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Kulkarni S, Seneviratne N, Tosun Ç, Madhusudan S. PARP inhibitors in ovarian cancer: Mechanisms of resistance and implications to therapy. DNA Repair (Amst) 2025; 149:103830. [PMID: 40203475 DOI: 10.1016/j.dnarep.2025.103830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 03/20/2025] [Accepted: 03/26/2025] [Indexed: 04/11/2025]
Abstract
Advanced epithelial ovarian cancer of the high-grade serous subtype (HGSOC) remains a significant clinical challenge due to the development of resistance to current platinum-based chemotherapies. PARP1/2 inhibitors (PARPi) exploit the well-characterised homologous recombination repair deficiency (HRD) in HGSOC and offer an effective targeted approach to treatment. Several clinical trials demonstrated that PARPi (olaparib, rucaparib, niraparib) significantly improved progression-free survival (PFS) in HGSOC in the recurrent maintenance setting. However, 40-70 % of patients develop Resistance to PARPi presenting an ongoing challenge in the clinic. Therefore, there is an unmet need for novel targeted therapies and biomarkers to identify intrinsic or acquired resistance to PARPi in ovarian cancer. Understanding the mechanisms of resistance to PARPi is crucial for identifying molecular vulnerabilities, developing effective biomarkers for patient stratification and guiding treatment decisions. Here, we summarise the current landscape of mechanisms associated with PARPi resistance such as restored homologous recombination repair functionality, replication fork stability and alterations to PARP1 and PARP2 and the DNA damage response. We highlight the role of circulating tumour DNA (ctDNA) in identifying acquired resistance biomarkers and its potential in guiding 'real-time' treatment decisions. Moreover, we explore other innovative treatment strategies aimed at overcoming specific resistance mechanisms, including the inhibition of ATR, WEE1 and POLQ. We also examine the role of PARPi rechallenge in patients with acquired resistance.
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Affiliation(s)
- Sanat Kulkarni
- Medical Sciences Division, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
| | | | - Çağla Tosun
- Naaz-Coker Ovarian Cancer Research Centre, Biodiscovery Institute, School of Medicine, University of Nottingham, University Park, Nottingham NG7 3RD, UK
| | - Srinivasan Madhusudan
- Naaz-Coker Ovarian Cancer Research Centre, Biodiscovery Institute, School of Medicine, University of Nottingham, University Park, Nottingham NG7 3RD, UK; Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK.
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Karim NA, Miao J, Reckamp KL, Gay CM, Byers LA, Zhao YQ, Redman MW, Carrizosa DR, Wang WL, Petty WJ, Mehta K, Faller BA, Agamah ES, Kasbari SS, Malisetti RK, Kumar A, Schallenkamp J, Alluri KC, Gray JE, Kelly K. Phase II Randomized Study of Maintenance Atezolizumab Versus Atezolizumab Plus Talazoparib in Patients With SLFN11 Positive Extensive-Stage SCLC: S1929. J Thorac Oncol 2025; 20:383-394. [PMID: 39505259 DOI: 10.1016/j.jtho.2024.10.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 09/03/2024] [Accepted: 10/29/2024] [Indexed: 11/08/2024]
Abstract
OBJECTIVE To evaluate whether the addition of a poly (adenosine diphosphate-ribose) polymerase inhibitor talazoparib to maintenance immune checkpoint inhibitor atezolizumab after frontline chemoimmunotherapy improved outcomes in patients with Schlafen 11 (SLFN11)-positive extensive-stage SCLC (ES-SCLC). METHODS Patients with newly diagnosed SLFN11 expressing (H-score ≥ 1, evaluated centrally) ES-SCLC were randomized to maintenance atezolizumab (A) versus atezolizumab plus talazoparib (AT) after frontline chemotherapy plus atezolizumab. The primary objective was to compare progression-free survival (PFS) using a one-sided 10% level stratified log-rank test. Secondary endpoints included objective response rate, overall survival, and toxicity. The target sample size was 84 eligible patients. RESULTS From June 15, 2020, to December 15, 2022, 106 eligible patients were randomized (54 to AT and 52 to A). Progression-free survival was improved with AT versus A (hazard ratio = 0.66, 80% confidence interval: 0.50-0.86, one-sided p = 0.019) with a median PFS of 2.9 and 2.4 months; overall survival was not different between groups (hazard ratio = 0.98, 80% confidence interval: 0.71-1.36, one-sided p = 0.47). Grade 3 and higher non-hematologic treatment-related adverse events occurred in 17% of patients with AT and 14% of patients with A. Grade 3 and higher hematological treatment-related adverse events were more common in AT (50%) than in A (4%) (p < 0.001). CONCLUSION Maintenance AT improved PFS in patients with SLFN11-positive ES-SCLC that did not progress after initial chemo-immunotherapy. Hematologic toxicity, primarily grade 3 anemia, was increased with AT, as expected. Prospective biomarker selection was demonstrated, paving the way for future evaluation of novel therapies in molecularly defined SCLC populations.
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Affiliation(s)
- Nagla Abdel Karim
- Inova Schar Cancer Institute, Fairfax, Virginia; University of Virginia, Fairfax, Virginia.
| | - Jieling Miao
- SWOG Statistical Center and Data Management Center, Seattle, Washington; Fred Hutchinson Cancer Center, Seattle, Washington
| | - Karen L Reckamp
- Cedars-Sinai Medical Center, Los Angeles, California; Department of Thoracic Head and Neck Medical Oncology, The University of Texas Maryland
| | | | | | - Ying-Qi Zhao
- SWOG Statistical Center and Data Management Center, Seattle, Washington; Fred Hutchinson Cancer Center, Seattle, Washington
| | - Mary W Redman
- SWOG Statistical Center and Data Management Center, Seattle, Washington; Fred Hutchinson Cancer Center, Seattle, Washington
| | | | - Wei-Lien Wang
- Department of Pathology, MD Anderson Cancer Center, The University of Texas Houston, Texas
| | | | - Kathan Mehta
- Medstar Georgetown Cancer Institute, Washington, District of Columbia
| | | | | | - Samer S Kasbari
- Southeastern Medical Oncology Center, Goldsboro, North Carolina
| | - Rajini K Malisetti
- Minnesota Oncology Hematology PA - Coon Rapids, Minneapolis, Minneapolis
| | - Atul Kumar
- University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico
| | | | | | | | - Karen Kelly
- UC Davis Comprehensive Cancer Center, Sacramento, California
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3
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Kawai-Kawachi A, Lenormand MM, Astier C, Herbel N, Cutrona MB, Ngo C, Garrido M, Eychenne T, Dorvault N, Bordelet L, Song F, Bouyakoub R, Loktev A, Romo-Morales A, Henon C, Colmet-Daage L, Vibert J, Drac M, Brough R, Schwob E, Martella O, Pinna G, Shipley JM, Mittnacht S, Zimmermann A, Gulati A, Mir O, Le Cesne A, Faron M, Honoré C, Lord CJ, Chabanon RM, Postel-Vinay S. Replication Stress Is an Actionable Genetic Vulnerability in Desmoplastic Small Round Cell Tumors. Cancer Res 2025; 85:154-170. [PMID: 39412947 DOI: 10.1158/0008-5472.can-23-3603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 07/10/2024] [Accepted: 10/02/2024] [Indexed: 10/18/2024]
Abstract
Desmoplastic small round cell tumor (DSRCT) is an aggressive sarcoma subtype that is driven by the EWS-WT1 chimeric transcription factor. The prognosis for DSRCT is poor, and major advances in treating DSRCT have not occurred for over two decades. To identify effective therapeutic approaches to target DSRCT, we conducted a high-throughput drug sensitivity screen in a DSRCT cell line assessing chemosensitivity profiles for 79 small-molecule inhibitors. DSRCT cells were sensitive to PARP inhibitors (PARPi) and ataxia-telangiectasia and Rad3-related inhibitors (ATRi), as monotherapies and in combination. These effects were recapitulated using multiple clinical PARPi and ATRi in three biologically distinct, clinically relevant models of DSRCT, including cell lines, a patient-derived xenograft-derived organoid model, and a cell line-derived xenograft mouse model. Mechanistically, exposure to a combination of PARPi and ATRi caused increased DNA damage, G2-M checkpoint activation, micronuclei accumulation, replication stress, and R-loop formation. EWS-WT1 silencing abrogated these phenotypes and was epistatic with exogenous expression of the R-loop resolution enzyme RNase H1 in reversing sensitivity to PARPi and ATRi monotherapies. The combination of PARPi and ATRi also induced EWS-WT1-dependent cell-autonomous activation of the cyclic GMP-AMP synthase-stimulator of IFN genes innate immune pathway and cell-surface expression of PD-L1. Taken together, these findings point toward a role for EWS-WT1 in generating R-loop-dependent replication stress that leads to a targetable vulnerability, providing a rationale for the clinical assessment of PARPi and ATRi in DSRCT. Significance: EWS-WT1, the unique oncogenic driver of desmoplastic small round cell tumors, confers sensitivity to PARP and ATR inhibitors, supporting the potential of these drugs in treating patients with this aggressive sarcoma subtype.
