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Abida W, Beltran H, Raychaudhuri R. State of the Art: Personalizing Treatment for Patients With Metastatic Castration-Resistant Prostate Cancer. Am Soc Clin Oncol Educ Book 2025; 45:e473636. [PMID: 40112242 DOI: 10.1200/edbk-25-473636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2025]
Abstract
Until recently, the treatment of metastatic castration-resistant prostate cancer (mCRPC) relied exclusively on hormonal therapies and taxane chemotherapy. The advent of modern molecular profiling methods applied in the clinic, namely, next-generation sequencing and advanced positron emission tomography (PET) imaging, has allowed for the development of biomarker-driven therapeutics including anti-PD-L1 therapy for microsatellite instability-high or tumor mutation burden-high disease, poly(ADP-ribose) polymerase (PARP) inhibitors for patients with DNA damage repair mutations, and lutetium 177 vipivotide tetraxetan (177Lu-PSMA-617) for patients with prostate-specific membrane antigen (PSMA) PET-avid disease. While these targeted therapies have improved outcomes, there is an opportunity to refine biomarkers to optimize patient selection, understand resistance, and develop novel combination strategies. In addition, studies in the laboratory and in patient-derived samples have shown that a subset of mCRPC tumors lose expression of common prostate cancer markers such as prostate-specific antigen and PSMA because of lineage plasticity and the development of non-androgen receptor (AR)-driven disease. Non-AR-driven prostate cancer has been associated with aggressive behavior and poor prognosis, including in some cases histologic transformation to a poorly differentiated neuroendocrine prostate cancer (NEPC). The clinical management of NEPC typically follows the treatment paradigm for small cell lung cancer and increasingly relies on genomic and phenotypic characterization of disease, including loss of tumor suppressors and expression of cell surface markers such as DLL3. Therefore, both genomic subtyping and phenotypic subtyping are important to consider and can guide the clinical management of patients with advanced prostate cancer.
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Affiliation(s)
- Wassim Abida
- Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Himisha Beltran
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Ruben Raychaudhuri
- University of Washington and the Fred Hutchinson Cancer Research Center, Seattle, WA
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Kazmi F, Shrestha N, Liu TFD, Foord T, Heesen P, Booth S, Dodwell D, Lord S, Yeoh KW, Blagden SP. Next-generation sequencing for guiding matched targeted therapies in people with relapsed or metastatic cancer. Cochrane Database Syst Rev 2025; 3:CD014872. [PMID: 40122129 PMCID: PMC11930395 DOI: 10.1002/14651858.cd014872.pub2] [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] [Indexed: 03/25/2025]
Abstract
BACKGROUND Matched targeted therapies (MTT) given alone or in combination with systemic anti-cancer therapies have delivered proven survival benefit for many people with newly diagnosed cancer. However, there is little evidence of their effectiveness in the recurrent or late-stage setting. With this uncertainty, alongside the perception that late-stage cancers are too genetically heterogenous or too mutationally diverse to benefit from matched targeted therapies, next-generation sequencing (NGS) of tumours in people with refractory cancer remains a low priority. As a result, next-generation sequencing testing of recurrent or late-stage disease is discouraged. We lack evidence to support the utility of next generation sequencing in guiding matched targeted therapies in this setting. OBJECTIVES To evaluate the benefits and harms of matched targeted therapies in people with advanced cancers in randomised controlled trials. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organisation International Clinical Trials Registry Platform (WHO-ICTRP) search portal up to 30th October 2024. We also screened reference lists of included studies and also the publications that cited these studies. SELECTION CRITERIA We included randomised controlled trials (RCTs) that had enroled participants with advanced/refractory solid or haematological cancers who had progressed through at least one line of standard anti-cancer systemic therapy. To be eligible, all participants should have received matched targeted therapy based on next-generation sequencing carried out on their tumour (tumour tissue, blood or bone marrow). DATA COLLECTION AND ANALYSIS We systematically searched medical databases (e.g. MEDLINE, Embase) and trial registers for randomised controlled trials (RCTs). Outcomes of interest were progression-free survival (PFS), overall survival (OS), overall response rates (ORR), serious (grade 3 or 4) adverse events (AEs) and quality of life (QOL). We used a random-effects model to pool outcomes across studies and compared predefined subgroups using interaction tests. Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment of certainty was used to evaluate the quality of evidence. MAIN RESULTS We identified a total of 37 studies, out of which 35 studies (including 9819 participants) were included in the meta-analysis. All included studies compared a matched targeted therapy intervention to standard-of-care treatment, non-matched targeted therapies or no treatment (best supportive care): Matched targeted therapy versus standard-of-care treatment Matched targeted therapy (MTT) compared with standard systematic therapy probably reduces the risk of disease progression by 34% (hazard ratio (HR) = 0.66, 95% confidence interval (CI) 0.59 to 0.74; 14 studies, 3848 participants; moderate-certainty evidence). However, MTT might have little to no difference in risk of death (HR = 0.85, 95% CI 0.75 to 0.97; 14 studies, 3848 participants; low-certainty evidence) and may increase overall response rates (low-certainty evidence). There was no clear evidence of a difference in severe (grade 3/4) adverse events between matched targeted therapy and standard-of-care treatment (low-certainty evidence). There was limited evidence of a difference in quality of life between groups (very low-certainty of evidence). Matched targeted therapy in combination with standard-of-care treatment versus standard-of-care treatment alone Matched targeted therapy in combination with standard-of-care treatment compared with standard-of-care treatment alone probably reduces the risk of disease progression by 39% (HR = 0.61, 95% CI 0.53-0.70, 14 studies, 2,637 participants; moderate-certainty evidence) and risk of death by 21% (HR = 0.79, 95% CI 0.70 to 0.89; 11 studies, 2575 participants, moderate-certainty evidence). The combination of MTT and standard-of-care treatment may also increase overall response rates (low-certainty evidence). There was limited evidence of a difference in the incidence of severe adverse events (very low-certainty evidence) and quality of life between the groups (very low-certainty of evidence). Matched targeted therapy versus non-matched targeted therapy Matched targeted therapy compared with non-matched targeted therapy probably reduces the risk of disease progression by 24% (HR = 0.76, 95% CI 0.64 to 0.89; 3 studies, 1568 participants; moderate-certainty evidence) and may reduce the risk of death by 25% (HR = 0.75, 95% CI 0.65 to 0.86, 1307 participants; low-certainty evidence). There was little to no effect on overall response rates between MTT and non-MTT. There was no clear evidence of a difference in overall response rates (low-certainty evidence) and severe adverse events between MTT and non-MTT (low-certainty evidence). None of the studies comparing MTT and non-MTT reported quality of life. Matched targeted therapy versus best supportive care Matched targeted therapy compared with the best supportive care (BSC) i.e. no active treatment probably reduces the risk of disease progression by 63% (HR 0.37, 95% CI 0.28 to 0.50; 4 studies, 858 participants; moderate-certainty evidence). There was no clear evidence of a difference in overall survival between groups (HR = 0.88, 95% CI 0.73 to 1.06, 3 studies, 783 participants; low-certainty evidence). There was no clear evidence of a difference in overall response rates (very low-certainty of evidence) and incidence of severe adverse events (very low-certainty of evidence) between the groups. Quality of life was reported in a single study but did not provide composite scores. Risk of bias The overall risk of bias was judged low for eight studies, unclear for two studies, and the remaining 27 studies were high risk. AUTHORS' CONCLUSIONS Matched targeted therapies guided by next-generation sequencing in people with advanced cancer prolongs the time before cancer progresses compared to standard therapies. However, there is limited evidence to suggest that it prolongs overall survival, improves the quality of life or increases adverse events. Importantly, this review supports equitable access to next-generation sequencing technology for all people with advanced cancer and offers them the opportunity to access genotype-matched targeted therapies.
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Affiliation(s)
- Farasat Kazmi
- Department of Oncology, University of Oxford, Oxford, UK
- Department of Oncology, Norfolk and Norwich University Hospital, Norwich, UK
| | - Nipun Shrestha
- Health Evidence Synthesis, Recommendations and Impact (HESRI), School of Public Health, University of Adelaide, Adelaide, South Australia, Australia
| | - Tik Fung Dave Liu
- Department of Oncology, Norfolk and Norwich University Hospital, Norwich, UK
| | | | | | - Stephen Booth
- Department of Haematology, Royal Berkshire Hospital, Reading, UK
| | - David Dodwell
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Simon Lord
- Department of Oncology, University of Oxford, Oxford, UK
| | - Kheng-Wei Yeoh
- Radiation Oncology, National Cancer Centre, Singapore, Singapore
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Hofstad M, Woods A, Parra K, Sychev ZE, Mazzagatti A, Huo X, Yu L, Gilbreath C, Chen WM, Davis AJ, Ly P, Drake JM, Kittler R. Dual inhibition of ATR and DNA-PKcs radiosensitizes ATM-mutant prostate cancer. Oncogene 2025:10.1038/s41388-025-03343-x. [PMID: 40119228 DOI: 10.1038/s41388-025-03343-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 01/31/2025] [Accepted: 03/06/2025] [Indexed: 03/24/2025]
Abstract
In advanced castration resistant prostate cancer (CRPC), mutations in the DNA damage response (DDR) gene ataxia telangiectasia mutated (ATM) are common. While poly(ADP-ribose) polymerase inhibitors are approved in this context, their clinical efficacy remains limited. Thus, there is a compelling need to identify alternative therapeutic avenues for ATM mutant prostate cancer patients. Here, we generated matched ATM-proficient and ATM-deficient CRPC lines to elucidate the impact of ATM loss on DDR in response to DNA damage via irradiation. Through unbiased phosphoproteomic screening, we unveiled that ATM-deficient CRPC lines maintain dependence on downstream ATM targets through activation of ATR and DNA-PKcs kinases. Dual inhibition of ATR and DNA-PKcs effectively inhibited downstream γH2AX foci formation in response to irradiation and radiosensitized ATM-deficient lines to a greater extent than either ATM-proficient controls or single drug treatment. Further, dual inhibition abrogated residual downstream ATM pathway signaling and impaired replication fork dynamics. To circumvent potential toxicity, we leveraged the RUVBL1/2 ATPase inhibitor Compound B, which leads to the degradation of both ATR and DNA-PKcs kinases. Compound B effectively radiosensitized ATM-deficient CRPC in vitro and in vivo, and impacted replication fork dynamics. Overall, dual targeting of both ATR and DNA-PKcs is necessary to block DDR in ATM-deficient CRPC, and Compound B could be utilized as a novel therapy in combination with irradiation in these patients.
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Affiliation(s)
- Mia Hofstad
- Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, USA.
- Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Andrea Woods
- Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Karla Parra
- Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Zoi E Sychev
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - Alice Mazzagatti
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Xiaofang Huo
- Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, USA
| | - Lan Yu
- Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Collin Gilbreath
- Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Wei-Min Chen
- Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Anthony J Davis
- Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Peter Ly
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Justin M Drake
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Ralf Kittler
- Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, USA.
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA.
- Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA.
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Custodio-Cabello S, Pacheco-Barcia V, Palka-Kotlowska M, Fernández-Hernández L, Del Álamo JF, Oliveros-Acebes E, Cabezón-Gutiérrez L. Prognostic value of germline mutations in metastatic hormone-sensitive prostate cancer (mHSPC). Urol Oncol 2024; 42:331.e13-331.e24. [PMID: 38926076 DOI: 10.1016/j.urolonc.2024.05.010] [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: 01/28/2024] [Revised: 05/02/2024] [Accepted: 05/16/2024] [Indexed: 06/28/2024]
Abstract
BACKGROUND About 8% to 12% of patients presenting with mHSPC exhibit germline pathogenic variants (PV) in cancer predisposition genes. The aim of this study is to assess the presence of germline PV as a prognostic factor in the setting of mHSPC and to determine whether mutational status can predict rapid progression to castration resistance. METHODS Genetic analysis using a multigene next-generation sequencing (NGS) panel was performed on 34 patients diagnosed with mHSPC undergoing treatment. We assessed the prevalence of germline PV and examined differences based on clinical-pathological characteristics, family history (FH), prostate-specific antigen (PSA) response, impact on time to castration-resistant prostate cancer (TTCRPC), and overall survival (OS). RESULTS Germline PV were identified in 6 patients (17,6%). When comparing the clinical-pathological characteristics of PV carriers (n = 6) to noncarriers (n = 28), no significant associations were observed except for the presence of FH of hereditary breast and ovarian cancer (HBOC) syndrome and/or Lynch syndrome (P = 0.024). At a median follow-up of 33 months, significant differences in OS were observed based on the presence of PV (26 months in carriers vs. 74 months in noncarriers; P < 0.01). Patients who harbored a BRCA2 mutation (n = 3) showed a worse clinical outcome, presenting a shorter TTCRPC (7 months vs. 23 months; P = 0.005) and lower OS (7 months vs. 74 months; P < 0.001) compared to noncarriers (n = 31). CONCLUSION mHSPC germline PV carriers had a worse survival outcome. Furthermore, BRCA2 germline mutation was an independent poor prognostic factor for mHSPC disease, associated with earlier progression to castration-resistant prostate cancer, and shorter OS. These results highlight the importance of evaluating germline mutational status in patients with hormone-sensitive prostate cancer.
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Affiliation(s)
| | | | | | | | | | | | - Luis Cabezón-Gutiérrez
- Medical Oncology, Hospital Universitario De Torrejón, Madrid, Spain; Faculty of Medicine, Francisco de Vitoria University, Pozuelo de Alarcón, Madrid, Spain.
