide to carboplatin and etoposide in extensive stage (ES) small-cell lung cancer (SCLC). Patients and Methods MATISSE was a randomized, open-label, adaptive phase III study. Previously untreated patients with ES SCLC were randomly assigned in a 1:1 fashion to receive carboplatin at area under the serum concentration-time curve 5 on day 1 plus etoposide 100 mg/m2 per day on days 1 to 3 every 21 days (CE) or carboplatin at area under the serum concentration-time curve 4 on day 1 plus etoposide 100 mg/m2 per day plus palifosfamide 130 mg/m2 per day on days 1 to 3 every 21 days (PaCE). The primary end point was overall survival. Results In all, 188 patients were enrolled; 94 patients received CE and 94 patients received PaCE. The median age on both arms was 61 years. Six cycles of chemotherapy were completed on both arms of the study by approximately 50% of the patients. Serious adverse events were documented and did not differ significantly between patients receiving PaCE and those receiving CE. Median overall survival was similar between both arms with 10.03 months on PaCE and 10.37 months on CE ( P = .096). Conclusion The addition of palifosfamide to CE failed to improve survival in ES SCLC.
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Affiliation(s)
- Shadia I Jalal
- Shadia I. Jalal and Lawrence Einhorn, Indiana University School of Medicine and Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; Philip Lavin, Lavin Consulting, Framingham; Francois Lebel, ZIOPHARM Oncology, Boston, MA; and Gregory Lo, R.S. McLaughlin Durham Regional Cancer Center at Lakeridge Health Oshawa, Oshawa, ON, Canada
| | - Philip Lavin
- Shadia I. Jalal and Lawrence Einhorn, Indiana University School of Medicine and Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; Philip Lavin, Lavin Consulting, Framingham; Francois Lebel, ZIOPHARM Oncology, Boston, MA; and Gregory Lo, R.S. McLaughlin Durham Regional Cancer Center at Lakeridge Health Oshawa, Oshawa, ON, Canada
| | - Gregory Lo
- Shadia I. Jalal and Lawrence Einhorn, Indiana University School of Medicine and Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; Philip Lavin, Lavin Consulting, Framingham; Francois Lebel, ZIOPHARM Oncology, Boston, MA; and Gregory Lo, R.S. McLaughlin Durham Regional Cancer Center at Lakeridge Health Oshawa, Oshawa, ON, Canada
| | - Francois Lebel
- Shadia I. Jalal and Lawrence Einhorn, Indiana University School of Medicine and Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; Philip Lavin, Lavin Consulting, Framingham; Francois Lebel, ZIOPHARM Oncology, Boston, MA; and Gregory Lo, R.S. McLaughlin Durham Regional Cancer Center at Lakeridge Health Oshawa, Oshawa, ON, Canada
| | - Lawrence Einhorn
- Shadia I. Jalal and Lawrence Einhorn, Indiana University School of Medicine and Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; Philip Lavin, Lavin Consulting, Framingham; Francois Lebel, ZIOPHARM Oncology, Boston, MA; and Gregory Lo, R.S. McLaughlin Durham Regional Cancer Center at Lakeridge Health Oshawa, Oshawa, ON, Canada
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12
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Fine B, Vunjak-Novakovic G. Shortcomings of Animal Models and the Rise of Engineered Human Cardiac Tissue. ACS Biomater Sci Eng 2017; 3:1884-1897. [PMID: 33440547 DOI: 10.1021/acsbiomaterials.6b00662] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
We provide here an historical context of how studies utilizing engineered human cardiac muscle can complement and in some cases substitute animal and cell models for studies of disease and drug testing. We give an overview of the development of animal models and discuss the ability of novel human tissue models to overcome limited predictive power of cell culture and animal models in studies of drug efficacy and safety. The in vitro generation of cardiac tissue is discussed in the context of state of the art in the field. Finally we describe the assembly of multitissue platforms for more accurate representation of integrated human cardiac physiology and consider the advantages of in silico drug trials to augment our ability to predict drug-drug and organ-organ interactions in humans.