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Affiliation(s)
- Asuka Kawai-Kawachi
- The ATIP-Avenir Inserm and ERC StG (Epi)genetic Vulnerabilities in Solid Tumors and Sarcoma Laboratory, Inserm Unit UMR 981, Université Paris-Saclay, Gustave Roussy, Villejuif, France
- Cancer RNA Research Unit, National Cancer Center Research Institute, Tokyo, Japan
| | - Madison M Lenormand
- The ATIP-Avenir Inserm and ERC StG (Epi)genetic Vulnerabilities in Solid Tumors and Sarcoma Laboratory, Inserm Unit UMR 981, Université Paris-Saclay, Gustave Roussy, Villejuif, France
- Department of Genomes and Genetics, Institut Pasteur, CNRS UMR3525, Paris, France
| | - Clémence Astier
- The ATIP-Avenir Inserm and ERC StG (Epi)genetic Vulnerabilities in Solid Tumors and Sarcoma Laboratory, Inserm Unit UMR 981, Université Paris-Saclay, Gustave Roussy, Villejuif, France
- Université Paris-Saclay, Université Paris-Sud XI, Faculté de Médicine, Le Kremlin Bicêtre, France
| | - Noé Herbel
- The ATIP-Avenir Inserm and ERC StG (Epi)genetic Vulnerabilities in Solid Tumors and Sarcoma Laboratory, Inserm Unit UMR 981, Université Paris-Saclay, Gustave Roussy, Villejuif, France
- Université Paris-Saclay, Université Paris-Sud XI, Faculté de Médicine, Le Kremlin Bicêtre, France
- Drug Development Department, DITEP, Gustave Roussy, Villejuif, France
- Sarcoma Committee, Gustave Roussy, Villejuif, France
- Viroxis SAS Biotech, Gustave Roussy, Villejuif, France
| | | | - Carine Ngo
- The ATIP-Avenir Inserm and ERC StG (Epi)genetic Vulnerabilities in Solid Tumors and Sarcoma Laboratory, Inserm Unit UMR 981, Université Paris-Saclay, Gustave Roussy, Villejuif, France
- Sarcoma Committee, Gustave Roussy, Villejuif, France
| | - Marlène Garrido
- The ATIP-Avenir Inserm and ERC StG (Epi)genetic Vulnerabilities in Solid Tumors and Sarcoma Laboratory, Inserm Unit UMR 981, Université Paris-Saclay, Gustave Roussy, Villejuif, France
| | - Thomas Eychenne
- The ATIP-Avenir Inserm and ERC StG (Epi)genetic Vulnerabilities in Solid Tumors and Sarcoma Laboratory, Inserm Unit UMR 981, Université Paris-Saclay, Gustave Roussy, Villejuif, France
| | - Nicolas Dorvault
- The ATIP-Avenir Inserm and ERC StG (Epi)genetic Vulnerabilities in Solid Tumors and Sarcoma Laboratory, Inserm Unit UMR 981, Université Paris-Saclay, Gustave Roussy, Villejuif, France
| | - Laetitia Bordelet
- Experimental and Translational Pathology (PETRA) Platform, AMMICa Unit (CNRS Unit UMS 3655, Inserm Unit US 23), Gustave Roussy, Villejuif, France
| | - Feifei Song
- The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Ryme Bouyakoub
- Organoid Core Facility, Gustave Roussy, Villejuif, France
| | - Anastasia Loktev
- Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom
| | - Antonio Romo-Morales
- Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom
| | - Clémence Henon
- The ATIP-Avenir Inserm and ERC StG (Epi)genetic Vulnerabilities in Solid Tumors and Sarcoma Laboratory, Inserm Unit UMR 981, Université Paris-Saclay, Gustave Roussy, Villejuif, France
- Drug Development Department, DITEP, Gustave Roussy, Villejuif, France
- Sarcoma Committee, Gustave Roussy, Villejuif, France
| | - Léo Colmet-Daage
- The ATIP-Avenir Inserm and ERC StG (Epi)genetic Vulnerabilities in Solid Tumors and Sarcoma Laboratory, Inserm Unit UMR 981, Université Paris-Saclay, Gustave Roussy, Villejuif, France
| | - Julien Vibert
- The ATIP-Avenir Inserm and ERC StG (Epi)genetic Vulnerabilities in Solid Tumors and Sarcoma Laboratory, Inserm Unit UMR 981, Université Paris-Saclay, Gustave Roussy, Villejuif, France
- Drug Development Department, DITEP, Gustave Roussy, Villejuif, France
- Sarcoma Committee, Gustave Roussy, Villejuif, France
| | - Marjorie Drac
- Institute of Molecular Genetics, CNRS Unit UMR 5535, Université de Montpellier, Montpellier, France
| | - Rachel Brough
- The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Etienne Schwob
- Institute of Molecular Genetics, CNRS Unit UMR 5535, Université de Montpellier, Montpellier, France
| | | | - Guillaume Pinna
- RNA Interference Platform PARi, IRCM/IBFJ/CEA UMRE008, Fontenay-aux-Roses, France
| | - Janet M Shipley
- Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom
| | - Sibylle Mittnacht
- UCL Cancer Institute, University College London, London, United Kingdom
| | - Astrid Zimmermann
- Research Unit Oncology, The Healthcare Business of Merck KGaA, Darmstadt, Germany
| | - Aditi Gulati
- The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Olivier Mir
- Sarcoma Committee, Gustave Roussy, Villejuif, France
| | - Axel Le Cesne
- Sarcoma Committee, Gustave Roussy, Villejuif, France
| | | | | | - Christopher J Lord
- The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Roman M Chabanon
- The ATIP-Avenir Inserm and ERC StG (Epi)genetic Vulnerabilities in Solid Tumors and Sarcoma Laboratory, Inserm Unit UMR 981, Université Paris-Saclay, Gustave Roussy, Villejuif, France
- Université Paris-Saclay, Université Paris-Sud XI, Faculté de Médicine, Le Kremlin Bicêtre, France
- The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Sophie Postel-Vinay
- The ATIP-Avenir Inserm and ERC StG (Epi)genetic Vulnerabilities in Solid Tumors and Sarcoma Laboratory, Inserm Unit UMR 981, Université Paris-Saclay, Gustave Roussy, Villejuif, France
- Université Paris-Saclay, Université Paris-Sud XI, Faculté de Médicine, Le Kremlin Bicêtre, France
- Drug Development Department, DITEP, Gustave Roussy, Villejuif, France
- Sarcoma Committee, Gustave Roussy, Villejuif, France
- UCL Cancer Institute, University College London, London, United Kingdom