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Sardar S, McNair CM, Ravindranath L, Chand SN, Yuan W, Bogdan D, Welti J, Sharp A, Ryan NK, Knudsen LA, Schiewer MJ, DeArment EG, Janas T, Su XA, Butler LM, de Bono JS, Frese K, Brooks N, Pegg N, Knudsen KE, Shafi AA. AR coactivators, CBP/p300, are critical mediators of DNA repair in prostate cancer. Oncogene 2024; 43:3197-3213. [PMID: 39266679 PMCID: PMC11493679 DOI: 10.1038/s41388-024-03148-4] [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: 06/24/2024] [Revised: 08/20/2024] [Accepted: 08/28/2024] [Indexed: 09/14/2024]
Abstract
Castration resistant prostate cancer (CRPC) remains an incurable disease stage with ineffective treatments options. Here, the androgen receptor (AR) coactivators CBP/p300, which are histone acetyltransferases, were identified as critical mediators of DNA damage repair (DDR) to potentially enhance therapeutic targeting of CRPC. Key findings demonstrate that CBP/p300 expression increases with disease progression and selects for poor prognosis in metastatic disease. CBP/p300 bromodomain inhibition enhances response to standard of care therapeutics. Functional studies, CBP/p300 cistrome mapping, and transcriptome in CRPC revealed that CBP/p300 regulates DDR. Further mechanistic investigation showed that CBP/p300 attenuation via therapeutic targeting and genomic knockdown decreases homologous recombination (HR) factors in vitro, in vivo, and in human prostate cancer (PCa) tumors ex vivo. Similarly, CBP/p300 expression in human prostate tissue correlates with HR factors. Lastly, targeting CBP/p300 impacts HR-mediate repair and patient outcome. Collectively, these studies identify CBP/p300 as drivers of PCa tumorigenesis and lay the groundwork to optimize therapeutic strategies for advanced PCa via CBP/p300 inhibition, potentially in combination with AR-directed and DDR therapies.
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Affiliation(s)
- Sumaira Sardar
- Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD, USA
| | | | - Lakshmi Ravindranath
- Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD, USA
| | - Saswati N Chand
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Wei Yuan
- The Institute of Cancer Research, London, United Kingdom
| | - Denisa Bogdan
- The Institute of Cancer Research, London, United Kingdom
| | - Jon Welti
- The Institute of Cancer Research, London, United Kingdom
| | - Adam Sharp
- The Institute of Cancer Research, London, United Kingdom
- The Royal Marsden Hospital, London, United Kingdom
| | - Natalie K Ryan
- South Australian Immunogenomics Cancer Institute, The University of Adelaide, Adelaide, SA, Australia
- South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Liam A Knudsen
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Matthew J Schiewer
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Elise G DeArment
- Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD, USA
| | - Thomas Janas
- Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD, USA
| | - Xiaofeng A Su
- Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD, USA
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Lisa M Butler
- South Australian Immunogenomics Cancer Institute, The University of Adelaide, Adelaide, SA, Australia
- South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Johann S de Bono
- The Institute of Cancer Research, London, United Kingdom
- The Royal Marsden Hospital, London, United Kingdom
| | - Kris Frese
- CellCentric Ltd., Cambridge, United Kingdom
| | | | - Neil Pegg
- CellCentric Ltd., Cambridge, United Kingdom
| | | | - Ayesha A Shafi
- Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
- The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD, USA.
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Xie J, Guo H, Dong B, Chen W, Jin C, Xu Q, Ding L, Liu W, Dong S, Zhao T, Yu Y, Guo C, Yao X, Peng B, Yang B. Olaparib Combined with Abiraterone versus Olaparib Monotherapy for Patients with Metastatic Castration-resistant Prostate Cancer Progressing after Abiraterone and Harboring DNA Damage Repair Deficiency: A Multicenter Real-world Study. Eur Urol Oncol 2024; 7:1088-1096. [PMID: 38458891 DOI: 10.1016/j.euo.2024.02.005] [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: 10/29/2023] [Revised: 02/07/2024] [Accepted: 02/16/2024] [Indexed: 03/10/2024]
Abstract
BACKGROUND AND OBJECTIVE Olaparib + abiraterone has a combined antitumor effect in metastatic castration-resistant prostate cancer (mCRPC), but the efficacy of this combination in patients with DNA damage repair (DDR)-deficient mCRPC progressing after abiraterone is unknown. Our aim was to compare the efficacy of olaparib + abiraterone versus olaparib monotherapy for patients with DDR-deficient mCRPC progressing after abiraterone. METHODS The study included 86 consecutive patients with DDR-deficient mCRPC progressing after abiraterone: 34 received olaparib + abiraterone, and 52 received olaparib monotherapy. DDR-deficient status was defined as the presence of a DDR gene with a pathogenic or likely pathogenic variant (DDR-PV), or with a variant of unknown significance (DDR-VUS). We assessed progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method. Potential factors influencing PFS and OS were compared between the treatment arms using Cox proportional-hazards models. The prostate-specific antigen (PSA) response, the treatment effect across subgroups, and adverse events (AEs) were also evaluated. KEY FINDINGS AND LIMITATIONS Median follow-up was 9 mo. In the overall cohort, median PFS and OS were significantly longer in the combination arm than in the monotherapy arm (PFS: 6.0 vs 3.0 mo; hazard ratio [HR] 0.41, 95% confidence interval [CI] 0.25-0.67; p < 0.01; OS: 25.0 vs 12.0 mo; HR 0.30, 95% CI 0.14-0.67; p < 0.01). PSA responses were significantly higher following combination therapy versus monotherapy. Combination therapy had significantly better efficacy in the DDR-PV and DDR-VUS subgroups, and was an independent predictor of better PFS and OS. AE rates were acceptable. The retrospective nature, small sample size, and short follow-up are limitations. CONCLUSIONS Olaparib + abiraterone resulted in better PFS and OS than olaparib alone for patients with DDR-deficient mCRPC progressing after abiraterone. These results need to be confirmed by a large-scale prospective randomized controlled trial. PATIENT SUMMARY Our study shows that the drug combination of olaparib plus abiraterone improved survival over olaparib alone for patients who have mutations in genes affecting DNA repair and metastatic prostate cancer resistant to hormone therapy. The results provide evidence of a synergistic effect of the two drugs in these patients.
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Affiliation(s)
- Jun Xie
- Department of Urology, Shanghai Tenth People's Hospital, Shanghai Clinical College, Fifth Clinical Medical College, Anhui Medical University, Shanghai, China
| | - Hanxu Guo
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Urologic Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Baijun Dong
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wei Chen
- Department of Urology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chengqi Jin
- Department of Urology, School of Medicine, Anhui University of Science and Technology, Huainan, China
| | - Qiufan Xu
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Urologic Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Li Ding
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Urologic Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Wujianhong Liu
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shengrong Dong
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Tingting Zhao
- School of Life Sciences and Technology, Tongji University, Shanghai, China; Research Institute, GloriousMed Clinical Laboratory, Shanghai, China
| | - Yang Yu
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Urologic Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Changcheng Guo
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Urologic Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Xudong Yao
- Department of Urology, Shanghai Tenth People's Hospital, Shanghai Clinical College, Fifth Clinical Medical College, Anhui Medical University, Shanghai, China; Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Urologic Cancer Institute, Tongji University School of Medicine, Shanghai, China; Department of Urology, School of Medicine, Anhui University of Science and Technology, Huainan, China.
| | - Bo Peng
- Department of Urology, Shanghai Tenth People's Hospital, Shanghai Clinical College, Fifth Clinical Medical College, Anhui Medical University, Shanghai, China; Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Urologic Cancer Institute, Tongji University School of Medicine, Shanghai, China.
| | - Bin Yang
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Urologic Cancer Institute, Tongji University School of Medicine, Shanghai, China; Department of Urology, School of Medicine, Anhui University of Science and Technology, Huainan, China.
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Hofstad M, Woods A, Parra K, Sychev ZE, Mazzagatti A, Yu L, Gilbreath C, Ly P, Drake JM, Kittler R. Dual inhibition of ATR and DNA-PKcs radiosensitizes ATM-mutant prostate cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.10.602941. [PMID: 39026771 PMCID: PMC11257504 DOI: 10.1101/2024.07.10.602941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/20/2024]
Abstract
In advanced castration resistant prostate cancer (CRPC), mutations in the DNA damage response (DDR) gene ataxia telangiectasia mutated ( ATM ) are common. While poly(ADP-ribose) polymerase inhibitors are approved in this context, their clinical efficacy remains limited. Thus, there is a compelling need to identify alternative therapeutic avenues for ATM mutant prostate cancer patients. Here, we generated matched ATM-proficient and ATM-deficient CRPC lines to elucidate the impact of ATM loss on DDR in response to DNA damage via irradiation. Through unbiased phosphoproteomic screening, we unveiled that ATM-deficient CRPC lines maintain dependence on downstream ATM targets through activation of ATR and DNA-PKcs kinases. Dual inhibition of ATR and DNA-PKcs effectively inhibited downstream γH2AX foci formation in response to irradiation and radiosensitized ATM-deficient lines to a greater extent than either ATM-proficient controls or single drug treatment. Further, dual inhibition abrogated residual downstream ATM pathway signaling and impaired replication fork dynamics. To circumvent potential toxicity, we leveraged the RUVBL1/2 ATPase inhibitor Compound B, which leads to the degradation of both ATR and DNA-PKcs kinases. Compound B effectively radiosensitized ATM-deficient CRPC in vitro and in vivo , and impacted replication fork dynamics. Overall, dual targeting of both ATR and DNA-PKcs is necessary to block DDR in ATM-deficient CRPC, and Compound B could be utilized as a novel therapy in combination with irradiation in these patients.
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8
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Sardar S, McNair CM, Ravindranath L, Chand SN, Yuan W, Bogdan D, Welti J, Sharp A, Ryan NK, Schiewer MJ, DeArment EG, Janas T, Su XA, Butler LM, de Bono JS, Frese K, Brooks N, Pegg N, Knudsen KE, Shafi AA. AR coactivators, CBP/p300, are critical mediators of DNA repair in prostate cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.07.592966. [PMID: 38766099 PMCID: PMC11100730 DOI: 10.1101/2024.05.07.592966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Castration resistant prostate cancer (CRPC) remains an incurable disease stage with ineffective treatments options. Here, the androgen receptor (AR) coactivators CBP/p300, which are histone acetyltransferases, were identified as critical mediators of DNA damage repair (DDR) to potentially enhance therapeutic targeting of CRPC. Key findings demonstrate that CBP/p300 expression increases with disease progression and selects for poor prognosis in metastatic disease. CBP/p300 bromodomain inhibition enhances response to standard of care therapeutics. Functional studies, CBP/p300 cistrome mapping, and transcriptome in CRPC revealed that CBP/p300 regulates DDR. Further mechanistic investigation showed that CBP/p300 attenuation via therapeutic targeting and genomic knockdown decreases homologous recombination (HR) factors in vitro, in vivo, and in human prostate cancer (PCa) tumors ex vivo. Similarly, CBP/p300 expression in human prostate tissue correlates with HR factors. Lastly, targeting CBP/p300 impacts HR-mediate repair and patient outcome. Collectively, these studies identify CBP/p300 as drivers of PCa tumorigenesis and lay the groundwork to optimize therapeutic strategies for advanced PCa via CBP/p300 inhibition, potentially in combination with AR-directed and DDR therapies.
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Affiliation(s)
- Sumaira Sardar
- Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, 20817, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, 20817 USA
| | - Christopher M. McNair
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, 19107, USA
| | - Lakshmi Ravindranath
- Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, 20817, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, 20817 USA
| | - Saswati N. Chand
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, 19107, USA
| | - Wei Yuan
- The Institute of Cancer Research, London, United Kingdom
| | - Denisa Bogdan
- The Institute of Cancer Research, London, United Kingdom
| | - Jon Welti
- The Institute of Cancer Research, London, United Kingdom
| | - Adam Sharp
- The Institute of Cancer Research, London, United Kingdom
- The Royal Marsden Hospital, London, United Kingdom
| | - Natalie K. Ryan
- South Australian Immunogenomics Cancer Institute, The University of Adelaide, Australia
- South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Matthew J. Schiewer
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, 19107, USA
| | - Elise G. DeArment
- Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, 20817, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, 20817 USA
| | - Thomas Janas
- Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, 20817, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, 20817 USA
| | - Xiaofeng A. Su
- Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, 20817, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, 20817 USA
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Lisa M. Butler
- South Australian Immunogenomics Cancer Institute, The University of Adelaide, Australia
- South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Johann S. de Bono
- The Institute of Cancer Research, London, United Kingdom
- The Royal Marsden Hospital, London, United Kingdom
| | - Kris Frese
- CellCentric Ltd., Cambridge, United Kingdom
| | | | - Neil Pegg
- CellCentric Ltd., Cambridge, United Kingdom
| | - Karen E. Knudsen
- The American Cancer Society, Philadelphia, Pennsylvania, 19103, USA
| | - Ayesha A. Shafi
- Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, 20817, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, 20817 USA
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9
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Slootbeek PHJ, Tolmeijer SH, Mehra N, Schalken JA. Therapeutic biomarkers in metastatic castration-resistant prostate cancer: does the state matter? Crit Rev Clin Lab Sci 2024; 61:178-204. [PMID: 37882463 DOI: 10.1080/10408363.2023.2266482] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 08/10/2023] [Accepted: 09/28/2023] [Indexed: 10/27/2023]
Abstract
The treatment of metastatic castration-resistant prostate cancer (mCRPC) has been fundamentally transformed by our greater understanding of its complex biological mechanisms and its entrance into the era of precision oncology. A broad aim is to use the extreme heterogeneity of mCRPC by matching already approved or new targeted therapies to the correct tumor genotype. To achieve this, tumor DNA must be obtained, sequenced, and correctly interpreted, with individual aberrations explored for their druggability, taking into account the hierarchy of driving molecular pathways. Although tumor tissue sequencing is the gold standard, tumor tissue can be challenging to obtain, and a biopsy from one metastatic site or primary tumor may not provide an accurate representation of the current genetic underpinning. Sequencing of circulating tumor DNA (ctDNA) might catalyze precision oncology in mCRPC, as it enables real-time observation of genomic changes in tumors and allows for monitoring of treatment response and identification of resistance mechanisms. Moreover, ctDNA can be used to identify mutations that may not be detected in solitary metastatic lesions and can provide a more in-depth understanding of inter- and intra-tumor heterogeneity. Finally, ctDNA abundance can serve as a prognostic biomarker in patients with mCRPC.The androgen receptor (AR)-axis is a well-established therapeutical target for prostate cancer, and through ctDNA sequencing, insights have been obtained in (temporal) resistance mechanisms that develop through castration resistance. New third-generation AR-axis inhibitors are being developed to overcome some of these resistance mechanisms. The druggability of defects in the DNA damage repair machinery has impacted the treatment landscape of mCRPC in recent years. For patients with deleterious gene aberrations in genes linked to homologous recombination, particularly BRCA1 or BRCA2, PARP inhibitors have shown efficacy compared to the standard of care armamentarium, but platinum-based chemotherapy may be equally effective. A hierarchy exists in genes associated with homologous recombination, where, besides the canonical genes in this pathway, not every other gene aberration predicts the same likelihood of response. Moreover, evidence is emerging on cross-resistance between therapies such as PARP inhibitors, platinum-based chemotherapy and even radioligand therapy that target this genotype. Mismatch repair-deficient patients can experience a beneficial response to immune checkpoint inhibitors. Activation of other cellular signaling pathways such as PI3K, cell cycle, and MAPK have shown limited success with monotherapy, but there is potential in co-targeting these pathways with combination therapy, either already witnessed or anticipated. This review outlines precision medicine in mCRPC, zooming in on the role of ctDNA, to identify genomic biomarkers that may be used to tailor molecularly targeted therapies. The most common druggable pathways and outcomes of therapies matched to these pathways are discussed.