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Affiliation(s)
- Barry Fine
- Department of Biomedical Engineering and ‡Department of Medicine, Columbia University, New York, New York 10027, United States
| | - Gordana Vunjak-Novakovic
- Department of Biomedical Engineering and Department of Medicine, Columbia University, New York, New York 10027, United States
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13
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Ryan CW, Merimsky O, Agulnik M, Blay JY, Schuetze SM, Van Tine BA, Jones RL, Elias AD, Choy E, Alcindor T, Keedy VL, Reed DR, Taub RN, Italiano A, Garcia del Muro X, Judson IR, Buck JY, Lebel F, Lewis JJ, Maki RG, Schöffski P. PICASSO III: A Phase III, Placebo-Controlled Study of Doxorubicin With or Without Palifosfamide in Patients With Metastatic Soft Tissue Sarcoma. J Clin Oncol 2016; 34:3898-3905. [DOI: 10.1200/jco.2016.67.6684] [Citation(s) in RCA: 125] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Purpose Palifosfamide is the active metabolite of ifosfamide and does not require prodrug activation, thereby avoiding the generation of toxic metabolites. The PICASSO III trial compared doxorubicin plus palifosfamide with doxorubicin plus placebo in patients who had received no prior systemic therapy for metastatic soft tissue sarcoma. Patients and Methods Patients were randomly assigned 1:1 to receive doxorubicin 75 mg/m2 intravenously day 1 plus palifosfamide 150 mg/m2/d intravenously days 1 to 3 or doxorubicin plus placebo once every 21 days for up to six cycles. The primary end point was progression-free survival (PFS) by independent radiologic review. Results In all, 447 patients were randomly assigned to receive doxorubicin plus palifosfamide (n = 226) or doxorubicin plus placebo (n = 221). Median PFS was 6.0 months for doxorubicin plus palifosfamide and 5.2 months for doxorubicin plus placebo (hazard ratio, 0.86; 95% CI, 0.68 to 1.08; P = .19). Median overall survival was 15.9 months for doxorubicin plus palifosfamide and 16.9 months for doxorubicin plus placebo (hazard ratio, 1.05; 95% CI, 0.79 to 1.39; P = .74). There was a higher incidence of grade 3 to 4 adverse events in the doxorubicin plus palifosfamide arm (63.6% v 50.9%) including a higher rate of febrile neutropenia (21.4% v 12.6%). Conclusion No significant difference in PFS was observed in patients receiving doxorubicin plus palifosfamide compared with those receiving doxorubicin plus placebo. The observed median PFS and overall survival in this large, international study can serve as a benchmark for future studies of doxorubicin in metastatic soft tissue sarcoma.
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Affiliation(s)
- Christopher W. Ryan
- Christopher W. Ryan, Oregon Health & Science University, Portland, OR; Ofer Merimsky, Sackler School of Medicine, Tel-Aviv, Israel; Mark Agulnik, Northwestern University, Chicago, IL; Jean-Yves Blay, Centre Léon Bérard, Lyon; Antoine Italiano, Institut Bergonié, Bordeaux, France; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Robin L. Jones and Ian R. Judson, The Royal Marsden Hospital, London, United Kingdom; Anthony D. Elias
| | - Ofer Merimsky
- Christopher W. Ryan, Oregon Health & Science University, Portland, OR; Ofer Merimsky, Sackler School of Medicine, Tel-Aviv, Israel; Mark Agulnik, Northwestern University, Chicago, IL; Jean-Yves Blay, Centre Léon Bérard, Lyon; Antoine Italiano, Institut Bergonié, Bordeaux, France; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Robin L. Jones and Ian R. Judson, The Royal Marsden Hospital, London, United Kingdom; Anthony D. Elias
| | - Mark Agulnik
- Christopher W. Ryan, Oregon Health & Science University, Portland, OR; Ofer Merimsky, Sackler School of Medicine, Tel-Aviv, Israel; Mark Agulnik, Northwestern University, Chicago, IL; Jean-Yves Blay, Centre Léon Bérard, Lyon; Antoine Italiano, Institut Bergonié, Bordeaux, France; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Robin L. Jones and Ian R. Judson, The Royal Marsden Hospital, London, United Kingdom; Anthony D. Elias
| | - Jean-Yves Blay
- Christopher W. Ryan, Oregon Health & Science University, Portland, OR; Ofer Merimsky, Sackler School of Medicine, Tel-Aviv, Israel; Mark Agulnik, Northwestern University, Chicago, IL; Jean-Yves Blay, Centre Léon Bérard, Lyon; Antoine Italiano, Institut Bergonié, Bordeaux, France; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Robin L. Jones and Ian R. Judson, The Royal Marsden Hospital, London, United Kingdom; Anthony D. Elias