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Brown SR, Vomhof-DeKrey EE, Al-Marsoummi S, Beyer T, Lauckner B, Samson M, Sattar S, Brown ND, Basson MD. SLFN12 Expression Significantly Effects the Response to Chemotherapy Drugs in Triple-Negative Breast Cancer. Cancers (Basel) 2024; 16:3848. [PMID: 39594803 PMCID: PMC11593201 DOI: 10.3390/cancers16223848] [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: 10/11/2024] [Revised: 11/04/2024] [Accepted: 11/14/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND/OBJECTIVES Schlafen12 (SLFN12) is an intermediate human Schlafen protein shown to correlate with survivability in triple-negative breast cancer (TNBC). SLFN12 causes differential expressions of significant cancer genes, but how they change in response to chemotherapy remains unknown. Our aim is to identify the effect of chemotherapy on genes that improve TNBC outcomes and other SLFN family members following SLFN12 knockout or overexpression. METHODS We overexpressed SLFN12 using a lentiviral vector and knocked out SLFN12 (AdvShSLFN12) using a hairpin adenovirus in MDA-MB-231 TNBC cells. Cells were treated with camptothecin, paclitaxel, zoledronic acid, or carboplatin to evaluate the SLFN12 signature cancer genes associated with improved TNBC outcomes using qPCR. Additionally, cells were treated alone and in combination with AdvShSLFN12, IFN-α2 (known SLFN12 stimulator), carboplatin, and paclitaxel. After treatment, the viable cell numbers were analyzed utilizing a colorimetric crystal violet assay for cell viability. RESULTS The SLFN family and SLFN12 cancer signature gene mRNA expressions were analyzed by RT-qPCR. Treating SLFN12-overexpressing TNBC cells with chemotherapy agents resulted in the differential expressions of eight cancer-related genes. Notably, GJB3 was downregulated following treatment with each chemotherapeutic drug. Inducing SLFN12 with IFN-α2 resulted in decreased cell viability and increased SLFN12 mRNA levels following treatment with paclitaxel or carboplatin. CONCLUSIONS These results suggest that SLFN12 overexpression significantly affects the expressions of genes driving phenotypic changes in response to chemotherapy and influences additional SLFN family members following IFN-α2 treatment. This may contribute to improving the survival of patients with SLFN12 overexpression. Additionally, patient SLFN12 levels can be used as a factor when pursuing personalized chemotherapy treatments.
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Affiliation(s)
- Savannah R. Brown
- Department of Pathology, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (S.R.B.); (E.E.V.-D.)
| | - Emilie Erin Vomhof-DeKrey
- Department of Pathology, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (S.R.B.); (E.E.V.-D.)
- Department of Biomedical Sciences, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (S.A.-M.); (T.B.); (B.L.); (M.S.); (S.S.); (N.D.B.)
- Department of Surgery, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA
| | - Sarmad Al-Marsoummi
- Department of Biomedical Sciences, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (S.A.-M.); (T.B.); (B.L.); (M.S.); (S.S.); (N.D.B.)
| | - Trysten Beyer
- Department of Biomedical Sciences, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (S.A.-M.); (T.B.); (B.L.); (M.S.); (S.S.); (N.D.B.)
| | - Bo Lauckner
- Department of Biomedical Sciences, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (S.A.-M.); (T.B.); (B.L.); (M.S.); (S.S.); (N.D.B.)
| | - Mckenzie Samson
- Department of Biomedical Sciences, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (S.A.-M.); (T.B.); (B.L.); (M.S.); (S.S.); (N.D.B.)
| | - Sarah Sattar
- Department of Biomedical Sciences, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (S.A.-M.); (T.B.); (B.L.); (M.S.); (S.S.); (N.D.B.)
| | - Nicholas D. Brown
- Department of Biomedical Sciences, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (S.A.-M.); (T.B.); (B.L.); (M.S.); (S.S.); (N.D.B.)
| | - Marc D. Basson
- Department of Surgery, Northeast Ohio Medical University, Rootstown, OH 44272, USA
- University Hospitals-NEOMED, Cleveland, OH 44106, USA
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Kaczorowski M, Ylaya K, Chłopek M, Taniyama D, Pommier Y, Lasota J, Miettinen M. Immunohistochemical Evaluation of Schlafen 11 (SLFN11) Expression in Cancer in the Search of Biomarker-Informed Treatment Targets: A Study of 127 Entities Represented by 6658 Tumors. Am J Surg Pathol 2024:00000478-990000000-00409. [PMID: 39185596 DOI: 10.1097/pas.0000000000002299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/27/2024]
Abstract
Schlafen 11 (SLFN11), a DNA/RNA helicase, acts as a regulator of cellular response to replicative stress and irreversibly triggers replication block and cell death. Several preclinical in vitro studies and clinical trials established that SLFN11 expression predicts outcomes in patients with advanced cancer treated with DNA-damaging chemotherapeutics and more recently with poly(ADP-ribose) polymerase inhibitors. SLFN11 expression status remains unknown in many cancer types, especially in mesenchymal tumors. This study evaluated a cohort of well characterized 3808 epithelial and 2850 mesenchymal and neuroectodermal tumors for SLFN11 expression using immunohistochemistry. Nuclear SLFN11 expression was rare in some of the most common carcinomas, for example, hepatocellular (1%), prostatic (2%), colorectal (5%), or breast (16%) cancers. In contrast, other epithelial tumors including mesotheliomas (92%), clear cell renal cell carcinomas (79%), small cell lung cancers (76%), squamous cell carcinomas of the tonsil (89%) and larynx (71%), or ovarian serous carcinomas (69%) were mostly SLFN11-positive. Compared with epithelial malignancies, SLFN11 expression was overall higher in neuroectodermal and mesenchymal tumors. Most positive entities included desmoplastic small round cell tumor (100%), Ewing sarcoma (92%), undifferentiated sarcoma (92%), solitary fibrous tumor (91%), dedifferentiated liposarcoma (89%), synovial sarcoma (86%), and malignant peripheral nerve sheath tumor (85%). Also, this study identifies tumors with potentially worse response to DNA-damaging drugs including antibody drug conjugates due to the absence of SLFN11 expression. Such entities may benefit from alternative treatments or strategies to overcome SLFN11 deficiency-related drug resistance. Our approach and results should serve as a foundation for future biomarker-associated clinical trials.