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Affiliation(s)
- Peter H J Slootbeek
- Department of Medical Oncology, Radboud university medical center, Nijmegen, The Netherland
| | - Sofie H Tolmeijer
- Department of Medical Oncology, Radboud university medical center, Nijmegen, The Netherland
| | - Niven Mehra
- Department of Medical Oncology, Radboud university medical center, Nijmegen, The Netherland
| | - Jack A Schalken
- Department of Experimental Urology, Research Institute of Medical Innovation, Radboud university medical center, Nijmegen, The Netherlands
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10
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Zaman N, Kushwah AS, Badriprasad A, Chakraborty G. Unravelling the molecular basis of PARP inhibitor resistance in prostate cancer with homologous recombination repair deficiency. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 389:257-301. [PMID: 39396849 PMCID: PMC11855062 DOI: 10.1016/bs.ircmb.2024.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Prostate cancer is a disease with heterogeneous characteristics, making its treatability and curability dependent on the cancer's stage. While prostate cancer is often indolent, some cases can be aggressive and evolve into metastatic castration-resistant prostate cancer (mCRPC), which is lethal. A significant subset of individuals with mCRPC exhibit germline and somatic variants in components of the DNA damage repair (DDR) pathway. Recently, PARP inhibitors (PARPi) have shown promise in treating mCRPC patients who carry deleterious alterations in BRCA2 and 13 other DDR genes that are important for the homologous recombination repair (HRR) pathway. These inhibitors function by trapping PARP, resulting in impaired PARP activity and increased DNA damage, ultimately leading to cell death through synthetic lethality. However, the response to these inhibitors only lasts for 3-4 months, after which the cancer becomes PARPi resistant. Cancer cells can develop resistance to PARPi through numerous mechanisms, such as secondary reversion mutations in DNA repair pathway genes, heightened drug efflux, loss of PARP expression, HRR reactivation, replication fork stability, and upregulation of Wnt/Catenin and ABCB1 pathways. Overcoming PARPi resistance is a critical and complex process, and there are two possible ways to sensitize the resistance. The first approach is to potentiate the PARPi agents through chemo/radiotherapy and combination therapy, while the second approach entails targeting different signaling pathways. This review article highlights the latest evidence on the resistance mechanism of PARPi in lethal prostate cancer and discusses additional therapeutic opportunities available for prostate cancer patients with DDR gene alterations who do not respond to PARPi.
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Affiliation(s)
- Nabila Zaman
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Atar Singh Kushwah
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Anagha Badriprasad
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Goutam Chakraborty
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
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11
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Dimitrov G, Mangaldzhiev R, Slavov C, Popov E. Precision Medicine in Castration-Resistant Prostate Cancer: Advances, Challenges, and the Landscape of PARPi Therapy-A Narrative Review. Int J Mol Sci 2024; 25:2184. [PMID: 38396858 PMCID: PMC10889419 DOI: 10.3390/ijms25042184] [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: 01/13/2024] [Revised: 02/08/2024] [Accepted: 02/10/2024] [Indexed: 02/25/2024] Open
Abstract
After recent approvals, poly-adenosine diphosphate [ADP]-ribose polymerase inhibitors (PARPis) have emerged as a frontline treatment for metastatic castration-resistant prostate cancer (mCRPC). Unlike their restricted use in breast or ovarian cancers, where approval is limited to those with BRCA1/2 alterations, PARPis in mCRPC are applied across a broader spectrum of genetic aberrations. Key findings from the phase III PROPEL trial suggest that PARPis' accessibility may broaden, even without mandatory testing. An increasing body of evidence underscores the importance of distinct alterations in homologous recombination repair (HRR) genes, revealing unique sensitivities to PARPis. Nonetheless, despite the initial effectiveness of PARPis in treating BRCA-mutated tumors, resistance to therapy is frequently encountered. This review aims to discuss patient stratification based on biomarkers and genetic signatures, offering insights into the nuances of first-line PARPis' efficacy in the intricate landscape of mCRPC.
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Affiliation(s)
- George Dimitrov
- Department of Medical Oncology, Medical University of Sofia, University Hospital “Tsaritsa Yoanna”, 1527 Sofia, Bulgaria; (G.D.)
| | - Radoslav Mangaldzhiev
- Department of Medical Oncology, Medical University of Sofia, University Hospital “Tsaritsa Yoanna”, 1527 Sofia, Bulgaria; (G.D.)
| | - Chavdar Slavov
- Department of Urology, Medical University of Sofia, University Hospital “Tsaritsa Yoanna”, 1527 Sofia, Bulgaria;
| | - Elenko Popov
- Department of Urology, Medical University of Sofia, University Hospital “Tsaritsa Yoanna”, 1527 Sofia, Bulgaria;
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12
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LaRose M, Manji GA, Bates SE. Beyond BRCA: Diagnosis and management of homologous recombination repair deficient pancreatic cancer. Semin Oncol 2024; 51:36-44. [PMID: 38171988 DOI: 10.1053/j.seminoncol.2023.11.001] [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: 11/08/2023] [Accepted: 11/08/2023] [Indexed: 01/05/2024]
Abstract
Approximately 4%-7% of patients diagnosed with pancreatic adenocarcinoma (PDAC) are found to harbor deleterious germline mutations in BRCA1 and/or BRCA2. Loss of function of BRCA1 and/or BRCA2 results in deficiency in homologous recombination repair (HRR), a critical DNA repair pathway, and confers sensitivity to certain DNA damaging agents, including platinum chemotherapy and PARP inhibitors. The PARP inhibitor olaparib is food and drug administration (FDA) approved for use in pancreatic cancer based on the POLO trial, which found that maintenance olaparib significantly prolonged progression free survival compared to placebo among patients with germline BRCA1 or BRCA2 mutations and metastatic PDAC that had not progressed following frontline platinum-based chemotherapy. Recently, there has been considerable interest in identifying patients without BRCA inactivation whose tumors also exhibit properties of HRR deficiency and thus may be susceptible to therapies with proven benefit in cancers harboring BRCA mutations. Here, we discuss methods for identification of HRR-deficiency and review the management of HRR-deficient cancers with a focus on HRR-deficient PDAC.
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Affiliation(s)
- Meredith LaRose
- Columbia University Irving Medical Center, New York NY, USA.
| | - Gulam A Manji
- Columbia University Irving Medical Center, New York NY, USA
| | - Susan E Bates
- Columbia University Irving Medical Center, New York NY, USA
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13
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Deng Z, Wang Y, Qin C, Sheng Z, Xu T, Qiu X. Expression and Clinical Significance of Non B Cell-Derived Immunoglobulins in the Urinary System and Male Reproductive System. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1445:101-117. [PMID: 38967753 DOI: 10.1007/978-981-97-0511-5_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/06/2024]
Abstract
The urinary system comprises kidneys, ureters, bladder, and urethra with its primary function being excretion, referring to the physiological process of transporting substances that are harmful or surplus out of the body. The male reproductive system consists of gonads (testis), vas deferens, and accessory glands such as the prostate. According to classical immunology theory, the tissues and organs mentioned above are not thought to produce immunoglobulins (Igs), and any Ig present in the relevant tissues under physiological and pathological conditions is believed to be derived from B cells. For instance, most renal diseases are associated with uncontrolled inflammation caused by pathogenic Ig deposited in the kidney. Generally, these pathological Igs are presumed to be produced by B cells. Recent studies have demonstrated that renal parenchymal cells can produce and secrete Igs, including IgA and IgG. Glomerular mesangial cells can express and secrete IgA, which is associated with cell survival and adhesion. Likewise, human podocytes demonstrate the ability to produce and secrete IgG, which is related to cell survival and adhesion. Furthermore, renal tubular epithelial cells also express IgG, potentially involved in the epithelial-mesenchymal transition (EMT). More significantly, renal cell carcinoma, bladder cancer, and prostate cancer have been revealed to express high levels of IgG, which promotes tumour progression. Given the widespread Ig expression in the urinary and male reproductive systems, continued efforts to elucidate the roles of Igs in renal physiological and pathological processes are necessary.
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Affiliation(s)
- Zhenling Deng
- Department of Nephrology, Peking University Third Hospital, Beijing, China
| | - Yue Wang
- Peking University Third Hospital, Beijing, China
| | - Caipeng Qin
- Department of Urology, Peking University People's Hospital, Beijing, China
| | - Zhengzuo Sheng
- Department of Thoracic Surgery, Fu Xing Hospital, Capital Medical University, Beijing, China
| | - Tao Xu
- Department of Urology, Peking University People's Hospital, Beijing, China
| | - Xiaoyan Qiu
- Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, China
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14
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Coquan E, Penel N, Lequesne J, Leman R, Lavaud P, Neviere Z, Brachet PE, Meriaux E, Carnot A, Boutrois J, Castera M, Goardon N, Muller E, Leconte A, Thiery-Vuillemin A, Clarisse B, Joly F. Carboplatin in metastatic castration-resistant prostate cancer patients with molecular alterations of the DNA damage repair pathway: the PRO-CARBO phase II trial. Ther Adv Urol 2024; 16:17562872241229876. [PMID: 38425504 PMCID: PMC10903225 DOI: 10.1177/17562872241229876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 01/08/2024] [Indexed: 03/02/2024] Open
Abstract
Introduction DNA damage repair genes are altered in 20-35% of metastatic castration-resistant prostate cancer (mCRPC). Poly-ADP (Adénosine Diphosphate)-ribose polymerase inhibitors (PARPi) showed significant activity for these selected tumors, especially with homologous recombination repair (HRR) deficiency. These alterations could also predict platinum sensitivity. Although carboplatin was inconclusive in unselected mCRPC, the literature suggests an anti-tumoral activity in mCRPC with HHR gene alterations. We aimed to assess the efficacy of carboplatin monotherapy in mCRPC patients with HRR deficiency. Methods This prospective multicenter single-arm two-stage phase II addressed mCRPC men with HRR somatic and/or germline alterations, pretreated with ⩾2 taxane chemotherapy regimens and one androgen receptor pathway inhibitor. Prior PARPi treatment was allowed. Enrolled patients received intravenous carboplatin (AUC5) every 21 days for 6-9 cycles. The primary endpoint was the best response rate according to adapted PCWG3 guidelines: radiological response (RECIST 1.1 criteria) and/or biological response [⩾50% prostate-specific antigen (PSA) decline]. Results A total of 15 out of 16 enrolled patients started carboplatin treatment. Genomic alterations were identified for BRCA2 (n = 5), CDK12 (n = 3), ATM (n = 3) CHEK2 (n = 2), CHEK1 (n = 1), and BRCA1 (n = 1) genes. Objective response (partial biological response + stable radiological response) was achieved in one patient (6.7%), carrying a BRCA2 mutation and not pre-treated with PARPi; stable disease was observed for five patients (33.5%). Among seven patients (46.7%) with previous PARPi treatment, four patients (57.1%) had a stable disease. The median progression-free and overall survivals were 1.9 [95% confidence interval (95% CI), 1.8-9.5] and 8.6 months (95% CI, 4.3-19.5), respectively. The most common severe (grade 3-4) treatment-related toxicities were thrombocytopenia (66.7%), anemia (66.7%), and nausea (60%). Overall, 8 (53.3%) patients experienced a severe hematological event. Conclusion The study was prematurely stopped as pre-planned considering the limited activity of carboplatin monotherapy in heavily pre-treated, HHR-deficient mCRPC patients. Larger experience is needed in mCRPC with BRCA alterations. Trial registration NCT03652493, EudraCT ID number 2017-004764-35.