| | - Scott M. Schuetze
- Christopher W. Ryan, Oregon Health & Science University, Portland, OR; Ofer Merimsky, Sackler School of Medicine, Tel-Aviv, Israel; Mark Agulnik, Northwestern University, Chicago, IL; Jean-Yves Blay, Centre Léon Bérard, Lyon; Antoine Italiano, Institut Bergonié, Bordeaux, France; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Robin L. Jones and Ian R. Judson, The Royal Marsden Hospital, London, United Kingdom; Anthony D. Elias
| | - Brian A. Van Tine
- Christopher W. Ryan, Oregon Health & Science University, Portland, OR; Ofer Merimsky, Sackler School of Medicine, Tel-Aviv, Israel; Mark Agulnik, Northwestern University, Chicago, IL; Jean-Yves Blay, Centre Léon Bérard, Lyon; Antoine Italiano, Institut Bergonié, Bordeaux, France; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Robin L. Jones and Ian R. Judson, The Royal Marsden Hospital, London, United Kingdom; Anthony D. Elias
| | - Robin L. Jones
- Christopher W. Ryan, Oregon Health & Science University, Portland, OR; Ofer Merimsky, Sackler School of Medicine, Tel-Aviv, Israel; Mark Agulnik, Northwestern University, Chicago, IL; Jean-Yves Blay, Centre Léon Bérard, Lyon; Antoine Italiano, Institut Bergonié, Bordeaux, France; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Robin L. Jones and Ian R. Judson, The Royal Marsden Hospital, London, United Kingdom; Anthony D. Elias
| | - Anthony D. Elias
- Christopher W. Ryan, Oregon Health & Science University, Portland, OR; Ofer Merimsky, Sackler School of Medicine, Tel-Aviv, Israel; Mark Agulnik, Northwestern University, Chicago, IL; Jean-Yves Blay, Centre Léon Bérard, Lyon; Antoine Italiano, Institut Bergonié, Bordeaux, France; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Robin L. Jones and Ian R. Judson, The Royal Marsden Hospital, London, United Kingdom; Anthony D. Elias
| | - Edwin Choy
- Christopher W. Ryan, Oregon Health & Science University, Portland, OR; Ofer Merimsky, Sackler School of Medicine, Tel-Aviv, Israel; Mark Agulnik, Northwestern University, Chicago, IL; Jean-Yves Blay, Centre Léon Bérard, Lyon; Antoine Italiano, Institut Bergonié, Bordeaux, France; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Robin L. Jones and Ian R. Judson, The Royal Marsden Hospital, London, United Kingdom; Anthony D. Elias
| | - Thierry Alcindor
- Christopher W. Ryan, Oregon Health & Science University, Portland, OR; Ofer Merimsky, Sackler School of Medicine, Tel-Aviv, Israel; Mark Agulnik, Northwestern University, Chicago, IL; Jean-Yves Blay, Centre Léon Bérard, Lyon; Antoine Italiano, Institut Bergonié, Bordeaux, France; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Robin L. Jones and Ian R. Judson, The Royal Marsden Hospital, London, United Kingdom; Anthony D. Elias
| | - Vicki L. Keedy
- Christopher W. Ryan, Oregon Health & Science University, Portland, OR; Ofer Merimsky, Sackler School of Medicine, Tel-Aviv, Israel; Mark Agulnik, Northwestern University, Chicago, IL; Jean-Yves Blay, Centre Léon Bérard, Lyon; Antoine Italiano, Institut Bergonié, Bordeaux, France; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Robin L. Jones and Ian R. Judson, The Royal Marsden Hospital, London, United Kingdom; Anthony D. Elias
| | - Damon R. Reed
- Christopher W. Ryan, Oregon Health & Science University, Portland, OR; Ofer Merimsky, Sackler School of Medicine, Tel-Aviv, Israel; Mark Agulnik, Northwestern University, Chicago, IL; Jean-Yves Blay, Centre Léon Bérard, Lyon; Antoine Italiano, Institut Bergonié, Bordeaux, France; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Robin L. Jones and Ian R. Judson, The Royal Marsden Hospital, London, United Kingdom; Anthony D. Elias
| | - Robert N. Taub
- Christopher W. Ryan, Oregon Health & Science University, Portland, OR; Ofer Merimsky, Sackler School of Medicine, Tel-Aviv, Israel; Mark Agulnik, Northwestern University, Chicago, IL; Jean-Yves Blay, Centre Léon Bérard, Lyon; Antoine Italiano, Institut Bergonié, Bordeaux, France; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Robin L. Jones and Ian R. Judson, The Royal Marsden Hospital, London, United Kingdom; Anthony D. Elias
| | - Antoine Italiano
- Christopher W. Ryan, Oregon Health & Science University, Portland, OR; Ofer Merimsky, Sackler School of Medicine, Tel-Aviv, Israel; Mark Agulnik, Northwestern University, Chicago, IL; Jean-Yves Blay, Centre Léon Bérard, Lyon; Antoine Italiano, Institut Bergonié, Bordeaux, France; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Robin L. Jones and Ian R. Judson, The Royal Marsden Hospital, London, United Kingdom; Anthony D. Elias