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Affiliation(s)
- Maciej Kaczorowski
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD
- Department of Clinical and Experimental Pathology, Wroclaw Medical University, Wrocław, Poland
| | - Kris Ylaya
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD
| | | | - Daiki Taniyama
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | - Yves Pommier
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | - Jerzy Lasota
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD
| | - Markku Miettinen
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD
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Magrath JW, Espinosa-Cotton M, Flinchum DA, Sampath SS, Cheung NK, Lee SB. Desmoplastic small round cell tumor: from genomics to targets, potential paths to future therapeutics. Front Cell Dev Biol 2024; 12:1442488. [PMID: 39139449 PMCID: PMC11319132 DOI: 10.3389/fcell.2024.1442488] [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: 06/02/2024] [Accepted: 06/26/2024] [Indexed: 08/15/2024] Open
Abstract
Desmoplastic Small Round Cell Tumor (DSRCT) is a highly aggressive pediatric cancer caused by a reciprocal translocation between chromosomes 11 and 22, leading to the formation of the EWSR1::WT1 oncoprotein. DSRCT presents most commonly in the abdominal and pelvic peritoneum and remains refractory to current treatment regimens which include chemotherapy, radiotherapy, and surgery. As a rare cancer, sample and model availability have been a limiting factor to DSRCT research. However, the establishment of rare tumor banks and novel cell lines have recently propelled critical advances in the understanding of DSRCT biology and the identification of potentially promising targeted therapeutics. Here we review model and dataset availability, current understanding of the EWSR1::WT1 oncogenic mechanism, and promising preclinical therapeutics, some of which are now advancing to clinical trials. We discuss efforts to inhibit critical dependencies including NTRK3, EGFR, and CDK4/6 as well as novel immunotherapy strategies targeting surface markers highly expressed in DSRCT such as B7-H3 or neopeptides either derived from or driven by the fusion oncoprotein. Finally, we discuss the prospect of combination therapies and strategies for prioritizing clinical translation.
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Affiliation(s)
- Justin W. Magrath
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, United States
| | - Madelyn Espinosa-Cotton
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Dane A. Flinchum
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, United States
| | - Shruthi Sanjitha Sampath
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, United States
| | - Nai Kong Cheung
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Sean B. Lee
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, United States
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Kulkarni S, Gajjar K, Madhusudan S. Poly (ADP-ribose) polymerase inhibitor therapy and mechanisms of resistance in epithelial ovarian cancer. Front Oncol 2024; 14:1414112. [PMID: 39135999 PMCID: PMC11317305 DOI: 10.3389/fonc.2024.1414112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 07/15/2024] [Indexed: 08/15/2024] Open
Abstract
Advanced epithelial ovarian cancer is the commonest cause of gynaecological cancer deaths. First-line treatment for advanced disease includes a combination of platinum-taxane chemotherapy (post-operatively or peri-operatively) and maximal debulking surgery whenever feasible. Initial response rate to chemotherapy is high (up to 80%) but most patients will develop recurrence (approximately 70-90%) and succumb to the disease. Recently, poly-ADP-ribose polymerase (PARP) inhibition (by drugs such as Olaparib, Niraparib or Rucaparib) directed synthetic lethality approach in BRCA germline mutant or platinum sensitive disease has generated real hope for patients. PARP inhibitor (PARPi) maintenance therapy can prolong survival but therapeutic response is not sustained due to intrinsic or acquired secondary resistance to PARPi therapy. Reversion of BRCA1/2 mutation can lead to clinical PARPi resistance in BRCA-germline mutated ovarian cancer. However, in the more common platinum sensitive sporadic HGSOC, the clinical mechanisms of development of PARPi resistance remains to be defined. Here we provide a comprehensive review of the current status of PARPi and the mechanisms of resistance to therapy.
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Affiliation(s)
- Sanat Kulkarni
- Department of Medicine, Sandwell and West Birmingham NHS Trust, West Bromwich, United Kingdom
| | - Ketankumar Gajjar
- Department of Gynaecological Oncology, Nottingham University Hospitals, Nottingham, United Kingdom
| | - Srinivasan Madhusudan
- Nottingham Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham, United Kingdom
- Department of Oncology, Nottingham University Hospitals, Nottingham, United Kingdom
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8
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Scattolin D, Maso AD, Ferro A, Frega S, Bonanno L, Guarneri V, Pasello G. The emerging role of Schlafen-11 (SLFN11) in predicting response to anticancer treatments: Focus on small cell lung cancer. Cancer Treat Rev 2024; 128:102768. [PMID: 38797062 DOI: 10.1016/j.ctrv.2024.102768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/16/2024] [Accepted: 05/21/2024] [Indexed: 05/29/2024]
Abstract
Small cell lung cancer (SCLC) is characterized by a dismal prognosis. Many efforts have been made so far for identifying novel biomarkers for a personalized treatment for SCLC patients. Schlafen 11 (SLFN11) is a protein differently expressed in many cancers and recently emerged as a new potential biomarker. Lower expression of SLFN11 correlates with a worse prognosis in SCLC and other tumors. SLFN11 has a role in tumorigenesis, inducing replication arrest in the presence of DNA damage through the block of the replication fork. SLFN11 interacts also with chromatin accessibility, proteotoxic stress and mammalian target of rapamycin signalling pathway. The expression of SLFN11 is regulated by epigenetic mechanisms, including promoter methylation, histone deacetylation, and the histone methylation. The downregulation of SLFN11 correlates with a worse response to topoisomerase I and II inhibitors, alkylating agents, and poly ADP-ribose polymerase inhibitors in different cancer types. Some studies exploring strategies for overcoming drug resistance in tumors with low levels of SLFN11 showed promising results. One of these strategies includes the interaction with the Ataxia Telangiectasia and Rad3-related pathway, constitutively activated and leading to cell survival and tumor growth in the presence of low levels of SLFN11. Furthermore, the expression of SLFN11 is dynamic through time and different anticancer therapy and liquid biopsy seems to be an attractive tool for catching SLFN11 different expressions. Despite this, further investigations exploring SLFN11 as a predictive biomarker, its longitudinal changes, and new strategies to overcome drug resistances are needed.