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Affiliation(s)
- Elodie Coquan
- Department of Medical Oncology, Centre François Baclesse, Caen, France
- Department of Clinical Research, Centre François Baclesse, Caen, France
| | - Nicolas Penel
- Department of Medical Oncology, Centre Oscar Lambret, Lille, France
- Université de Lille, CHU Lille, ULR 2694 – Metrics: Evaluation des technologies de santé et des pratiques médicales, Lille, France
| | - Justine Lequesne
- Department of Clinical Research, Centre François Baclesse, 3 Avenue du Général Harris, F-14076 CAEN Cedex 05, France
| | - Raphaël Leman
- Genetic and Oncology Biology Department, Centre François Baclesse, Caen, France
- Inserm U1245, Cancer Brain and Genome, Normandie Univ, UNICAEN, FHU G4 Génomique, Rouen, France
| | - Pernelle Lavaud
- Department of Oncology, Institut Gustave Roussy, Villejuif, France
| | - Zoé Neviere
- Department of Medical Oncology, Centre François Baclesse, Caen, France
| | - Pierre-Emmanuel Brachet
- Department of Medical Oncology, Centre François Baclesse, Caen, France
- Department of Clinical Research, Centre François Baclesse, Caen, France
| | - Emeline Meriaux
- Department of Medical Oncology, Centre François Baclesse, Caen, France
- Department of Clinical Research, Centre François Baclesse, Caen, France
| | - Aurélien Carnot
- Department of Medical Oncology, Centre Oscar Lambret, Lille, France
| | - Jérémy Boutrois
- Department of Clinical Research, Centre François Baclesse, Caen, France
| | - Marie Castera
- Department of Clinical Research, Centre François Baclesse, Caen, France
| | - Nicolas Goardon
- Genetic and Oncology Biology Department, Centre François Baclesse, Caen, France
- Inserm U1245, Cancer Brain and Genome, Normandie Univ, UNICAEN, FHU G4 Génomique, Rouen, France
| | - Etienne Muller
- Genetic and Oncology Biology Department, Centre François Baclesse, Caen, France
| | - Alexandra Leconte
- Department of Clinical Research, Centre François Baclesse, Caen, France
| | | | | | - Florence Joly
- Department of Medical Oncology, Centre François Baclesse, Caen, France
- Department of Clinical Research, Centre François Baclesse, Caen, France
- Normandie University, UNICAEN, INSERM U1086 “ANTICIPE” (Interdisciplinary Research Unit for Cancers Prevention and Treatment), Centre François Baclesse, Caen, France
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15
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Incorvaia L, Perez A, Marchetti C, Brando C, Gristina V, Cancelliere D, Pivetti A, Contino S, Di Giovanni E, Barraco N, Bono M, Giurintano A, Bazan Russo TD, Gottardo A, Cutaia S, Pedone E, Peri M, Corsini LR, Fanale D, Galvano A, Scambia G, Badalamenti G, Russo A, Bazan V. Theranostic biomarkers and PARP-inhibitors effectiveness in patients with non-BRCA associated homologous recombination deficient tumors: Still looking through a dirty glass window? Cancer Treat Rev 2023; 121:102650. [PMID: 37939446 DOI: 10.1016/j.ctrv.2023.102650] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/16/2023] [Accepted: 10/30/2023] [Indexed: 11/10/2023]
Abstract
Breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2) deleterious variants were the first and, still today, the main biomarkers of poly(ADP)ribose polymerase (PARP)-inhibitors (PARPis) benefit. The recent, increased, numbers of individuals referred for counseling and multigene panel testing, and the remarkable expansion of approved PARPis, not restricted to BRCA1/BRCA2-Pathogenic Variants (PVs), produced a strong clinical need for non-BRCA biomarkers. Significant limitations of the current testing and assays exist. The different approaches that identify the causes of Homologous Recombination Deficiency (HRD), such as the germline and somatic Homologous Recombination Repair (HRR) gene PVs, the testing showing its consequences, such as the genomic scars, or the novel functional assays such as the RAD51 foci testing, are not interchangeable, and should not be considered as substitutes for each other in clinical practice for guiding use of PARPi in non-BRCA, HRD-associated tumors. Today, the deeper knowledge on the significant relationship among all proteins involved in the HRR, not limited to BRCA, expands the possibility of a successful non-BRCA, HRD-PARPi synthetic lethality and, at the same time, reinforces the need for enhanced definition of HRD biomarkers predicting the magnitude of PARPi benefit.
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Affiliation(s)
- Lorena Incorvaia
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Alessandro Perez
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Claudia Marchetti
- Department of Woman's and Child Health and Public Health Sciences, Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy; Catholic University of the Sacred Heart, Rome, Italy
| | - Chiara Brando
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Valerio Gristina
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Daniela Cancelliere
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Alessia Pivetti
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Silvia Contino
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Emilia Di Giovanni
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Nadia Barraco
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Marco Bono
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Ambra Giurintano
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Tancredi Didier Bazan Russo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Andrea Gottardo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Sofia Cutaia
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Erika Pedone
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Marta Peri
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Lidia Rita Corsini
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Daniele Fanale
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Antonio Galvano
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Giovanni Scambia
- Department of Woman's and Child Health and Public Health Sciences, Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy; Catholic University of the Sacred Heart, Rome, Italy
| | - Giuseppe Badalamenti
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Antonio Russo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy.
| | - Viviana Bazan
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
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Celik S, Aktas T, Gokbayrak O, Erol A, Yorukoglu K, Yilmaz B, Sari H, Altun Z, Mungan MU, Celebi I, Aslan G, Aktas S. Genomic Alterations of Signaling and DNA Damage Repair Pathways in Non-Muscle Invasive Bladder Cancer. Cancer Invest 2023; 41:848-857. [PMID: 37997757 DOI: 10.1080/07357907.2023.2288640] [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: 02/25/2023] [Accepted: 11/23/2023] [Indexed: 11/25/2023]
Abstract
The aim of the study was to demonstrate the most common genetic alterations and evaluate possible targets involving phosphatidylinositol-3-OH kinase (PIK3)/AKT/mammalian target of rapamycin (mTOR) signaling and DNA damage repair (DDR) pathways for personalized treatment in patients with non-muscle invasive bladder cancer (NMIBC). Alterations of these pathways were observed in 89.5% and 100% of patients, respectively. Among them, BARD1 was more frequently altered in low/intermediate-risk cases, but PARP4 was more frequently affected in intermediate/high-risk patients. The possible target feasibility of BARD1 and PARP4 alterations should be evaluated for personalized treatment using PARP-inhibitors in NMIBC. It is important to detect high tumor mutation burden (TMB) in patients in terms of immunotherapy.
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Affiliation(s)
- Serdar Celik
- Department of Urology, Izmir Faculty of Medicine, Health Sciences University, Izmir Bozyaka Education and Research Hospital, Izmir, Turkey
- Department of Basic Oncology, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey
| | - Tekincan Aktas
- Department of Basic Oncology, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey
| | - Ozde Gokbayrak
- Department of Basic Oncology, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey
| | - Aylin Erol
- Department of Basic Oncology, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey
| | - Kutsal Yorukoglu
- Department of Pathology, School of Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Batuhan Yilmaz
- Department of Urology, School of Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Hilmi Sari
- Department of Urology, School of Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Zekiye Altun
- Department of Basic Oncology, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey
| | - Mehmet Ugur Mungan
- Department of Urology, School of Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Ilhan Celebi
- Department of Urology, School of Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Guven Aslan
- Department of Urology, School of Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Safiye Aktas
- Department of Basic Oncology, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey
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17
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Bhoir S, Ogundepo O, Yu X, Shi R, De Benedetti A. Exploiting TLK1 and Cisplatin Synergy for Synthetic Lethality in Androgen-Insensitive Prostate Cancer. Biomedicines 2023; 11:2987. [PMID: 38001987 PMCID: PMC10669050 DOI: 10.3390/biomedicines11112987] [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: 09/20/2023] [Revised: 10/26/2023] [Accepted: 11/01/2023] [Indexed: 11/26/2023] Open
Abstract
Cellular organisms possess intricate DNA damage repair and tolerance pathways to manage various DNA lesions arising from endogenous or exogenous sources. The dysregulation of these pathways is associated with cancer development and progression. Synthetic lethality (SL), a promising cancer therapy concept, involves exploiting the simultaneous functional loss of two genes for selective cell death. PARP inhibitors (PARPis) have demonstrated success in BRCA-deficient tumors. Cisplatin (CPT), a widely used chemotherapy agent, forms DNA adducts and crosslinks, rendering it effective against various cancers, but less so for prostate cancer (PCa) due to resistance and toxicity. Here, we explore the therapeutic potential of TLK1, a kinase upregulated in androgen-insensitive PCa cells, as a target for enhancing CPT-based therapy. TLK1 phosphorylates key homologous recombination repair (HRR) proteins, RAD54L and RAD54B, which are critical for HRR alongside RAD51. The combination of CPT with TLK1 inhibitor J54 exhibits SL in androgen-insensitive PCa cells. The formation of double-strand break intermediates during inter-strand crosslink processing necessitates HRR for effective repair. Therefore, targeting TLK1 with J54 enhances the SL of CPT by impeding HRR, leading to increased sensitivity in PCa cells. These findings suggest a promising approach for improving CPT-based therapies in PCa, particularly in androgen-insensitive cases. By elucidating the role of TLK1 in CPT resistance, this study provides valuable insights into potential therapeutic targets to overcome PCa resistance to CPT chemotherapy. Further investigations into TLK1 inhibition in combination with other DNA-damaging agents may pave the way for more effective and targeted treatments for PCa and other cancers that exhibit resistance to traditional chemotherapy agents.
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Affiliation(s)
- Siddhant Bhoir
- Department of Biochemistry and Molecular Biology, LSU Health Shreveport, 1501 Kings Hwy, Shreveport, LA 71103, USA; (S.B.); (O.O.); (X.Y.)
| | - Oluwatobi Ogundepo
- Department of Biochemistry and Molecular Biology, LSU Health Shreveport, 1501 Kings Hwy, Shreveport, LA 71103, USA; (S.B.); (O.O.); (X.Y.)
| | - Xiuping Yu
- Department of Biochemistry and Molecular Biology, LSU Health Shreveport, 1501 Kings Hwy, Shreveport, LA 71103, USA; (S.B.); (O.O.); (X.Y.)
| | - Runhua Shi
- Department of Medicine, LSU Health Shreveport, 1501 Kings Hwy, Shreveport, LA 71103, USA
| | - Arrigo De Benedetti
- Department of Biochemistry and Molecular Biology, LSU Health Shreveport, 1501 Kings Hwy, Shreveport, LA 71103, USA; (S.B.); (O.O.); (X.Y.)
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18
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Alameddine Z, Niazi MRK, Rajavel A, Behgal J, Keesari PR, Araji G, Mustafa A, Wei C, Jahangir A, Terjanian TO. A Meta-Analysis of Randomized Clinical Trials Assessing the Efficacy of PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer. Curr Oncol 2023; 30:9262-9275. [PMID: 37887569 PMCID: PMC10605202 DOI: 10.3390/curroncol30100669] [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: 09/20/2023] [Revised: 10/16/2023] [Accepted: 10/18/2023] [Indexed: 10/28/2023] Open
Abstract
Prostate cancer ranks as the second most common malignancy in males. Prostate cancer progressing on androgen deprivation therapy (ADT) is castration-resistant prostate cancer (CRPC). Poly-ADP ribose polymerase (PARP) inhibitors (PARPis) have been at the forefront of the treatment of CRPC. We aim to better characterize the progression-free survival (PFS) and overall survival (OS) in metastatic CRPC patients treated with PARPis. A systemic review search was conducted using National Clinical Trial (NCT), PubMed, Embase, Scopus, and Central Cochrane Registry. The improvement in overall survival was statistically significant, favoring PARPis (hazard ratio (HR) 0.855; 95% confidence interval (CI) 0.752-0.974; p = 0.018). The improvement in progression-free survival was also statistically significant, with results favoring PARPis (HR 0.626; 95%CI 0.566-0.692; p = 0.000). In a subgroup analysis, similar results were observed where the efficacy of PARPis was evaluated in a subgroup of patients without homologous recombination repair (HRR) gene mutation, which showed improvement in PFS favoring PARPis (HR 0.747; 95%CI 0.0.637-0.877; p = 0.000). Our meta-analysis of seven RCTs showed that PARPis significantly increased PFS and OS when used with or without antihormonal agents like abiraterone or enzalutamide.