| | - Xavier Garcia del Muro
- Christopher W. Ryan, Oregon Health & Science University, Portland, OR; Ofer Merimsky, Sackler School of Medicine, Tel-Aviv, Israel; Mark Agulnik, Northwestern University, Chicago, IL; Jean-Yves Blay, Centre Léon Bérard, Lyon; Antoine Italiano, Institut Bergonié, Bordeaux, France; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Robin L. Jones and Ian R. Judson, The Royal Marsden Hospital, London, United Kingdom; Anthony D. Elias
| | - Ian R. Judson
- Christopher W. Ryan, Oregon Health & Science University, Portland, OR; Ofer Merimsky, Sackler School of Medicine, Tel-Aviv, Israel; Mark Agulnik, Northwestern University, Chicago, IL; Jean-Yves Blay, Centre Léon Bérard, Lyon; Antoine Italiano, Institut Bergonié, Bordeaux, France; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Robin L. Jones and Ian R. Judson, The Royal Marsden Hospital, London, United Kingdom; Anthony D. Elias
| | - Jill Y. Buck
- Christopher W. Ryan, Oregon Health & Science University, Portland, OR; Ofer Merimsky, Sackler School of Medicine, Tel-Aviv, Israel; Mark Agulnik, Northwestern University, Chicago, IL; Jean-Yves Blay, Centre Léon Bérard, Lyon; Antoine Italiano, Institut Bergonié, Bordeaux, France; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Robin L. Jones and Ian R. Judson, The Royal Marsden Hospital, London, United Kingdom; Anthony D. Elias
| | - Francois Lebel
- Christopher W. Ryan, Oregon Health & Science University, Portland, OR; Ofer Merimsky, Sackler School of Medicine, Tel-Aviv, Israel; Mark Agulnik, Northwestern University, Chicago, IL; Jean-Yves Blay, Centre Léon Bérard, Lyon; Antoine Italiano, Institut Bergonié, Bordeaux, France; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Robin L. Jones and Ian R. Judson, The Royal Marsden Hospital, London, United Kingdom; Anthony D. Elias
| | - Jonathan J. Lewis
- Christopher W. Ryan, Oregon Health & Science University, Portland, OR; Ofer Merimsky, Sackler School of Medicine, Tel-Aviv, Israel; Mark Agulnik, Northwestern University, Chicago, IL; Jean-Yves Blay, Centre Léon Bérard, Lyon; Antoine Italiano, Institut Bergonié, Bordeaux, France; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Robin L. Jones and Ian R. Judson, The Royal Marsden Hospital, London, United Kingdom; Anthony D. Elias
| | - Robert G. Maki
- Christopher W. Ryan, Oregon Health & Science University, Portland, OR; Ofer Merimsky, Sackler School of Medicine, Tel-Aviv, Israel; Mark Agulnik, Northwestern University, Chicago, IL; Jean-Yves Blay, Centre Léon Bérard, Lyon; Antoine Italiano, Institut Bergonié, Bordeaux, France; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Robin L. Jones and Ian R. Judson, The Royal Marsden Hospital, London, United Kingdom; Anthony D. Elias
| | - Patrick Schöffski
- Christopher W. Ryan, Oregon Health & Science University, Portland, OR; Ofer Merimsky, Sackler School of Medicine, Tel-Aviv, Israel; Mark Agulnik, Northwestern University, Chicago, IL; Jean-Yves Blay, Centre Léon Bérard, Lyon; Antoine Italiano, Institut Bergonié, Bordeaux, France; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Robin L. Jones and Ian R. Judson, The Royal Marsden Hospital, London, United Kingdom; Anthony D. Elias
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Kim HK, Kim SY, Lee SJ, Kang M, Kim ST, Jang J, Rath O, Schueler J, Lee DW, Park WY, Kim SJ, Park SH, Lee J. BEZ235 (PIK3/mTOR inhibitor) Overcomes Pazopanib Resistance in Patient-Derived Refractory Soft Tissue Sarcoma Cells. Transl Oncol 2016; 9:197-202. [PMID: 27267837 PMCID: PMC4907899 DOI: 10.1016/j.tranon.2016.03.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 03/23/2016] [Accepted: 03/23/2016] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND: Although pazopanib treatment has become the standard chemotherapy in salvage setting for metastatic sarcoma patients, most patients progress after pazopanib treatment in 4 to 6 months. After failure to pazopanib, patients have limited options for treatment. Therefore, subsequent therapy in patients who failed to pazopanib is urgently needed and the use of patient derived cells or patient derived tumors for accompanying testing with various pharmacological inhibitors could offer additional treatment options for these patients. METHODS: Patient derived tumor cells were collected from ascites at the time of progression to pazopanib and a 13-drug panel was tested for drug sensitivity. We confirmed the results using in