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Affiliation(s)
- Daniela Scattolin
- Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | | | - Alessandra Ferro
- Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
| | - Stefano Frega
- Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
| | - Laura Bonanno
- Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Valentina Guarneri
- Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Giulia Pasello
- Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
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9
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Zhou J, Zhang MY, Gao AA, Zhu C, He T, Herman JG, Guo MZ. Epigenetic silencing schlafen-11 sensitizes esophageal cancer to ATM inhibitor. World J Gastrointest Oncol 2024; 16:2060-2073. [PMID: 38764821 PMCID: PMC11099458 DOI: 10.4251/wjgo.v16.i5.2060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 02/26/2024] [Accepted: 04/01/2024] [Indexed: 05/09/2024] Open
Abstract
BACKGROUND Targeting DNA damage response (DDR) pathway is a cutting-edge strategy. It has been reported that Schlafen-11 (SLFN11) contributes to increase chemosensitivity by participating in DDR. However, the detailed mechanism is unclear. AIM To investigate the role of SLFN11 in DDR and the application of synthetic lethal in esophageal cancer with SLFN11 defects. METHODS To reach the purpose, eight esophageal squamous carcinoma cell lines, 142 esophageal dysplasia (ED) and 1007 primary esophageal squamous cell carcinoma (ESCC) samples and various techniques were utilized, including methylation-specific polymerase chain reaction, CRISPR/Cas9 technique, Western blot, colony formation assay, and xenograft mouse model. RESULTS Methylation of SLFN11 was exhibited in 9.15% of (13/142) ED and 25.62% of primary (258/1007) ESCC cases, and its expression was regulated by promoter region methylation. SLFN11 methylation was significantly associated with tumor differentiation and tumor size (both P < 0.05). However, no significant associations were observed between promoter region methylation and age, gender, smoking, alcohol consumption, TNM stage, or lymph node metastasis. Utilizing DNA damaged model induced by low dose cisplatin, SLFN11 was found to activate non-homologous end-joining and ATR/CHK1 signaling pathways, while inhibiting the ATM/CHK2 signaling pathway. Epigenetic silencing of SLFN11 was found to sensitize the ESCC cells to ATM inhibitor (AZD0156), both in vitro and in vivo. CONCLUSION SLFN11 is frequently methylated in human ESCC. Methylation of SLFN11 is sensitive marker of ATM inhibitor in ESCC.
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Affiliation(s)
- Jing Zhou
- School of Medicine, NanKai University, Tianjin 300071, China
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Mei-Ying Zhang
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Ai-Ai Gao
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Cheng Zhu
- School of Medicine, NanKai University, Tianjin 300071, China
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Tao He
- Departments of Pathology, Characteristic Medical Center of The Chinese People’s Armed Police Force, Tianjin 300162, China
| | - James G Herman
- The Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, United States
| | - Ming-Zhou Guo
- School of Medicine, NanKai University, Tianjin 300071, China
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
- National Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing 100853, China
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10
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Magrath JW, Goldberg IN, Truong DD, Hartono AB, Sampath SS, Jackson CE, Ghosh A, Cardin DL, Zhang H, Ludwig JA, Lee SB. Enzalutamide induces cytotoxicity in desmoplastic small round cell tumor independent of the androgen receptor. Commun Biol 2024; 7:411. [PMID: 38575753 PMCID: PMC10995187 DOI: 10.1038/s42003-024-06003-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 03/01/2024] [Indexed: 04/06/2024] Open
Abstract
Desmoplastic Small Round Cell Tumor (DSRCT) is a rare, pediatric cancer caused by the EWSR1::WT1 fusion protein. DSRCT predominantly occurs in males, which comprise 80-90% of the patient population. While the reason for this male predominance remains unknown, one hypothesis is that the androgen receptor (AR) plays a critical role in DSRCT and elevated testosterone levels in males help drive tumor growth. Here, we demonstrate that AR is highly expressed in DSRCT relative to other fusion-driven sarcomas and that the AR antagonists enzalutamide and flutamide reduce DSRCT growth. However, despite these findings, which suggest an important role for AR in DSRCT, we show that DSRCT cell lines form xenografts in female mice at the same rate as male mice and AR depletion does not significantly alter DSRCT growth in vitro. Further, we find that AR antagonists reduce DSRCT growth in cells depleted of AR, establishing an AR-independent mechanism of action. These findings suggest that AR dependence is not the reason for male predominance in DSRCT and that AR-targeted therapies may provide therapeutic benefit primarily through an AR-independent mechanism that requires further elucidation.
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Affiliation(s)
- Justin W Magrath
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, USA
| | - Ilon N Goldberg
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, USA
| | - Danh D Truong
- Sarcoma Medical Oncology Department, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Alifiani B Hartono
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, USA
| | - Shruthi Sanjitha Sampath
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, USA
| | - Chandler E Jackson
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, USA
| | - Anushka Ghosh
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, USA
| | - Derrick L Cardin
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, USA
| | - Haitao Zhang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, USA
| | - Joseph A Ludwig
- Sarcoma Medical Oncology Department, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Sean B Lee
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, USA.
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11
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Magrath JW, Goldberg IN, Truong DD, Hartono AB, Sampath SS, Jackson CE, Ghosh A, Cardin DL, Zhang H, Ludwig JA, Lee SB. Enzalutamide Induces Cytotoxicity in Desmoplastic Small Round Cell Tumor Independent of the Androgen Receptor. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.06.565842. [PMID: 37986851 PMCID: PMC10659336 DOI: 10.1101/2023.11.06.565842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2023]
Abstract
Desmoplastic Small Round Cell Tumor (DSRCT) is a rare, pediatric cancer caused by the EWSR1::WT1 fusion protein. DSRCT predominantly occurs in males, which comprise 80-90% of the patient population. While the reason for this male predominance remains unknown, one hypothesis is that the androgen receptor (AR) plays a critical role in DSRCT and elevated testosterone levels in males help drive tumor growth. Here, we demonstrate that AR is highly expressed in DSRCT relative to other fusion-driven sarcomas and that the AR antagonists enzalutamide and flutamide reduce DSRCT growth. However, despite these findings, which suggest an important role for AR in DSRCT, we show that DSRCT cell lines form xenografts in female mice at the same rate as male mice and AR depletion does not significantly alter DSRCT growth in vitro. Further, we find that AR antagonists reduce DSRCT growth in cells depleted of AR, establishing an AR-independent mechanism of action. These findings suggest that AR dependence is not the reason for male predominance in DSRCT and that AR-targeted therapies may provide therapeutic benefit primarily through an AR-independent mechanism that requires further elucidation.
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Affiliation(s)
- Justin W Magrath
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
| | - Ilon N Goldberg
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
| | - Danh D Truong
- Sarcoma Medical Oncology Department, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Alifiani B Hartono
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
| | - Shruthi Sanjitha Sampath
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
| | - Chandler E Jackson
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
| | - Anushka Ghosh
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
| | - Derrick L Cardin
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
| | - Haitao Zhang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
| | - Joseph A Ludwig
- Sarcoma Medical Oncology Department, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Sean B Lee
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
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12
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Magrath JW, Flinchum DA, Hartono AB, Goldberg IN, Espinosa-Cotton M, Moroz K, Cheung NKV, Lee SB. Genomic Breakpoint Characterization and Transcriptome Analysis of Metastatic, Recurrent Desmoplastic Small Round Cell Tumor. Sarcoma 2023; 2023:6686702. [PMID: 37457440 PMCID: PMC10344636 DOI: 10.1155/2023/6686702] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 04/27/2023] [Accepted: 06/28/2023] [Indexed: 07/18/2023] Open
Abstract
Desmoplastic small round cell tumor (DSRCT) is a rare pediatric cancer caused by the EWSR1-WT1 fusion oncogene. Despite initial response to chemotherapy, DSRCT has a recurrence rate of over 80% leading to poor patient prognosis with a 5-year survival rate of only 15-25%. Owing to the rarity of DSRCT, sample scarcity is a barrier in understanding DSRCT biology and developing effective therapies. Utilizing a novel pair of primary and recurrent DSRCTs, we present the first map of DSRCT genomic breakpoints and the first comparison of gene expression alterations between primary and recurrent DSRCT. Our genomic breakpoint map includes the lone previously published DSRCT genomic breakpoint, the breakpoint from our novel primary/recurrent DSRCT pair, as well as the breakpoints of five available DSRCT cell lines and five additional DSRCTs. All mapped breakpoints were unique and most breakpoints included a 1-3 base pair microhomology suggesting microhomology-mediated end-joining as the mechanism of translocation fusion and providing novel insights into the etiology of DSRCT. Through RNA-sequencing analysis, we identified altered genes and pathways between primary and recurrent DSRCTs. Upregulated pathways in the recurrent tumor included several DNA repair and mRNA splicing-related pathways, while downregulated pathways included immune system function and focal adhesion. We further found higher expression of the EWSR1-WT1 upregulated gene set in the recurrent tumor as compared to the primary tumor and lower expression of the EWSR1-WT1 downregulated gene set, suggesting the EWSR1-WT1 fusion continues to play a prominent role in recurrent tumors. The identified pathways including upregulation of DNA repair and downregulation of immune system function may help explain DSRCT's high rate of recurrence and can be utilized to improve the understanding of DSRCT biology and identify novel therapies to both help prevent recurrence and treat recurrent tumors.