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Affiliation(s)
- Zakaria Alameddine
- Staten Island University Hospital, Staten Island, NY 10305, USA; (Z.A.); (M.R.K.N.); (A.R.); (J.B.); (P.R.K.); (G.A.); (A.M.); (C.W.)
| | - Muhammad Rafay Khan Niazi
- Staten Island University Hospital, Staten Island, NY 10305, USA; (Z.A.); (M.R.K.N.); (A.R.); (J.B.); (P.R.K.); (G.A.); (A.M.); (C.W.)
| | - Anisha Rajavel
- Staten Island University Hospital, Staten Island, NY 10305, USA; (Z.A.); (M.R.K.N.); (A.R.); (J.B.); (P.R.K.); (G.A.); (A.M.); (C.W.)
| | - Jai Behgal
- Staten Island University Hospital, Staten Island, NY 10305, USA; (Z.A.); (M.R.K.N.); (A.R.); (J.B.); (P.R.K.); (G.A.); (A.M.); (C.W.)
| | - Praneeth Reddy Keesari
- Staten Island University Hospital, Staten Island, NY 10305, USA; (Z.A.); (M.R.K.N.); (A.R.); (J.B.); (P.R.K.); (G.A.); (A.M.); (C.W.)
| | - Ghada Araji
- Staten Island University Hospital, Staten Island, NY 10305, USA; (Z.A.); (M.R.K.N.); (A.R.); (J.B.); (P.R.K.); (G.A.); (A.M.); (C.W.)
| | - Ahmad Mustafa
- Staten Island University Hospital, Staten Island, NY 10305, USA; (Z.A.); (M.R.K.N.); (A.R.); (J.B.); (P.R.K.); (G.A.); (A.M.); (C.W.)
| | - Chapman Wei
- Staten Island University Hospital, Staten Island, NY 10305, USA; (Z.A.); (M.R.K.N.); (A.R.); (J.B.); (P.R.K.); (G.A.); (A.M.); (C.W.)
| | - Abdullah Jahangir
- University of Oklahoma Health Sciences Center, Oklahoma, OK 73104, USA;
| | - Terenig O Terjanian
- Staten Island University Hospital, Staten Island, NY 10305, USA; (Z.A.); (M.R.K.N.); (A.R.); (J.B.); (P.R.K.); (G.A.); (A.M.); (C.W.)
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19
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Rendon RA, Selvarajah S, Wyatt AW, Kolinsky M, Schrader KA, Fleshner NE, Kinnaird A, Merrimen J, Niazi T, Saad F, Shayegan B, Wood L, Chi KN. 2023 Canadian Urological Association guideline: Genetic testing in prostate cancer. Can Urol Assoc J 2023; 17:314-325. [PMID: 37851913 PMCID: PMC10581723 DOI: 10.5489/cuaj.8588] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2023]
Affiliation(s)
| | - Shamini Selvarajah
- Department of Clinical Laboratory Genetics, UHN Laboratory Medicine Program, University of Toronto, Toronto, ON, Canada
| | - Alexander W. Wyatt
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Michael Kolinsky
- Division of Medical Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
| | | | - Neil E. Fleshner
- Division of Urology, Department of Surgery, University of Toronto, Toronto, ON, Canada
| | - Adam Kinnaird
- Divison of Urology, Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | | | - Tamim Niazi
- Division of Radiation Oncology, Department of Oncology, McGill University, Montreal, QC, Canada
| | - Fred Saad
- Division of Urology, Department of Surgery, Université de Montréal, Montreal, QC, Canada
| | - Bobby Shayegan
- Division of Urology, Department of Surgery, McMaster University, Hamilton, ON, Canada
| | - Lori Wood
- Division of Medical Oncology, Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada
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20
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Bhoir S, De Benedetti A. Targeting Prostate Cancer, the 'Tousled Way'. Int J Mol Sci 2023; 24:11100. [PMID: 37446279 DOI: 10.3390/ijms241311100] [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: 06/13/2023] [Revised: 07/01/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023] Open
Abstract
Androgen deprivation therapy (ADT) has been the mainstay of prostate cancer (PCa) treatment, with success in developing more effective inhibitors of androgen synthesis and antiandrogens in clinical practice. However, hormone deprivation and AR ablation have caused an increase in ADT-insensitive PCas associated with a poor prognosis. Resistance to ADT arises through various mechanisms, and most castration-resistant PCas still rely on the androgen axis, while others become truly androgen receptor (AR)-independent. Our research identified the human tousled-like kinase 1 (TLK1) as a crucial early mediator of PCa cell adaptation to ADT, promoting androgen-independent growth, inhibiting apoptosis, and facilitating cell motility and metastasis. Although explicit, the growing role of TLK1 biology in PCa has remained underrepresented and elusive. In this review, we aim to highlight the diverse functions of TLK1 in PCa, shed light on the molecular mechanisms underlying the transition from androgen-sensitive (AS) to an androgen-insensitive (AI) disease mediated by TLK1, and explore potential strategies to counteract this process. Targeting TLK1 and its associated signaling could prevent PCa progression to the incurable metastatic castration-resistant PCa (mCRPC) stage and provide a promising approach to treating PCa.
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Affiliation(s)
- Siddhant Bhoir
- Department of Biochemistry and Molecular Biology, LSU Health Shreveport, Shreveport, LA 71103, USA
| | - Arrigo De Benedetti
- Department of Biochemistry and Molecular Biology, LSU Health Shreveport, Shreveport, LA 71103, USA
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21
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Marshall CH. Acting on Actionable Mutations in Metastatic Prostate Cancer. J Clin Oncol 2023; 41:3295-3299. [PMID: 37098244 PMCID: PMC10414732 DOI: 10.1200/jco.23.00350] [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] [Revised: 02/24/2023] [Accepted: 03/24/2023] [Indexed: 04/27/2023] Open
Abstract
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.Approximately a quarter of men with metastatic castration-resistant prostate cancer have genomic alterations within the homologous recombination repair pathway with poly (ADP-ribose) polymerase (PARP) inhibitors as corresponding treatment options. How to incorporate genomic information and associated therapeutic options into treatment decision making and sequencing of therapies in prostate cancer remains challenging. Men with BRCA2 alterations seem to derive the most benefit from PARP inhibitors, and although early treatment in combination with standard therapies has not yet shown an overall survival benefit, there may be other benefits to incorporating PARP inhibitors early for some men.
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22
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Hernandez-Martinez JM, Rosell R, Arrieta O. Somatic and germline ATM variants in non-small-cell lung cancer: Therapeutic implications. Crit Rev Oncol Hematol 2023:104058. [PMID: 37343657 DOI: 10.1016/j.critrevonc.2023.104058] [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: 05/15/2023] [Accepted: 06/16/2023] [Indexed: 06/23/2023] Open
Abstract
ATM is an apical kinase of the DNA damage response involved in the repair of DNA double-strand breaks. Germline ATM variants (gATM) have been associated with an increased risk of developing lung adenocarcinoma (LUAD), and approximately 9% of LUAD tumors harbor somatic ATM mutations (sATM). Biallelic carriers of pathogenic gATM exhibit a plethora of immunological abnormalities, but few studies have evaluated the contribution of immune dysfunction to lung cancer susceptibility. Indeed, little is known about the clinicopathological characteristics of lung cancer patients with sATM or gATM alterations. The introduction of targeted therapies and immunotherapies, and the increasing number of clinical trials evaluating treatment combinations, warrants a careful reexamination of the benefits and harms that different therapeutic approaches have had in lung cancer patients with sATM or gATM. This review will discuss the role of ATM in the pathogenesis of lung cancer, highlighting potential therapeutic approaches to manage ATM-deficient lung cancers.
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Affiliation(s)
- Juan-Manuel Hernandez-Martinez
- Thoracic Oncology Unit and Experimental Oncology Laboratory, Instituto Nacional de Cancerología de México (INCan); CONACYT-Instituto Nacional de Cancerología, Mexico City, Mexico
| | - Rafael Rosell
- Institut d'Investigació en Ciències Germans Trias i Pujol, Badalona, Spain; (4)Institut Català d'Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain
| | - Oscar Arrieta
- Thoracic Oncology Unit and Experimental Oncology Laboratory, Instituto Nacional de Cancerología de México (INCan).
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23
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Slootbeek PHJ, Kloots ISH, van Oort IM, Kroeze LI, Schalken JA, Bloemendal HJ, Mehra N. Cross-Resistance between Platinum-Based Chemotherapy and PARP Inhibitors in Castration-Resistant Prostate Cancer. Cancers (Basel) 2023; 15:2814. [PMID: 37345149 PMCID: PMC10216363 DOI: 10.3390/cancers15102814] [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: 04/07/2023] [Revised: 05/12/2023] [Accepted: 05/16/2023] [Indexed: 06/23/2023] Open
Abstract
Patients with metastatic castration-resistant prostate cancer (mCRPC) harbouring homologous recombination repair-related gene aberrations (HRRm) can derive meaningful benefits from both platinum-based chemotherapy (PlCh) and PARP inhibitors (PARPi). Cross-resistance between these agents is well-recognised in other tumour types but data on prostate cancer is lacking. In this retrospective pre-planned study, we assessed 28 HRRm mCRPC patients who received PlCh and PARPi. Progression-free survival (PFS) on initial therapy was longer than on subsequent therapy (median 5.3 vs. 3.4 months, p = 0.016). The median PFS of PlCh was influenced by the order of agents, with 3.6 months shorter PFS after PARPi than when administered first. The median PFS of PARPi was less influenced, with 0.9 months shorter PFS after PlCh than before. In the PARPi-first subgroup, six out of 16 evaluable patients (37.5%) had a >50% PSA decline to PlCh, and two of eight (25.0%) had a radiographic response to PlCh. In the PlCh-first subgroup, 6/10 (60.0%) had a >50% PSA decline, and 5/9 (55.6%) had a radiographic response to PARPi. These data show >40% of the cohort is sensitive to a subsequent HRR-targeting agent. PlCh appears to induce less cross-resistance than PARPi. Additional data on resistance mechanisms will be crucial in defining an optimal treatment sequence in HRRm mCRPC patients.
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Affiliation(s)
- Peter H. J. Slootbeek
- Department of Medical Oncology, Radboud University Medical Center, Geert Grooteplein-Zuid 10, 6525 GA Nijmegen, The Netherlands
| | - Iris S. H. Kloots
- Department of Medical Oncology, Radboud University Medical Center, Geert Grooteplein-Zuid 10, 6525 GA Nijmegen, The Netherlands
| | - Inge M. van Oort
- Department of Urology, Radboud University Medical Center, Geert Grooteplein-Zuid 10, 6525 GA Nijmegen, The Netherlands
| | - Leonie I. Kroeze
- Department of Pathology, Radboud University Medical Center, Geert Grooteplein-Zuid 10, 6525 GA Nijmegen, The Netherlands
| | - Jack A. Schalken
- Department of Urology, Radboud University Medical Center, Geert Grooteplein-Zuid 10, 6525 GA Nijmegen, The Netherlands
| | - Haiko J. Bloemendal
- Department of Medical Oncology, Radboud University Medical Center, Geert Grooteplein-Zuid 10, 6525 GA Nijmegen, The Netherlands
| | - Niven Mehra
- Department of Medical Oncology, Radboud University Medical Center, Geert Grooteplein-Zuid 10, 6525 GA Nijmegen, The Netherlands
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24
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Dai Q, Zhang J, Long W, Haybaeck J, Yang Z. Genetic alterations of GI-NECs involving three main signaling pathways. Cancer Med 2023; 12:8238-8250. [PMID: 36653904 PMCID: PMC10134267 DOI: 10.1002/cam4.5633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 12/06/2022] [Accepted: 01/08/2023] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Gastrointestinal (GI)-neuroendocrine neoplasms (NENs) are subclassified in neuroendocrine tumors (NETs), neuroendocrine carcinomas (NECs), and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). The genetic characteristics of GI-NEN has been a hot issue in recent years, but more studies are needed to provide further details. This study aims to provide additional data about genomic characteristics of GI-NENs and the genetic differences between NETs and NECs. PATIENTS AND METHODS Thirteen samples were selected for next-generation sequencing (NGS) analysis with a 425-gene panel. Microsatellite instability (MSI) and tumor mutational burden (TMB) were calculated as well as immunohistochemistry (IHC) was used to test for protein expression. RESULTS Genetic alterations were very common in NECs, but rare in NETs. The average TMB of NETs and NECs was 2.3 and 6.9, respectively. The TMB of NECs was significantly higher compared to NETs. The TP53 mutation rate was significantly higher in NECs than in NETs (100% vs. 20%), other mutations involved MTOR (n = 2, 15.4%), DDR2 (n = 3, 23.1%), ERBB4 (n = 1, 7.7%), BRCA1 (n = 1, 7.7%), BRCA2 (n = 1, 7.7%), ATM (n = 1, 7.7%), and SMAD4 (n = 1, 7.7%). Deep loss of SMAD4 (1/3, 33.3%), SDHB (1/3, 33.3%), RB1 (1/3, 33.3%), and BRCA2 (1/3, 33.3%), high-level amplification of CRKL (1/3, 33.3%), CCNE1(1/3, 33.3%), and MCL1(1/3, 33.3%) were found in NECs. The integrated analysis found these genetic alterations frequently involve DNA repair and cell cycle, PI3K/AKT/mTOR and TGF-β/SMAD4 signaling pathways. CONCLUSION Genetic alterations were very common in NECs and rare in NETs, and frequently involved three main signaling pathways. NEC patients harboring these genetic alterations may benefit from targeted therapy and PD-1/PD-L1 immunotherapy.