vitro cell viability assay and immunoblot assay. We also performed the genomic profiling of PDX model. RESULTS: The growth of patient derived tumor cells was significantly reduced by exposure to 1.0 μM AZD2014 compared with control (control versus AZD2014, mean growth = 100.0% vs 16.04%, difference = 83.96%, 95% CI = 70.01% to 97.92%, P = .0435). Similarly, 1.0 μM BEZ235 profoundly inhibited tumor cell growth in vitro when compared to control (control versus BEZ235, mean growth = 100.0% vs 7.308%, difference = 92.69%, 95% CI = 78.87% to 106.5%, P < .0001). Despite the presence of CDK4 amplification in the patient-derived tumor cells, LEE011 did not considerably inhibit cell proliferation when compared with control (control vs LEE011, mean growth = 100.0% vs 80.23%, difference = 19.77%, 95% CI = 1.828% to 37.72%, P = .0377). The immunoblot analysis showed that BEZ235 treatment decreased pAKT, pmTOR and pERK whereas AZD2014 decreased only pmTOR. CONCLUSION: Taken together, upregulation of mTOR/AKT pathway in sarcoma patient derived cells was considerably inhibited by the treatment of AZD2014 and BEZ235 with downregulation of AKT pathway (greater extent for BEZ235). These molecules may be considered as treatment option in STS patient who have failed to pazopanib in the context of clinical trials.
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Affiliation(s)
- Hee Kyung Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sun Young Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Su Jin Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Mihyeon Kang
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jiryeon Jang
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | | | | | | | - Woong Yang Park
- Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea; Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sung Joo Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Se Hoon Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
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Edmondson R, Broglie JJ, Adcock AF, Yang L. Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay Drug Dev Technol 2015; 12:207-18. [PMID: 24831787 DOI: 10.1089/adt.2014.573] [Citation(s) in RCA: 1578] [Impact Index Per Article: 157.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Three-dimensional (3D) cell culture systems have gained increasing interest in drug discovery and tissue engineering due to their evident advantages in providing more physiologically relevant information and more predictive data for in vivo tests. In this review, we discuss the characteristics of 3D cell culture systems in comparison to the two-dimensional (2D) monolayer culture, focusing on cell growth conditions, cell proliferation, population, and gene and protein expression profiles. The innovations and development in 3D culture systems for drug discovery over the past 5 years are also reviewed in the article, emphasizing the cellular response to different classes of anticancer drugs, focusing particularly on similarities and differences between 3D and 2D models across the field. The progression and advancement in the application of 3D cell cultures in cell-based biosensors is another focal point of this review.
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Affiliation(s)
- Rasheena Edmondson
- Biomanufacturing Research Institute and Technology Enterprises (BRITE), and Department of Pharmaceutical Sciences, North Carolina Central University , Durham, North Carolina
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Abstract
Cytochrome 450 (CYP450) designates a group of enzymes abundant in smooth endoplasmic reticulum of hepatocytes and epithelial cells of small intestines. The main function of CYP450 is oxidative catalysis of various endogenous and exogenous substances. CYP450 are implicated in phase I metabolism of 80% of drugs currently in use, including anticancer drugs. They are also involved in synthesis of various hormones and influence hormone-related cancers. CYP450 genes are highly polymorphic and their variants play an important role in cancer risk and treatment. Association studies and meta-analyses have been performed to decipher the role of CYP450 polymorphisms in cancer susceptibility. Cancer treatment involves multimodal therapies and evaluation of CYP450 polymorphisms is necessary for pharmacogenetic assessment of anticancer therapy outcomes. In addition, CYP450 inhibitors are being evaluated for improved pharmacokinetics and oral formulation of several anticancer drugs.