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Affiliation(s)
- Justin W. Magrath
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
| | - Dane A. Flinchum
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
| | - Alifiani B. Hartono
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
| | - Ilon N. Goldberg
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
| | | | - Krzysztof Moroz
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
| | - Nai-Kong V. Cheung
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sean B. Lee
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
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13
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Hovsepyan S, Giani C, Pasquali S, Di Giannatale A, Chiaravalli S, Colombo C, Orbach D, Bergamaschi L, Vennarini S, Gatz SA, Gasparini P, Berlanga P, Casanova M, Ferrari A. Desmoplastic small round cell tumor: from state of the art to future clinical prospects. Expert Rev Anticancer Ther 2023; 23:471-484. [PMID: 37017324 DOI: 10.1080/14737140.2023.2200171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 04/04/2023] [Indexed: 04/06/2023]
Abstract
INTRODUCTION Desmoplastic small round cell tumor (DSRCT) is an extremely rare and highly aggressive soft tissue sarcoma, presenting mainly in male adolescents and young adults with multiple nodules disseminated within the abdominopelvic cavity. Despite a multimodal approach including aggressive cytoreductive surgery, intensive multi-agent chemotherapy, and postoperative whole abdominopelvic radiotherapy, the prognosis for DSRCT remains dismal. Median progression-free survival ranges between 4 and 21 months, and overall survival between 17 and 60 months, with the 5-year overall survival rate in the range of 10-20%. AREA COVERED This review discusses the treatment strategies used for DSRCT over the years, the state of the art of current treatments, and future clinical prospects. EXPERT OPINION The unsatisfactory outcomes for patients with DSRCT warrant investigations into innovative treatment combinations. An international multidisciplinary and multi-stakeholder collaboration, involving both pediatric and adult sarcoma communities, is needed to propel preclinical model generation and drug development, and innovative clinical trial designs to enable the timely testing of treatments involving novel agents guided by biology to boost the chances of survival for patients with this devastating disease.
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Affiliation(s)
- Shushan Hovsepyan
- Department of Pediatric Oncology, Pediatric Cancer and Blood Disorders Center of Armenia, Yerevan, Armenia
| | - Claudia Giani
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Sandro Pasquali
- Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Sarcoma Service, Department of Surgery, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Angela Di Giannatale
- Department of Hematology/Oncology, Hematology/Oncology, Ospedale Pediatrico Bambino Gesù IRCCS, Roma, Italy
| | - Stefano Chiaravalli
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Chiara Colombo
- Sarcoma Service, Department of Surgery, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Daniel Orbach
- SIREDO Oncology Center, Institut Curie, PSL University, Paris, France
| | - Luca Bergamaschi
- Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Sabina Vennarini
- Pediatric Radiotherapy Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Susanne Andrea Gatz
- Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Patrizia Gasparini
- Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Pablo Berlanga
- Department of Pediatric and Adolescent Oncology, Gustave-Roussy, Villejuif, France
| | - Michela Casanova
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Andrea Ferrari
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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14
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Abstract
Undifferentiated small round cell sarcomas (SRCSs) of bone and soft tissue comprise a heterogeneous group of highly aggressive tumours associated with a poor prognosis, especially in metastatic disease. SRCS entities mainly occur in the third decade of life and can exhibit striking disparities regarding preferentially affected sex and tumour localization. SRCSs comprise new entities defined by specific genetic abnormalities, namely EWSR1-non-ETS fusions, CIC-rearrangements or BCOR genetic alterations, as well as EWSR1-ETS fusions in the prototypic SRCS Ewing sarcoma. These gene fusions mainly encode aberrant oncogenic transcription factors that massively rewire the transcriptome and epigenome of the as yet unknown cell or cells of origin. Additional mutations or copy number variants are rare at diagnosis and, depending on the tumour entity, may involve TP53, CDKN2A and others. Histologically, these lesions consist of small round cells expressing variable levels of CD99 and specific marker proteins, including cyclin B3, ETV4, WT1, NKX3-1 and aggrecan, depending on the entity. Besides locoregional treatment that should follow standard protocols for sarcoma management, (neo)adjuvant treatment is as yet ill-defined but generally follows that of Ewing sarcoma and is associated with adverse effects that might compromise quality of life. Emerging studies on the molecular mechanisms of SRCSs and the development of genetically engineered animal models hold promise for improvements in early detection, disease monitoring, treatment-related toxicity, overall survival and quality of life.
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15
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Multi-site desmoplastic small round cell tumors are genetically related and immune-cold. NPJ Precis Oncol 2022; 6:21. [PMID: 35379887 PMCID: PMC8980094 DOI: 10.1038/s41698-022-00257-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 02/03/2022] [Indexed: 12/12/2022] Open
Abstract
Desmoplastic small round cell tumor (DSRCT) is a highly aggressive soft tissue sarcoma that is characterized by the EWSR1-WT1 fusion protein. Patients present with hundreds of tumor implants in their abdominal cavity at various sites. To determine the genetic relatedness among these sites, exome and RNA sequencing were performed on 22 DSRCT specimens from 14 patients, four of whom had specimens from various tissue sites. Multi-site tumors from individual DSRCT patients had a shared origin and were highly related. Other than the EWSR1-WT1 fusion, very few secondary cancer gene mutations were shared among the sites. Among these, ARID1A, was recurrently mutated, which corroborates findings by others in DSRCT patients. Knocking out ARID1A in JN-DSRCT cells using CRISPR/CAS9 resulted in significantly lower cell proliferation and increased drug sensitivity. The transcriptome data were integrated using network analysis and drug target database information to identify potential therapeutic opportunities in EWSR1-WT1-associated pathways, such as PI3K and mTOR pathways. Treatment of JN-DSRCT cells with the PI3K inhibitor alpelisib and mTOR inhibitor temsirolimus reduced cell proliferation. In addition, the low mutation burden was associated with an immune-cold state in DSRCT. Together, these data reveal multiple genomic and immune features of DSRCT and suggest therapeutic opportunities in patients.