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Affiliation(s)
- Qiong Dai
- Department of Human AnatomySouthwest Medical UniversityLuzhouSichuanChina
| | - Jinping Zhang
- Department of PathologyThe Affiliated Hospital of Southwest Medical UniversityLuzhouSichuanChina
| | - Weili Long
- Department of PathologyThe Affiliated Hospital of Southwest Medical UniversityLuzhouSichuanChina
| | - Johannes Haybaeck
- Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of InnsbruckInnsbruckAustria
- Diagnostic & Research Center for Molecular BioMedicine, Institute of Pathology, Medical University of GrazGrazAustria
| | - Zhihui Yang
- Department of PathologyThe Affiliated Hospital of Southwest Medical UniversityLuzhouSichuanChina
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25
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Antonarakis ES, Abida W. Combining Poly(ADP)-Ribose Polymerase Inhibitors With Abiraterone in Castration-Resistant Prostate Cancer: Is Biomarker Testing Necessary? J Clin Oncol 2023:JCO2300270. [PMID: 36952642 DOI: 10.1200/jco.23.00270] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/25/2023] Open
Affiliation(s)
| | - Wassim Abida
- Memorial Sloan Kettering Cancer Center, New York, NY
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26
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Imyanitov EN, Kuligina ES, Sokolenko AP, Suspitsin EN, Yanus GA, Iyevleva AG, Ivantsov AO, Aleksakhina SN. Hereditary cancer syndromes. World J Clin Oncol 2023; 14:40-68. [PMID: 36908677 PMCID: PMC9993141 DOI: 10.5306/wjco.v14.i2.40] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/09/2022] [Accepted: 02/14/2023] [Indexed: 02/21/2023] Open
Abstract
Hereditary cancer syndromes (HCSs) are arguably the most frequent category of Mendelian genetic diseases, as at least 2% of presumably healthy subjects carry highly-penetrant tumor-predisposing pathogenic variants (PVs). Hereditary breast-ovarian cancer and Lynch syndrome make the highest contribution to cancer morbidity; in addition, there are several dozen less frequent types of familial tumors. The development of the majority albeit not all hereditary malignancies involves two-hit mechanism, i.e. the somatic inactivation of the remaining copy of the affected gene. Earlier studies on cancer families suggested nearly fatal penetrance for the majority of HCS genes; however, population-based investigations and especially large-scale next-generation sequencing data sets demonstrate that the presence of some highly-penetrant PVs is often compatible with healthy status. Hereditary cancer research initially focused mainly on cancer detection and prevention. Recent studies identified multiple HCS-specific drug vulnerabilities, which translated into the development of highly efficient therapeutic options.
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Affiliation(s)
- Evgeny N Imyanitov
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Ekaterina S Kuligina
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Anna P Sokolenko
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Evgeny N Suspitsin
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Grigoriy A Yanus
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Aglaya G Iyevleva
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Alexandr O Ivantsov
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Svetlana N Aleksakhina
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
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27
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Barnett ES, Schultz N, Stopsack KH, Lam ET, Arfe A, Lee J, Zhao JL, Schonhoft JD, Carbone EA, Keegan NM, Wibmer A, Wang Y, Solit DB, Abida W, Wenstrup R, Scher HI. Analysis of BRCA2 Copy Number Loss and Genomic Instability in Circulating Tumor Cells from Patients with Metastatic Castration-resistant Prostate Cancer. Eur Urol 2023; 83:112-120. [PMID: 36123219 PMCID: PMC10228632 DOI: 10.1016/j.eururo.2022.08.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 07/13/2022] [Accepted: 08/10/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND BRCA2 alterations predict for a response to poly-ADP-ribose polymerase inhibition in metastatic castration-resistant prostate cancer (mCRPC). However, detection is hindered by insufficient tumor tissue and low sensitivity of cell-free DNA for detecting copy number loss. OBJECTIVE To evaluate the BRCA2 loss detection using single-cell, shallow whole-genome sequencing (sWGS) of circulating tumor cells (CTCs) in patients with mCRPC. DESIGN, SETTING, AND PARTICIPANTS We analyzed CTC samples collected concurrently with tumor biopsies intended for clinical sequencing in patients with progressing mCRPC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Differences in proportions were evaluated using the chi-square test. Correlations between assays were analyzed in linear regression models. Associations between alterations and genomic instability were assessed on the single-cell level using mixed-effect negative binomial models. RESULTS AND LIMITATIONS We identified 138 patients with concurrent CTC and biopsy samples. CTC sWGS generated copy number profiles in a similar proportion of patients to biopsy samples (83% vs 78%, p = 0.23), but was more effective than bone biopsies (79% vs 50%; p = 0.009). CTC sWGS detected BRCA2 loss in more patients than tissue at the ≥1 (42% vs 16%; p < 0.001) and ≥2 (27% vs 16%; p = 0.028) CTC thresholds. The overall prevalence of BRCA2 loss was not increased in CTCs using sample-level composite z scores (p = 0.4), but was significantly increased compared with a lower-than-expected prevalence in bone samples (21% vs 3%, p = 0.014). Positive/negative predictive values for CTC BRCA2 loss were 89%/96% using the ≥1 CTC threshold and 67%/92% using the composite z score. CTC BRCA2 loss was associated with higher genomic instability in univariate (1.4-fold large-scale transition difference, 95% confidence interval [CI]: 1.2-1.6; p < 0.001) and multivariable analysis (1.4-fold difference, 95% CI: 1.2-1.6; p < 0.001). CONCLUSIONS Copy number profiles can reliably be generated using CTC sWGS, which detected a majority of tissue-confirmed BRCA2 loss and "CTC-only" losses. BRCA2 losses were supported by increases in genomic instability. PATIENT SUMMARY Current testing strategies have limitations in their ability to detect BRCA2 loss, a relatively common alteration in prostate cancer that is used to identify patients who may benefit from targeted therapy. In this paper, we evaluated whether we could detect BRCA2 loss in individual tumor cells isolated from patient blood samples and found this method to be suitable for further analysis.
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Affiliation(s)
- Ethan S Barnett
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nikolaus Schultz
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Konrad H Stopsack
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Andrea Arfe
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Jimmy L Zhao
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Emily A Carbone
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Niamh M Keegan
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Andreas Wibmer
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - David B Solit
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Wassim Abida
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Howard I Scher
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
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Tsujino T, Takai T, Hinohara K, Gui F, Tsutsumi T, Bai X, Miao C, Feng C, Gui B, Sztupinszki Z, Simoneau A, Xie N, Fazli L, Dong X, Azuma H, Choudhury AD, Mouw KW, Szallasi Z, Zou L, Kibel AS, Jia L. CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer. Nat Commun 2023; 14:252. [PMID: 36650183 PMCID: PMC9845315 DOI: 10.1038/s41467-023-35880-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 01/05/2023] [Indexed: 01/18/2023] Open
Abstract
Prostate cancer harboring BRCA1/2 mutations are often exceptionally sensitive to PARP inhibitors. However, genomic alterations in other DNA damage response genes have not been consistently predictive of clinical response to PARP inhibition. Here, we perform genome-wide CRISPR-Cas9 knockout screens in BRCA1/2-proficient prostate cancer cells and identify previously unknown genes whose loss has a profound impact on PARP inhibitor response. Specifically, MMS22L deletion, frequently observed (up to 14%) in prostate cancer, renders cells hypersensitive to PARP inhibitors by disrupting RAD51 loading required for homologous recombination repair, although this response is TP53-dependent. Unexpectedly, loss of CHEK2 confers resistance rather than sensitivity to PARP inhibition through increased expression of BRCA2, a target of CHEK2-TP53-E2F7-mediated transcriptional repression. Combined PARP and ATR inhibition overcomes PARP inhibitor resistance caused by CHEK2 loss. Our findings may inform the use of PARP inhibitors beyond BRCA1/2-deficient tumors and support reevaluation of current biomarkers for PARP inhibition in prostate cancer.
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Affiliation(s)
- Takuya Tsujino
- Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
- Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Tomoaki Takai
- Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
- Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Kunihiko Hinohara
- Department of Medical Oncology, Dana-Farber Cancer Institute & Harvard Medical School, Boston, MA, USA
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Fu Gui
- Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
| | - Takeshi Tsutsumi
- Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
- Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Xiao Bai
- Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
| | - Chenkui Miao
- Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
| | - Chao Feng
- Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
| | - Bin Gui
- Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
| | - Zsofia Sztupinszki
- Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA
- Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Antoine Simoneau
- Department of Pathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Ning Xie
- Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada
| | - Ladan Fazli
- Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada
| | - Xuesen Dong
- Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada
- Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Haruhito Azuma
- Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Atish D Choudhury
- Department of Medical Oncology, Dana-Farber Cancer Institute & Harvard Medical School, Boston, MA, USA
| | - Kent W Mouw
- Department of Radiation Oncology, Dana-Farber Cancer Institute & Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
| | - Zoltan Szallasi
- Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA
- Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Lee Zou
- Department of Pathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Adam S Kibel
- Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
| | - Li Jia
- Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA.
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The TLK1-MK5 Axis Regulates Motility, Invasion, and Metastasis of Prostate Cancer Cells. Cancers (Basel) 2022; 14:cancers14235728. [PMID: 36497211 PMCID: PMC9736944 DOI: 10.3390/cancers14235728] [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: 10/10/2022] [Revised: 11/14/2022] [Accepted: 11/18/2022] [Indexed: 11/24/2022] Open
Abstract
Background: Metastatic dissemination of prostate cancer (PCa) accounts for the majority of PCa-related deaths. However, the exact mechanism of PCa cell spread is still unknown. We uncovered a novel interaction between two unrelated promotility factors, tousled-like kinase 1 (TLK1) and MAPK-activated protein kinase 5 (MK5), that initiates a signaling cascade promoting metastasis. In PCa, TLK1−MK5 signaling might be crucial, as androgen deprivation therapy (ADT) leads to increased expression of both TLK1 and MK5 in metastatic patients, but in this work, we directly investigated the motility, invasive, and metastatic capacity of PCa cells following impairment of the TLK1 > MK5 axis. Results: We conducted scratch wound repair and transwell invasion assays with LNCaP and PC3 cells to determine if TLK1 and MK5 can regulate motility and invasion. Both genetic depletion and pharmacologic inhibition of TLK1 and MK5 resulted in reduced migration and invasion through a Matrigel plug. We further elucidated the potential mechanisms underlying these effects and found that this is likely due to the reorganization of the actin fibers at lamellipodia and the focal adhesions network, in conjunction with increased expression of some MMPs that can affect penetration through the ECM. PC3, a highly metastatic cell line when assayed in xenografts, was further tested in a tail-vein injection/lung metastasis model, and we showed that, following inoculation, treatment with GLPG0259 (MK5 specific inhibitor) or J54 (TLK1 inhibitor) resulted in the lung tumor nodules being greatly diminished in number, and for J54, also in size. Conclusion: Our data support that the TLK1−MK5 axis is functionally involved in driving PCa cell metastasis and clinical aggressiveness; hence, disruption of this axis may inhibit the metastatic capacity of PCa.
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Characteristics of BRCA2 Mutated Prostate Cancer at Presentation. Int J Mol Sci 2022; 23:ijms232113426. [PMID: 36362213 PMCID: PMC9659116 DOI: 10.3390/ijms232113426] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 10/26/2022] [Accepted: 10/28/2022] [Indexed: 11/06/2022] Open
Abstract
Genetic alterations of DNA repair genes, particularly BRCA2 in patients with prostate cancer, are associated with aggressive behavior of the disease. It has reached consensus that somatic and germline tests are necessary when treating advanced prostate cancer patients. Yet, it is unclear whether the mutations are associated with any presenting clinical features. We assessed the incidences and characteristics of BRCA2 mutated cancers by targeted sequencing in 126 sets of advanced prostate cancer tissue sequencing data. At the time of diagnosis, cT3/4, N1 and M1 stages were 107 (85%), 54 (43%) and 35 (28%) samples, respectively. BRCA2 alterations of clinical significance by AMP/ASCO/CAP criteria were found in 19 of 126 samples (15.1%). The BRCA2 mutated cancer did not differ in the distributions of TNM stage, Gleason grade group or histological subtype compared to BRCA2 wild-type cancers. Yet, they had higher tumor mutation burden, and higher frequency of ATM and BRCA1 mutations (44% vs. 10%, p = 0.002 and 21% vs. 4%, p = 0.018, respectively). Of the metastatic subgroup (M1, n = 34), mean PSA was significantly lower in BRCA2 mutated cancers than wild-type (p = 0.018). In the non-metastatic subgroup (M0, n = 64), PSA was not significantly different (p = 0.425). A similar trend was noted in multiple metastatic prostate cancer public datasets. We conclude that BRCA2 mutated metastatic prostate cancers may present in an advanced stage with relatively low PSA.
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Imyanitov E, Sokolenko A. Integrative Genomic Tests in Clinical Oncology. Int J Mol Sci 2022; 23:13129. [PMID: 36361916 PMCID: PMC9656402 DOI: 10.3390/ijms232113129] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 10/24/2022] [Accepted: 10/25/2022] [Indexed: 09/12/2023] Open
Abstract
Many clinical decisions in oncology practice rely on the presence or absence of an alteration in a single genetic locus, be it a pathogenic variant in a hereditary cancer gene or activating mutation in a drug target. In addition, there are integrative tests that produce continuous variables and evaluate complex characteristics of the entire tumor genome. Microsatellite instability (MSI) analysis identifies tumors with the accumulation of mutations in short repetitive nucleotide sequences. This procedure is utilized in Lynch syndrome diagnostic pipelines and for the selection of patients for immunotherapy. MSI analysis is well-established for colorectal malignancies, but its applications in other cancer types lack standardization and require additional research. Homologous repair deficiency (HRD) indicates tumor sensitivity to PARP inhibitors and some cytotoxic drugs. HRD-related "genomic scars" are manifested by a characteristic pattern of allelic imbalances, accumulation of deletions with flanking homology, and specific mutation signatures. The detection of the genetic consequences of HRD is particularly sophisticated and expensive, as it involves either whole genome sequencing (WGS) or the utilization of large next-generation sequencing (NGS) panels. Tumor mutation burden (TMB) can be determined by whole exome sequencing (WES) or middle-throughput NGS multigene testing. Although TMB is regarded as an agnostic indicator of tumor sensitivity to immunotherapy, the clinical utility of this test is proven only for a few cancer types.