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Movva S. Emerging therapies for sarcoma. Curr Probl Cancer 2013; 37:87-101. [PMID: 23719333 DOI: 10.1016/j.currproblcancer.2013.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
STS are uncommon tumors of the connective tissues. The OS of patients with advanced sarcomas has improved in the last 20 years, but remains under 2 years. Drug discovery for this disease has been complicated by the fact that there are many different subtypes that comprise STS. In fact, emerging data suggest that each of these subtypes may represent a different entity, with a unique molecular profile and responsiveness to therapy. Testing of new agents and determining predictors for response in this heterogeneous disease is therefore of utmost importance.
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Affiliation(s)
- Sujana Movva
- Department of Medical Oncology, Fox Chase Cancer Center, Temple Health, USA
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19
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Bertucci F, Bouvier-Labit C, Finetti P, Metellus P, Adelaide J, Mokhtari K, Figarella-Branger D, Decouvelaere AV, Miquel C, Coindre JM, Birnbaum D. Gene expression profiling of solitary fibrous tumors. PLoS One 2013; 8:e64497. [PMID: 23734203 PMCID: PMC3667191 DOI: 10.1371/journal.pone.0064497] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Accepted: 04/15/2013] [Indexed: 12/12/2022] Open
Abstract
Background Solitary fibrous tumors (SFTs) are rare spindle-cell tumors. Their cell-of-origin and molecular basis are poorly known. They raise several clinical problems. Differential diagnosis may be difficult, prognosis is poorly apprehended by histoclinical features, and no effective therapy exists for advanced stages. Methods We profiled 16 SFT samples using whole-genome DNA microarrays and analyzed their expression profiles with publicly available profiles of 36 additional SFTs and 212 soft tissue sarcomas (STSs). Immunohistochemistry was applied to validate the expression of some discriminating genes. Results SFTs displayed whole-genome expression profiles more homogeneous and different from STSs, but closer to genetically-simple than genetically-complex STSs. The SFTs/STSs comparison identified a high percentage (∼30%) of genes as differentially expressed, most of them without any DNA copy number alteration. One of the genes most overexpressed in SFTs encoded the ALDH1 stem cell marker. Several upregulated genes and associated ontologies were also related to progenitor/stem cells. SFTs also overexpressed genes encoding therapeutic targets such as kinases (EGFR, ERBB2, FGFR1, JAK2), histone deacetylases, or retinoic acid receptors. Their overexpression was found in all SFTs, regardless the anatomical location. Finally, we identified a 31-gene signature associated with the mitotic count, containing many genes related to cell cycle/mitosis, including AURKA. Conclusion We established a robust repertoire of genes differentially expressed in SFTs. Certain overexpressed genes could provide new diagnostic (ALDH1A1), prognostic (AURKA) and/or therapeutic targets.
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Affiliation(s)
- François Bertucci
- Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes (IPC), UMR1068 Inserm; Marseille, France
- Département d'Oncologie Médicale, IPC, CRCM, UMR1068 Inserm, Marseille, France
- Faculté de Médecine, Aix-Marseille Université, Marseille, France
- * E-mail:
| | - Corinne Bouvier-Labit
- Faculté de Médecine, Aix-Marseille Université, Marseille, France
- Département d’Anatomopathologie, Hôpital de la Timone, Marseille, France
| | - Pascal Finetti
- Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes (IPC), UMR1068 Inserm; Marseille, France
| | - Philippe Metellus
- Faculté de Médecine, Aix-Marseille Université, Marseille, France
- Département de Neurochirurgie, Hôpital de la Timone, Marseille, France
| | - José Adelaide
- Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes (IPC), UMR1068 Inserm; Marseille, France
| | - Karima Mokhtari
- Département de Neuropathologie, Hôpital Pitié Salpétrière, Paris, France
| | - Dominique Figarella-Branger
- Faculté de Médecine, Aix-Marseille Université, Marseille, France
- Département d’Anatomopathologie, Hôpital de la Timone, Marseille, France
| | | | - Catherine Miquel
- Département de Neuropathologie, Hôpital Sainte Anne, Paris, France
| | | | - Daniel Birnbaum
- Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes (IPC), UMR1068 Inserm; Marseille, France
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20