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16
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ElHarouni D, Berker Y, Peterziel H, Gopisetty A, Turunen L, Kreth S, Stainczyk SA, Oehme I, Pietiäinen V, Jäger N, Witt O, Schlesner M, Oppermann S. iTReX: Interactive exploration of mono- and combination therapy dose response profiling data. Pharmacol Res 2021; 175:105996. [PMID: 34848323 DOI: 10.1016/j.phrs.2021.105996] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 11/18/2021] [Accepted: 11/19/2021] [Indexed: 12/11/2022]
Abstract
High throughput screening methods, measuring the sensitivity and resistance of tumor cells to drug treatments have been rapidly evolving. Not only do these screens allow correlating response profiles to tumor genomic features for developing novel predictors of treatment response, but they can also add evidence for therapy decision making in precision oncology. Recent analysis methods developed for either assessing single agents or combination drug efficacies enable quantification of dose-response curves with restricted symmetric fit settings. Here, we introduce iTReX, a user-friendly and interactive Shiny/R application, for both the analysis of mono- and combination therapy responses. The application features an extended version of the drug sensitivity score (DSS) based on the integral of an advanced five-parameter dose-response curve model and a differential DSS for combination therapy profiling. Additionally, iTReX includes modules that visualize drug target interaction networks and support the detection of matches between top therapy hits and the sample omics features to enable the identification of druggable targets and biomarkers. iTReX enables the analysis of various quantitative drug or therapy response readouts (e.g. luminescence, fluorescence microscopy) and multiple treatment strategies (drug treatments, radiation). Using iTReX we validate a cost-effective drug combination screening approach and reveal the application's ability to identify potential sample-specific biomarkers based on drug target interaction networks. The iTReX web application is accessible at https://itrex.kitz-heidelberg.de.
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Affiliation(s)
- Dina ElHarouni
- Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Yannick Berker
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Heike Peterziel
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Apurva Gopisetty
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Laura Turunen
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
| | - Sina Kreth
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Sabine A Stainczyk
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Ina Oehme
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Vilja Pietiäinen
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
| | - Natalie Jäger
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Olaf Witt
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Pediatric Oncology, Hematology, Immunology and Pulmonology Heidelberg University Hospital, Heidelberg, Germany
| | - Matthias Schlesner
- Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), Heidelberg, Germany; Biomedical Informatics, Data Mining and Data Analytics, Faculty of Applied Computer Science and Medical Faculty, University of Augsburg, Augsburg, Germany
| | - Sina Oppermann
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
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17
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A wake-up call for cancer DNA damage: the role of Schlafen 11 (SLFN11) across multiple cancers. Br J Cancer 2021; 125:1333-1340. [PMID: 34294893 PMCID: PMC8576031 DOI: 10.1038/s41416-021-01476-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/25/2021] [Accepted: 06/17/2021] [Indexed: 02/06/2023] Open
Abstract
DNA-damaging agents exploit increased genomic instability, a hallmark of cancer. Recently, inhibitors targeting the DNA damage response (DDR) pathways, such as PARP inhibitors, have also shown promising therapeutic potential. However, not all tumors respond well to these treatments, suggesting additional determinants of response are required. Schlafen 11 (SLFN11), a putative DNA/RNA helicase that induces irreversible replication block, is emerging as an important regulator of cellular response to DNA damage. Preclinical and emerging clinical trial data suggest that SLFN11 is a predictive biomarker of response to a wide range of therapeutics that cause DNA damage including platinum salts and topoisomerase I/II inhibitors, as well as PARP inhibitors, which has raised exciting possibilities for its clinical application. In this article, we review the function, prevalence, and clinical testing of SLFN11 in tumor biopsy samples and circulating tumor cells. We discuss mounting evidence of SLFN11 as a key predictive biomarker for a wide range of cancer therapeutics and as a prognostic marker across several cancer types. Furthermore, we discuss emerging areas of investigation such as epigenetic reactivation of SLFN11 and its role in activating immune response. We then provide perspectives on open questions and future directions in studying this important biomarker.
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Wei G, Shu X, Zhou Y, Liu X, Chen X, Qiu M. Intra-Abdominal Desmoplastic Small Round Cell Tumor: Current Treatment Options and Perspectives. Front Oncol 2021; 11:705760. [PMID: 34604040 PMCID: PMC8479161 DOI: 10.3389/fonc.2021.705760] [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: 06/11/2021] [Accepted: 08/25/2021] [Indexed: 02/05/2023] Open
Abstract
Intra-abdominal desmoplastic small round cell tumor (IDSRCT) is a rare and highly malignant soft tissue neoplasm, which is characterized by rapid progression and poor prognosis. The mechanism underlying the development of this neoplasm remains elusive, but all cases are characterized by the chromosomal translocation t (11;22) (p13; q12), which results in a formation of EWSR1-WT1 gene fusion. The diagnosis of IDSRCT is often made with core-needle tissue biopsy specimens or laparoscopy or laparotomy. Immunohistochemical analyses have shown the co-expression of epithelial, neuronal, myogenic, and mesenchymal differentiation markers. FISH or reverse transcription polymerase chain reaction detecting EWS-WT1 fusion can be performed to assist in molecular confirmation. There is no standard of care for patients with IDSRCT currently, and majority of newly diagnosed patients received the aggressive therapy, which includes >90% resection of surgical debulking, high-dose alkylator-based chemotherapy, and radiotherapy. More recently, targeted therapy has been increasingly administered to recurrent IDSRCT patients and has been associated with improved survival in clinical conditions. Immunotherapy as a possible therapeutic strategy is being explored in patients with IDSRCT. In this review, we summarize currently available knowledge regarding the epidemiology, potential mechanisms, clinical manifestations, diagnosis, treatment, and prognosis of IDSRCT to assist oncologists in comprehensively recognizing and accurately treating this malignancy.
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Affiliation(s)
- Guixia Wei
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Xinyao Shu
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Yuwen Zhou
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Xia Liu
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Xiaorong Chen
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Meng Qiu
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
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Al-Marsoummi S, Vomhof-DeKrey EE, Basson MD. Schlafens: Emerging Proteins in Cancer Cell Biology. Cells 2021; 10:2238. [PMID: 34571887 PMCID: PMC8465726 DOI: 10.3390/cells10092238] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 08/23/2021] [Accepted: 08/25/2021] [Indexed: 12/29/2022] Open
Abstract
Schlafens (SLFN) are a family of genes widely expressed in mammals, including humans and rodents. These intriguing proteins play different roles in regulating cell proliferation, cell differentiation, immune cell growth and maturation, and inhibiting viral replication. The emerging evidence is implicating Schlafens in cancer biology and chemosensitivity. Although Schlafens share common domains and a high degree of homology, different Schlafens act differently. In particular, they show specific and occasionally opposing effects in some cancer types. This review will briefly summarize the history, structure, and non-malignant biological functions of Schlafens. The roles of human and mouse Schlafens in different cancer types will then be outlined. Finally, we will discuss the implication of Schlafens in the anti-tumor effect of interferons and the use of Schlafens as predictors of chemosensitivity.
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Affiliation(s)
- Sarmad Al-Marsoummi
- Department of Biomedical Sciences, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (S.A.-M.); (E.E.V.-D.)
| | - Emilie E. Vomhof-DeKrey
- Department of Biomedical Sciences, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (S.A.-M.); (E.E.V.-D.)
- Department of Surgery, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA
| | - Marc D. Basson
- Department of Biomedical Sciences, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (S.A.-M.); (E.E.V.-D.)