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Affiliation(s)
- Evgeny Imyanitov
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St. Petersburg, Russia
- Department of Medical Genetics, St.-Petersburg Pediatric Medical University, 194100 St. Petersburg, Russia
| | - Anna Sokolenko
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St. Petersburg, Russia
- Department of Medical Genetics, St.-Petersburg Pediatric Medical University, 194100 St. Petersburg, Russia
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Li S, Wang L, Wang Y, Zhang C, Hong Z, Han Z. The synthetic lethality of targeting cell cycle checkpoints and PARPs in cancer treatment. J Hematol Oncol 2022; 15:147. [PMID: 36253861 PMCID: PMC9578258 DOI: 10.1186/s13045-022-01360-x] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 09/30/2022] [Indexed: 11/17/2022] Open
Abstract
Continuous cell division is a hallmark of cancer, and the underlying mechanism is tumor genomics instability. Cell cycle checkpoints are critical for enabling an orderly cell cycle and maintaining genome stability during cell division. Based on their distinct functions in cell cycle control, cell cycle checkpoints are classified into two groups: DNA damage checkpoints and DNA replication stress checkpoints. The DNA damage checkpoints (ATM-CHK2-p53) primarily monitor genetic errors and arrest cell cycle progression to facilitate DNA repair. Unfortunately, genes involved in DNA damage checkpoints are frequently mutated in human malignancies. In contrast, genes associated with DNA replication stress checkpoints (ATR-CHK1-WEE1) are rarely mutated in tumors, and cancer cells are highly dependent on these genes to prevent replication catastrophe and secure genome integrity. At present, poly (ADP-ribose) polymerase inhibitors (PARPi) operate through “synthetic lethality” mechanism with mutant DNA repair pathways genes in cancer cells. However, an increasing number of patients are acquiring PARP inhibitor resistance after prolonged treatment. Recent work suggests that a combination therapy of targeting cell cycle checkpoints and PARPs act synergistically to increase the number of DNA errors, compromise the DNA repair machinery, and disrupt the cell cycle, thereby increasing the death rate of cancer cells with DNA repair deficiency or PARP inhibitor resistance. We highlight a combinational strategy involving PARP inhibitors and inhibition of two major cell cycle checkpoint pathways, ATM-CHK2-TP53 and ATR-CHK1-WEE1. The biological functions, resistance mechanisms against PARP inhibitors, advances in preclinical research, and clinical trials are also reviewed.
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Affiliation(s)
- Shuangying Li
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Liangliang Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Yuanyuan Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Changyi Zhang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Zhenya Hong
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
| | - Zhiqiang Han
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
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Boussios S, Rassy E, Moschetta M, Ghose A, Adeleke S, Sanchez E, Sheriff M, Chargari C, Pavlidis N. BRCA Mutations in Ovarian and Prostate Cancer: Bench to Bedside. Cancers (Basel) 2022; 14:cancers14163888. [PMID: 36010882 PMCID: PMC9405840 DOI: 10.3390/cancers14163888] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/09/2022] [Accepted: 08/10/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary DNA damage is one of the hallmarks of cancer. Epithelial ovarian cancer (EOC) —especially the high-grade serous subtype—harbors a defect in at least one DNA damage response (DDR) pathway. Defective DDR results from a variety of lesions affecting homologous recombination (HR) and nonhomologous end joining (NHEJ) for double strand breaks, base excision repair (BER), and nucleotide excision repair (NER) for single strand breaks and mismatch repair (MMR). Apart from the EOC, mutations in the DDR genes, such as BRCA1 and BRCA2, are common in prostate cancer as well. Among them, BRCA2 lesions are found in 12% of metastatic castration-resistant prostate cancers, but very rarely in primary prostate cancer. Better understanding of the DDR pathways is essential in order to optimize the therapeutic choices, and has led to the design of biomarker-driven clinical trials. Poly(ADP-ribose) polymerase (PARP) inhibitors are now a standard therapy for EOC patients, and more recently have been approved for the metastatic castration-resistant prostate cancer with alterations in DDR genes. They are particularly effective in tumours with HR deficiency. Abstract DNA damage repair (DDR) defects are common in different cancer types, and these alterations can be exploited therapeutically. Epithelial ovarian cancer (EOC) is among the tumours with the highest percentage of hereditary cases. BRCA1 and BRCA2 predisposing pathogenic variants (PVs) were the first to be associated with EOC, whereas additional genes comprising the homologous recombination (HR) pathway have been discovered with DNA sequencing technologies. The incidence of DDR alterations among patients with metastatic prostate cancer is much higher compared to those with localized disease. Genetic testing is playing an increasingly important role in the treatment of patients with ovarian and prostate cancer. The development of poly (ADP-ribose) polymerase (PARP) inhibitors offers a therapeutic strategy for patients with EOC. One of the mechanisms of PARP inhibitors exploits the concept of synthetic lethality. Tumours with BRCA1 or BRCA2 mutations are highly sensitive to PARP inhibitors. Moreover, the synthetic lethal interaction may be exploited beyond germline BRCA mutations in the context of HR deficiency, and this is an area of ongoing research. PARP inhibitors are in advanced stages of development as a treatment for metastatic castration-resistant prostate cancer. However, there is a major concern regarding the need to identify reliable biomarkers predictive of treatment response. In this review, we explore the mechanisms of DDR, the potential for genomic analysis of ovarian and prostate cancer, and therapeutics of PARP inhibitors, along with predictive biomarkers.
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Affiliation(s)
- Stergios Boussios
- Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK
- Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, King’s College London, London SE1 9RT, UK
- AELIA Organization, 9th Km Thessaloniki-Thermi, 57001 Thessaloniki, Greece
- Correspondence:
| | - Elie Rassy
- Department of Medical Oncology, Gustave Roussy Institut, 94805 Villejuif, France
| | - Michele Moschetta
- Novartis Institutes for BioMedical Research, CH 4033 Basel, Switzerland
| | - Aruni Ghose
- Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK
- Department of Medical Oncology, Barts Cancer Centre, St. Bartholomew’s Hospital, Barts Health NHS Trust, London E1 1BB, UK
- Department of Medical Oncology, Mount Vernon Cancer Centre, East and North Hertfordshire NHS Trust, London KT1 2EE, UK
- Centre for Education, Faculty of Life Sciences and Medicine, King’s College London, London SE1 9RT, UK
| | - Sola Adeleke
- High Dimensional Neurology Group, UCL Queen’s Square Institute of Neurology, London WC1N 3BG, UK
- Department of Oncology, Guy’s and St Thomas’ Hospital, London SE1 9RT, UK
- School of Cancer & Pharmaceutical Sciences, King’s College London, Strand, London WC2R 2LS, UK
| | - Elisabet Sanchez
- Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK
| | - Matin Sheriff
- Department of Urology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK
| | - Cyrus Chargari
- Department of Medical Oncology, Gustave Roussy Institut, 94805 Villejuif, France
| | - Nicholas Pavlidis
- Medical School, University of Ioannina, Stavros Niarchou Avenue, 45110 Ioannina, Greece
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Paulet L, Trecourt A, Leary A, Peron J, Descotes F, Devouassoux-Shisheboran M, Leroy K, You B, Lopez J. Cracking the homologous recombination deficiency code: how to identify responders to PARP inhibitors. Eur J Cancer 2022; 166:87-99. [DOI: 10.1016/j.ejca.2022.01.037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 01/10/2022] [Accepted: 01/24/2022] [Indexed: 12/16/2022]
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Dalmasso B, Puccini A, Catalano F, Borea R, Iaia ML, Bruno W, Fornarini G, Sciallero S, Rebuzzi SE, Ghiorzo P. Beyond BRCA: The Emerging Significance of DNA Damage Response and Personalized Treatment in Pancreatic and Prostate Cancer Patients. Int J Mol Sci 2022; 23:4709. [PMID: 35563100 PMCID: PMC9099822 DOI: 10.3390/ijms23094709] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/19/2022] [Accepted: 04/20/2022] [Indexed: 12/07/2022] Open
Abstract
The BRCA1/2 germline and/or somatic pathogenic variants (PVs) are key players in the hereditary predisposition and therapeutic response for breast, ovarian and, more recently, pancreatic and prostate cancers. Aberrations in other genes involved in homologous recombination and DNA damage response (DDR) pathways are being investigated as promising targets in ongoing clinical trials. However, DDR genes are not routinely tested worldwide. Due to heterogeneity in cohort selection and dissimilar sequencing approaches across studies, neither the burden of PVs in DDR genes nor the prevalence of PVs in genes in common among pancreatic and prostate cancer can be easily quantified. We aim to contextualize these genes, altered in both pancreatic and prostate cancers, in the DDR process, to summarize their hereditary and somatic burden in different studies and harness their deficiency for cancer treatments in the context of currently ongoing clinical trials. We conclude that the inclusion of DDR genes, other than BRCA1/2, shared by both cancers considerably increases the detection rate of potentially actionable variants, which are triplicated in pancreatic and almost doubled in prostate cancer. Thus, DDR alterations are suitable targets for drug development and to improve the outcome in both pancreatic and prostate cancer patients. Importantly, this will increase the detection of germline pathogenic variants, thereby patient referral to genetic counseling.
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Affiliation(s)
- Bruna Dalmasso
- IRCCS Ospedale Policlinico San Martino, Genetics of Rare Cancers, 16132 Genoa, Italy; (B.D.); (W.B.)
| | - Alberto Puccini
- IRCCS Ospedale Policlinico San Martino, Medical Oncology Unit 1, 16132 Genoa, Italy; (A.P.); (F.C.); (R.B.); (M.L.I.); (G.F.); (S.S.)
| | - Fabio Catalano
- IRCCS Ospedale Policlinico San Martino, Medical Oncology Unit 1, 16132 Genoa, Italy; (A.P.); (F.C.); (R.B.); (M.L.I.); (G.F.); (S.S.)
| | - Roberto Borea
- IRCCS Ospedale Policlinico San Martino, Medical Oncology Unit 1, 16132 Genoa, Italy; (A.P.); (F.C.); (R.B.); (M.L.I.); (G.F.); (S.S.)
| | - Maria Laura Iaia
- IRCCS Ospedale Policlinico San Martino, Medical Oncology Unit 1, 16132 Genoa, Italy; (A.P.); (F.C.); (R.B.); (M.L.I.); (G.F.); (S.S.)
| | - William Bruno
- IRCCS Ospedale Policlinico San Martino, Genetics of Rare Cancers, 16132 Genoa, Italy; (B.D.); (W.B.)
- Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genoa, Italy;
| | - Giuseppe Fornarini
- IRCCS Ospedale Policlinico San Martino, Medical Oncology Unit 1, 16132 Genoa, Italy; (A.P.); (F.C.); (R.B.); (M.L.I.); (G.F.); (S.S.)
| | - Stefania Sciallero
- IRCCS Ospedale Policlinico San Martino, Medical Oncology Unit 1, 16132 Genoa, Italy; (A.P.); (F.C.); (R.B.); (M.L.I.); (G.F.); (S.S.)
| | - Sara Elena Rebuzzi
- Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genoa, Italy;
- Ospedale San Paolo, Medical Oncology, 17100 Savona, Italy
| | - Paola Ghiorzo
- IRCCS Ospedale Policlinico San Martino, Genetics of Rare Cancers, 16132 Genoa, Italy; (B.D.); (W.B.)
- Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genoa, Italy;
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Bieńkowski M, Tomasik B, Braun M, Jassem J. PARP inhibitors for metastatic castration-resistant prostate cancer: Biological rationale and current evidence. Cancer Treat Rev 2022; 104:102359. [DOI: 10.1016/j.ctrv.2022.102359] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 02/06/2022] [Accepted: 02/07/2022] [Indexed: 12/27/2022]
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Imyanitov EN, Iyevleva AG. Molecular tests for prediction of tumor sensitivity to cytotoxic drugs. Cancer Lett 2022; 526:41-52. [PMID: 34808283 DOI: 10.1016/j.canlet.2021.11.021] [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: 09/25/2021] [Revised: 11/15/2021] [Accepted: 11/16/2021] [Indexed: 11/15/2022]
Abstract
Chemotherapy constitutes the backbone of cancer treatment. Several predictive assays assist personalized administration of cytotoxic drugs and are recommended for use in a clinical setting. The deficiency of DNA repair by homologous recombination (HRD), which is caused by inactivation of BRCA1/2 genes or other genetic events, is associated with high tumor responsiveness to platinum compounds, bifunctional alkylating agents and topoisomerase II poisons. Low activity of MGMT predicts the efficacy of nitrosoureas and tetrazines. Some clinically established pharmacogenetic tests allow for the adjustment of drug dosage, for example, the analysis of DPYD allelic variants for administration of fluoropyrimidines and UGT1A1 genotyping for the use of irinotecan. While there are promising molecular predictors of tumor sensitivity to pemetrexed, gemcitabine and taxanes, they remain in the investigational stage and require additional validation. Comprehensive molecular analysis of tumors obtained from drug responders and non-responders is likely to reveal new clinically useful predictive markers for cytotoxic therapy.