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Bouvier C, Bertucci F, Métellus P, Finetti P, de Paula AM, Forest F, Mokhtari K, Miquel C, Birnbaum D, Vasiljevic A, Jouvet A, Coindre JM, Loundou A, Figarella-Branger D. ALDH1 is an immunohistochemical diagnostic marker for solitary fibrous tumours and haemangiopericytomas of the meninges emerging from gene profiling study. Acta Neuropathol Commun 2013; 1:10. [PMID: 24252471 PMCID: PMC3893364 DOI: 10.1186/2051-5960-1-10] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2013] [Accepted: 03/17/2013] [Indexed: 01/23/2023] Open
Abstract
Background Solitary Fibrous Tumours (SFT) and haemangiopericytomas (HPC) are rare meningeal tumours that have to be distinguished from meningiomas and more rarely from synovial sarcomas. We recently found that ALDH1A1 was overexpressed in SFT and HPC as compared to soft tissue sarcomas. Using whole-genome DNA microarrays, we defined the gene expression profiles of 16 SFT/HPC (9 HPC and 7 SFT). Expression profiles were compared to publicly available expression profiles of additional SFT or HPC, meningiomas and synovial sarcomas. We also performed an immunohistochemical (IHC) study with anti-ALDH1 and anti-CD34 antibodies on Tissue Micro-Arrays including 38 SFT (25 meningeal and 13 extrameningeal), 55 meningeal haemangiopericytomas (24 grade II, 31 grade III), 163 meningiomas (86 grade I, 62 grade II, 15 grade III) and 98 genetically confirmed synovial sarcomas. Results ALDH1A1 gene was overexpressed in SFT/HPC, as compared to meningiomas and synovial sarcomas. These findings were confirmed at the protein level. 84% of the SFT and 85.4% of the HPC were positive with anti-ALDH1 antibody, while only 7.1% of synovial sarcomas and 1.2% of meningiomas showed consistent expression. Positivity was usually more diffuse in SFT/HPC compared to other tumours with more than 50% of tumour cells immunostained in 32% of SFT and 50.8% of HPC. ALDH1 was a sensitive and specific marker for the diagnosis of SFT (SE = 84%, SP = 98.8%) and HPC (SE = 84.5%, SP = 98.7%) of the meninges. In association with CD34, ALDH1 expression had a specificity and positive predictive value of 100%. Conclusion We show that ALDH1, a stem cell marker, is an accurate diagnostic marker for SFT and HPC, which improves the diagnostic value of CD34. ALDH1 could also be a new therapeutic target for these tumours which are not sensitive to conventional chemotherapy.
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21
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Ryan CW, Desai J. The past, present, and future of cytotoxic chemotherapy and pathway-directed targeted agents for soft tissue sarcoma. Am Soc Clin Oncol Educ Book 2013:0011300386. [PMID: 23714556 DOI: 10.14694/edbook_am.2013.33.e386] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
The individual rarity of the many subtypes of soft tissue sarcomas has historically mandated an empiric approach to systemic therapy. Doxorubicin, first reported to have activity in sarcomas 40 years ago, remains the generalizable first-line treatment of choice for many subtypes, with no other drug or combination having shown an overall-survival advantage. Other cytotoxic agents, such as paclitaxel for angiosarcoma or gemcitabine with docetaxel for leiomyosarcoma, are commonly used for certain histologic subtypes based on relatively small studies. Trabectedin, particularly active against leiomyosarcoma and myxoid liposarcoma, is approved in many countries worldwide but not yet in the United States or Australia. Newer cytotoxic agents, including ifosfamide derivatives, are in current phase III testing. Although advances is systemic therapy of soft-tissue sarcomas have been hampered by their biologic heterogeneity, this diversity also serves as fertile ground for discovery and validation of targetable molecular drivers. The most notable success in this regard has been the development of small molecule therapies for gastrointestinal stromal tumors. Other targets of recent interest include mouse double minute 2 homolog (MDM2) in dedifferentiated liposarcoma and anaplastic lymphoma kinase (ALK) in inflammatory myofibroblastic tumor. Molecular therapies that have shown activity in diverse sarcoma populations include mammalian target of rapamycin (mTOR) inhibitors and vascular endothelial growth factor (VEGF-R) inhibitors. Among the latter, pazopanib demonstrated a progression-free survival over placebo in prior-treated patients with advanced sarcoma, and is now approved for use in the sarcomas in many countries. Efforts to understand the key molecular aberrations in any particular tumor continue towards a goal of individualized sarcoma therapy.