- Department of Surgery, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA
- Department of Pathology, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA
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PARP inhibition in UV-associated angiosarcoma preclinical models. J Cancer Res Clin Oncol 2021; 147:2579-2590. [PMID: 34085099 PMCID: PMC8310857 DOI: 10.1007/s00432-021-03678-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 05/27/2021] [Indexed: 10/27/2022]
Abstract
PURPOSE Angiosarcoma (AS) is a rare vasoformative sarcoma, with poor overall survival and a high need for novel treatment options. Clinically, AS consists of different subtypes, including AS related to previous UV exposure (UV AS) which could indicate susceptibility to DNA damage repair inhibition. We, therefore, investigated the presence of biomarkers PARP1 (poly(ADP-ribose)polymerase-1) and Schlafen-11 (SLFN11) in UV AS. Based on experiences in other sarcomas, we examined (combination) treatment of PARP inhibitor (PARPi) olaparib and temozolomide (TMZ) in UV AS cell lines. METHODS Previously collected UV AS (n = 47) and non-UV AS (n = 96) patient samples and two UV AS cell lines (MO-LAS and AS-M) were immunohistochemically assessed for PARP1 and SLFN11 expression. Both cell lines were treated with single agents PARPi olaparib and TMZ, and the combination treatment. Next, cell viability and treatment synergy were analyzed. In addition, effects on apoptosis and DNA damage were examined. RESULTS In 46/47 UV AS samples (98%), PARP1 expression was present. SLFN11 was expressed in 80% (37/46) of cases. Olaparib and TMZ combination treatment was synergistic in both cell lines, with significantly increased apoptosis compared to single agent treatment. Furthermore, a significant increase in DNA damage marker γH2AX was present in both cell lines after combination therapy. CONCLUSION We showed combination treatment of olaparib with TMZ was synergistic in UV AS cell lines. Expression of PARP1 and SLFN11 was present in the majority of UV AS tumor samples. Together, these results suggest combination treatment of olaparib and TMZ is a potential novel AS subtype-specific treatment option for UV AS patients.
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Mello CA, Campos FAB, Santos TG, Silva MLG, Torrezan GT, Costa FD, Formiga MN, Nicolau U, Nascimento AG, Silva C, Curado MP, Nakagawa SA, Lopes A, Aguiar S. Desmoplastic Small Round Cell Tumor: A Review of Main Molecular Abnormalities and Emerging Therapy. Cancers (Basel) 2021; 13:cancers13030498. [PMID: 33525546 PMCID: PMC7865637 DOI: 10.3390/cancers13030498] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/08/2021] [Accepted: 01/20/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Desmoplastic small round cell tumor is a rare neoplasm with extremely aggressive behavior. Despite the multimodal treatment for newly diagnosed patients with chemotherapy, cytoreductive surgery and radiation, the cure rate is still low. For relapsed or progressive disease, there is limited data regarding second and third-line therapies. Novel agents have shown only modest activity. Recent molecular changes have been identified in this disease and this opens opportunities to be explored in future clinical trials. Abstract Desmoplastic small round cell tumor (DSRCT) is an extremely rare, aggressive sarcoma affecting adolescents and young adults with male predominance. Generally, it originates from the serosal surface of the abdominal cavity. The hallmark characteristic of DSRCT is the EWSR1–WT1 gene fusion. This translocation up-regulates the expression of PDGFRα, VEGF and other proteins related to tumor and vascular cell proliferation. Current management of DSRCT includes a combination of chemotherapy, radiation and aggressive cytoreductive surgery plus intra-peritoneal hyperthermic chemotherapy (HIPEC). Despite advances in multimodal therapy, outcomes remain poor since the majority of patients present disease recurrence and die within three years. The dismal survival makes DSRCT an orphan disease with an urgent need for new drugs. The treatment of advanced and recurrent disease with tyrosine kinase inhibitors, such as pazopanib, sunitinib, and mTOR inhibitors was evaluated by small trials. Recent studies using comprehensive molecular profiling of DSRCT identified potential therapeutic targets. In this review, we aim to describe the current studies conducted to better understand DSRCT biology and to explore the new therapeutic strategies under investigation in preclinical models and in early phase clinical trials.
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Affiliation(s)
- Celso Abdon Mello
- Department of Medical Oncology, A.C.Camargo Cancer Center, Sao Paulo 01509-010, Brazil; (F.A.B.C.); (M.N.F.); (U.N.); (C.S.)
- Correspondence: ; Tel.: +55-11-2189-2779
| | - Fernando Augusto Batista Campos
- Department of Medical Oncology, A.C.Camargo Cancer Center, Sao Paulo 01509-010, Brazil; (F.A.B.C.); (M.N.F.); (U.N.); (C.S.)
| | - Tiago Goss Santos
- Laboratory of Tumor Biology and Biomarkers, International Center of Research CIPE, A.C.Camargo Cancer Center, Sao Paulo 01509-010, Brazil;
- National Institute of Science and Technology in Oncogenomics and Therapeutic Innovation, Sao Paulo 05403-010, Brazil;
| | | | - Giovana Tardin Torrezan
- National Institute of Science and Technology in Oncogenomics and Therapeutic Innovation, Sao Paulo 05403-010, Brazil;
- Genomics and Molecular Biology Group, International Center of Research CIPE, A.C.Camargo Cancer Center, Sao Paulo 01508-010, Brazil
| | - Felipe D’Almeida Costa
- Department of Pathology, A.C.Camargo Cancer Center, Sao Paulo 01509-010, Brazil; (F.D.C.); (A.G.N.)
| | - Maria Nirvana Formiga
- Department of Medical Oncology, A.C.Camargo Cancer Center, Sao Paulo 01509-010, Brazil; (F.A.B.C.); (M.N.F.); (U.N.); (C.S.)
| | - Ulisses Nicolau
- Department of Medical Oncology, A.C.Camargo Cancer Center, Sao Paulo 01509-010, Brazil; (F.A.B.C.); (M.N.F.); (U.N.); (C.S.)
| | | | - Cassia Silva
- Department of Medical Oncology, A.C.Camargo Cancer Center, Sao Paulo 01509-010, Brazil; (F.A.B.C.); (M.N.F.); (U.N.); (C.S.)
| | - Maria Paula Curado
- Department of Epidemiology, A.C.Camargo Cancer Center, Sao Paulo 01508-010, Brazil;
| | - Suely Akiko Nakagawa
- Department of Surgery, A.C.Camargo Cancer Center, Sao Paulo 01509-010, Brazil; (S.A.N.); (A.L.)
| | - Ademar Lopes
- Department of Surgery, A.C.Camargo Cancer Center, Sao Paulo 01509-010, Brazil; (S.A.N.); (A.L.)
| | - Samuel Aguiar
- Department of Surgery, A.C.Camargo Cancer Center, Sao Paulo 01509-010, Brazil; (S.A.N.); (A.L.)
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The role of Schlafen 11 (SLFN11) as a predictive biomarker for targeting the DNA damage response. Br J Cancer 2020; 124:857-859. [PMID: 33328609 PMCID: PMC7921443 DOI: 10.1038/s41416-020-01202-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 11/09/2020] [Accepted: 11/17/2020] [Indexed: 01/25/2023] Open
Abstract
The therapeutic landscape of drugs targeting the DNA damage response (DDR) is rapidly expanding; however, an urgent unmet need remains for validated predictive biomarkers of response. SLFN11 has emerged as a promising predictor of sensitivity to DNA-damaging chemotherapies, and recently, been associated with sensitivity to PARP inhibition. We discuss its use as a predictive biomarker of response for targeting the DDR.
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