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Affiliation(s)
- Christopher W Ryan
- From the Knight Cancer Institute, Oregon Health & Science University, Portland, OR; Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Walter and Eliza Hall Institute for Medical Research, Melbourne, Australia
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22
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Hassan M, Andersson BS. Role of pharmacogenetics in busulfan/cyclophosphamide conditioning therapy prior to hematopoietic stem cell transplantation. Pharmacogenomics 2013; 14:75-87. [PMID: 23252950 DOI: 10.2217/pgs.12.185] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Hematopoietic stem cell transplantation (HSCT) is a curative treatment for several malignant and nonmalignant disorders. Busulfan (Bu) and cyclophosphamide (Cy) are the most commonly used alkylators in high-dose pretransplant conditioning for HSCT; a treatment that is correlated with drug-related toxicity and relapse. Pharmacogenetic investigations have shown that CYP450, as well as aldehyde dehydrogenase, are clearly involved with Cy metabolism and are associated with altered treatment response, Cy metabolism and the unique stem-cell sparing capacity. Moreover, glutathione-S-transferase isoenzymes have been associated with cellular outward transport of various alkylating agents, including Cy metabolites, melphalan, Bu and chlorambucil. A shift from genetic-based studies to whole-genome-based investigations of Cy- and Bu-associated markers may contribute to personalizing the conditioning therapy and enhancing the clinical outcome of HSCT.
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Affiliation(s)
- Moustapha Hassan
- Experimental Cancer Medicine (ECM), Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
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23
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Somaiah N, von Mehren M. New drugs and combinations for the treatment of soft-tissue sarcoma: a review. Cancer Manag Res 2012; 4:397-411. [PMID: 23226072 PMCID: PMC3514064 DOI: 10.2147/cmar.s23257] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Sarcomas are a heterogeneous group of solid tumors arising from either soft tissues or bone, accounting for approximately 1% of all cancers in adults. Management of these diseases has changed little over the past 10 years, with the exception of treatment of gastrointestinal stromal tumors. Reasons for this stagnation include multiple histologies commonly grouped together in clinical trials limiting the understanding of benefit of treatment and limited investigation of molecular targeted therapies. More recently, advances in molecular pathogenesis, the advent of novel and targeted therapeutics, and increasing collaborations between sarcoma investigators has helped move the field forward in the right direction. Here, we review the recent data on novel agents tested for the management of adult soft-tissue sarcomas, excluding gastrointestinal stromal tumors.
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Affiliation(s)
- Neeta Somaiah
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Margaret von Mehren
- Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
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Anticancer activity of stabilized palifosfamide in vivo: schedule effects, oral bioavailability, and enhanced activity with docetaxel and doxorubicin. Anticancer Drugs 2012; 23:173-84. [PMID: 22027537 DOI: 10.1097/cad.0b013e32834d73a6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Palifosfamide, the DNA-alkylating metabolite of ifosfamide (IFOS), has been synthesized as a stabilized tris or lysine salt and found to have preclinical and clinical antitumor activity. Stabilized palifosfamide overcomes limitations of IFOS because of patient-to-patient variability in response resulting from variable prodrug activation, resistance and toxicities of metabolic byproducts, acrolein and chloroacetaldehyde. Palifosfamide represents an effective alternative to IFOS and other DNA-alkylating prodrugs. The antitumor activities of stabilized palifosfamide were investigated in vivo. Dose response, route and schedule of administration, and interaction with docetaxel or doxorubicin were investigated in NCr-nu/nu mice bearing established orthotopic mammary MX-1 tumor xenografts. Oral activity was investigated in P388-1 leukemia in CD2F1 mice. Oral and intraperitoneal bioavailabilities were compared in Sprague-Dawley rats. Stabilized palifosfamide administered by optimized regimens suppressed MX-1 tumor growth (P<0.05) by greater than 80% with 17% complete antitumor responses and up to three-fold increase in time to three tumor doublings over controls. Median survival in the P388-1 (P<0.001) model was increased by 9 days over controls. Oral bioavailability in rats was 48-73% of parenteral administration, and antitumor activity in mice was equivalent by both routes. Treatment with palifosfamide-tris combined with docetaxel or doxorubicin at optimal regimens resulted in complete tumor regression in 62-75% of mice. These studies support investigation of stabilized palifosfamide in human cancers by parenteral or oral administration as a single agent and in combination with other approved drugs. The potential for clinical translation of the cooperative interaction of palifosfamide-tris with doxorubicin by intravenous administration is supported by results from a recent randomized Phase-II study in unresectable or metastatic soft-tissue sarcoma.
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Abstract
Soft tissue sarcomas (STS) are malignancies of mesenchymal origin that represent approximately 1% of cancers in adults. Systematic research into the treatment of STS is challenging given its rarity and disease heterogeneity. Despite the ability to histologically subtype STS, only recently has our approach to therapy begun to differentiate along these lines. The purpose of this review is to highlight emerging therapeutic targets and therapies that hold the potential to add to the current state of systemic treatment for STS.
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Affiliation(s)
- Jason L Smith
- Divisions of Hematology, Medical Oncology, Cellular Therapy, Duke University Medical Center, Durham, NC 27710, USA.
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