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Affiliation(s)
- Evgeny N Imyanitov
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg, 197758, Russia; Department of Medical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg, 194100, Russia; Department of Oncology, I.I. Mechnikov North-Western Medical University, St.-Petersburg, 191015, Russia.
| | - Aglaya G Iyevleva
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg, 197758, Russia; Department of Medical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg, 194100, Russia
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Iyevleva AG, Aleksakhina SN, Sokolenko AP, Baskina SV, Venina AR, Anisimova EI, Bizin IV, Ivantsov AO, Belysheva YV, Chernyakova AP, Togo AV, Imyanitov EN. Somatic loss of the remaining allele occurs approximately in half of CHEK2-driven breast cancers and is accompanied by a border-line increase of chromosomal instability. Breast Cancer Res Treat 2022; 192:283-291. [PMID: 35020107 DOI: 10.1007/s10549-022-06517-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 01/03/2022] [Indexed: 02/06/2023]
Abstract
PURPOSE Germline mutations in CHEK2 gene represent the second most frequent cause of hereditary breast cancer (BC) after BRCA1/2 lesions. This study aimed to identify the molecular characteristics of CHEK2-driven BCs. METHODS Loss of heterozygosity (LOH) for the remaining CHEK2 allele was examined in 50 CHEK2-driven BCs using allele-specific PCR assays for the germline mutations and analysis of surrounding single-nucleotide polymorphisms (SNPs). Paired tumor and normal DNA samples from 25 cases were subjected to next-generation sequencing analysis. RESULTS CHEK2 LOH was detected in 28/50 (56%) BCs. LOH involved the wild-type allele in 24 BCs, mutant CHEK2 copy was deleted in 3 carcinomas, while in one case the origin of the deleted allele could not be identified. Somatic PIK3CA and TP53 mutations were present in 13/25 (52%) and 4/25 (16%) tumors, respectively. Genomic features of homologous recombination deficiency (HRD), including the HRD score ≥ 42, the predominance of BRCA-related mutational signature 3, and the high proportion of long (≥ 5 bp) indels, were observed only in 1/20 (5%) BC analyzed for chromosomal instability. Tumors with the deleted wild-type CHEK2 allele differed from LOH-negative cases by elevated HRD scores (median 23 vs. 7, p = 0.010) and higher numbers of chromosomal segments affected by copy number aberrations (p = 0.008). CONCLUSION Somatic loss of the wild-type CHEK2 allele is observed in approximately half of CHEK2-driven BCs. Tumors without CHEK2 LOH are chromosomally stable. BCs with LOH demonstrate some signs of chromosomal instability; however, its degree is significantly lower as compared to BRCA1/2-associated cancers.
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Affiliation(s)
- Aglaya G Iyevleva
- N.N. Petrov Institute of Oncology, Leningradskaya str. 68, Pesochny, Saint Petersburg, Russia, 197758.
| | - Svetlana N Aleksakhina
- N.N. Petrov Institute of Oncology, Leningradskaya str. 68, Pesochny, Saint Petersburg, Russia, 197758
| | - Anna P Sokolenko
- N.N. Petrov Institute of Oncology, Leningradskaya str. 68, Pesochny, Saint Petersburg, Russia, 197758
| | - Sofia V Baskina
- N.N. Petrov Institute of Oncology, Leningradskaya str. 68, Pesochny, Saint Petersburg, Russia, 197758
| | - Aigul R Venina
- N.N. Petrov Institute of Oncology, Leningradskaya str. 68, Pesochny, Saint Petersburg, Russia, 197758
| | | | - Ilya V Bizin
- N.N. Petrov Institute of Oncology, Leningradskaya str. 68, Pesochny, Saint Petersburg, Russia, 197758
| | - Alexandr O Ivantsov
- N.N. Petrov Institute of Oncology, Leningradskaya str. 68, Pesochny, Saint Petersburg, Russia, 197758
| | - Yana V Belysheva
- N.N. Petrov Institute of Oncology, Leningradskaya str. 68, Pesochny, Saint Petersburg, Russia, 197758
| | - Alexandra P Chernyakova
- N.N. Petrov Institute of Oncology, Leningradskaya str. 68, Pesochny, Saint Petersburg, Russia, 197758
| | - Alexandr V Togo
- N.N. Petrov Institute of Oncology, Leningradskaya str. 68, Pesochny, Saint Petersburg, Russia, 197758
| | - Evgeny N Imyanitov
- N.N. Petrov Institute of Oncology, Leningradskaya str. 68, Pesochny, Saint Petersburg, Russia, 197758.,St.-Petersburg State Pediatric Medical University, Saint Petersburg, Russia, 194100.,I.I. Mechnikov North-Western Medical University, Saint Petersburg, Russia, 191015
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Pilot Study: PARP1 Imaging in Advanced Prostate Cancer. Mol Imaging Biol 2022; 24:853-861. [PMID: 35701722 PMCID: PMC9681698 DOI: 10.1007/s11307-022-01746-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 06/06/2022] [Accepted: 06/07/2022] [Indexed: 02/02/2023]
Abstract
PURPOSE PARP inhibitor (PARPi) therapy is approved for patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) genomic aberrations. However, only a fraction of patients with BRCA1/2 mutations respond to PARPi therapy. In this pilot study, we assess PARP-1 expression in prostate cancer patients with and without HRR genomic alternations using a novel PARP-based imaging agent. PROCEDURES Nine advanced prostate cancer patients were studied with PET/CT and [18F]FluorThanatrace (FTT), an analogue of the PARPi rucaparib. Images were analyzed using maximum standardized uptake values (SUVmax). PARP expression was assessed by immunohistochemistry (IHC) when feasible (n = 4). RESULTS We found great variability in FTT uptake (SUVmax range: 2.3-15.4). Patients with HRR mutations had a significantly higher SUVmax (p = 0.0379) than patients with non-HRR mutations although there was an overlap in FTT uptake between groups. Three patients without HRR and one with HRR mutations had similarly high PARP1 IHC expression. CONCLUSIONS FTT-PET/CT may serve as an alternate biomarker for PARP1 expression and a potential method for PARPi treatment selection.
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Tsujino T, Komura K, Inamoto T, Azuma H. CRISPR Screen Contributes to Novel Target Discovery in Prostate Cancer. Int J Mol Sci 2021; 22:ijms222312777. [PMID: 34884583 PMCID: PMC8658029 DOI: 10.3390/ijms222312777] [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: 10/30/2021] [Revised: 11/25/2021] [Accepted: 11/25/2021] [Indexed: 02/07/2023] Open
Abstract
Prostate cancer (PCa) is one of the common malignancies in male adults. Recent advances in omics technology, especially in next-generation sequencing, have increased the opportunity to identify genes that correlate with cancer diseases, including PCa. In addition, a genetic screen based on CRISPR/Cas9 technology has elucidated the mechanisms of cancer progression and drug resistance, which in turn has enabled the discovery of new targets as potential genes for new therapeutic targets. In the era of precision medicine, such knowledge is crucial for clinicians in their decision-making regarding patient treatment. In this review, we focus on how CRISPR screen for PCa performed to date has contributed to the identification of biologically critical and clinically relevant target genes.
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Affiliation(s)
- Takuya Tsujino
- Department of Urology, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan; (T.I.); (H.A.)
- Division of Urology, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Correspondence: (T.T.); (K.K.); Tel.: +81-72-683-1221 (T.T. & K.K.)
| | - Kazumasa Komura
- Department of Urology, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan; (T.I.); (H.A.)
- Translational Research Program, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan
- Correspondence: (T.T.); (K.K.); Tel.: +81-72-683-1221 (T.T. & K.K.)
| | - Teruo Inamoto
- Department of Urology, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan; (T.I.); (H.A.)
| | - Haruhito Azuma
- Department of Urology, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan; (T.I.); (H.A.)
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Shah S, Rachmat R, Enyioma S, Ghose A, Revythis A, Boussios S. BRCA Mutations in Prostate Cancer: Assessment, Implications and Treatment Considerations. Int J Mol Sci 2021; 22:12628. [PMID: 34884434 PMCID: PMC8657599 DOI: 10.3390/ijms222312628] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/20/2021] [Accepted: 11/21/2021] [Indexed: 12/12/2022] Open
Abstract
Prostate cancer ranks fifth in cancer-related mortality in men worldwide. DNA damage is implicated in cancer and DNA damage response (DDR) pathways are in place against this to maintain genomic stability. Impaired DDR pathways play a role in prostate carcinogenesis and germline or somatic mutations in DDR genes have been found in both primary and metastatic prostate cancer. Among these, BRCA mutations have been found to be especially clinically relevant with a role for germline or somatic testing. Prostate cancer with DDR defects may be sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors which target proteins in a process called PARylation. Initially they were used to target BRCA-mutated tumor cells in a process of synthetic lethality. However, recent studies have found potential for PARP inhibitors in a variety of other genetic settings. In this review, we explore the mechanisms of DNA repair, potential for genomic analysis of prostate cancer and therapeutics of PARP inhibitors along with their safety profile.
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Affiliation(s)
- Sidrah Shah
- Department of Palliative Care, Guy’s and St Thomas’ Hospital, Great Maze Pond, London SE1 9RT, UK;
| | - Rachelle Rachmat
- Department of Radiology, Guy’s and St Thomas’ Hospital, Great Maze Pond, London SE1 9RT, UK;
| | - Synthia Enyioma
- Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK; (S.E.); (A.R.)
| | - Aruni Ghose
- Department of Medical Oncology, Barts Cancer Centre, St. Bartholomew’s Hospital, Barts Health NHS Trust, W Smithfield, London EC1A 7BE, UK;
- Faculty of Life Sciences & Medicine, King’s College London, London WC2R 2LS, UK
| | - Antonios Revythis
- Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK; (S.E.); (A.R.)
| | - Stergios Boussios
- Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK; (S.E.); (A.R.)
- School of Cancer & Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King’s College London, London SE1 9RT, UK
- AELIA Organization, 9th Km Thessaloniki-Thermi, 57001 Thessaloniki, Greece
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LeVee A, Lin CY, Posadas E, Figlin R, Bhowmick NA, Di Vizio D, Ellis L, Rosser CJ, Freeman MR, Theodorescu D, Freedland SJ, Gong J. Clinical Utility of Olaparib in the Treatment of Metastatic Castration-Resistant Prostate Cancer: A Review of Current Evidence and Patient Selection. Onco Targets Ther 2021; 14:4819-4832. [PMID: 34552338 PMCID: PMC8450162 DOI: 10.2147/ott.s315170] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 09/03/2021] [Indexed: 11/23/2022] Open
Abstract
Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive and fatal disease with a median survival of 36 months. With the advent of genetic sequencing to identify individual genomic profiles and acquired tumor-specific pathways, targeted therapies have revolutionized cancer treatment, including the treatment strategy in mCRPC. Poly(adenosine 5'-diphosphate) ribose polymerase inhibitors (PARPi) are oral drugs that target mutations in the homologous recombination repair (HRR) pathway, which are found in approximately 27% of prostate cancer patients. In May 2020, the first PARP inhibitor, olaparib, was approved by the US Food and Drug Administration for men with mCRPC with HHR gene mutations based on the findings of the Phase III PROfound trial that showed improved overall survival in men with mCRPC who received olaparib and whose disease had progressed on a novel hormonal agent. This review summarizes the current evidence and clinical utility of olaparib as treatment in men with mCRPC. We describe the mechanism of action of PARPi, key clinical trials of olaparib in men with mCRPC, and ongoing Phase II and III clinical trials investigating olaparib in combination therapy and as front-line therapy in mCRPC.
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Affiliation(s)
- Alexis LeVee
- Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ching Ying Lin
- Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Edwin Posadas
- Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Robert Figlin
- Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Neil A Bhowmick
- Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Dolores Di Vizio
- Department of Surgery, Division of Cancer Biology and Therapeutics, Biomedical Sciences, and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Leigh Ellis
- Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Charlos J Rosser
- Department of Surgery, Division of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Michael R Freeman
- Department of Surgery, Division of Cancer Biology and Therapeutics, Biomedical Sciences, and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Dan Theodorescu
- Department of Surgery, Division of Cancer Biology and Therapeutics, Biomedical Sciences, and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Stephen J Freedland
- Department of Surgery, Division of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.,Section of Urology, Durham VA Medical Center, Durham, NC, USA
| | - Jun Gong
- Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Imyanitov EN. Cytotoxic and targeted therapy for BRCA1/2-driven cancers. Hered Cancer Clin Pract 2021; 19:36. [PMID: 34454564 PMCID: PMC8399736 DOI: 10.1186/s13053-021-00193-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 08/17/2021] [Indexed: 12/24/2022] Open
Abstract
Tumors arising in BRCA1/2 germline mutation carriers usually demonstrate somatic loss of the remaining BRCA1/2 allele and increased sensitivity to platinum compounds, anthracyclines, mitomycin C and poly (ADP-ribose) polymerase inhibitors (PARPi). Exposure to conventional platinum-based therapy or PARPi results in the restoration of BRCA1/2 function and development of resistance to systemic therapy, therefore, there is a need for other treatment options. Some studies suggested that the use of specific drug combinations or administration of high-dose chemotherapy may result in pronounced tumor responses. BRCA1/2-driven tumors are characterized by increased immunogenicity; promising efficacy of immune therapy has been demonstrated in a number of preclinical and clinical investigations. There are outstanding issues, which require further consideration. Platinum compounds and PARPi have very similar mode of antitumor action and are likely to render cross-resistance to each other, so their optimal position in cancer treatment schemes may be a subject of additional studies. Sporadic tumors with somatically acquired inactivation of BRCA1/2 or related genes resemble hereditary neoplasms with regard to the spectrum of drug sensitivity; the development of user-friendly BRCAness tests presents a challenge. Many therapeutic decisions are now based on the BRCA1/2 status, so the significant reduction of the turn-around time for predictive laboratory assays is of particular importance.
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Affiliation(s)
- Evgeny N Imyanitov
- N.N. Petrov Institute of Oncology, Pesochny, Saint-Petersburg, 197758, Russia. .,St.-Petersburg Pediatric Medical University, Saint Petersburg, 194100, Russia. .,I.I. Mechnikov North-Western Medical University, St.-Petersburg, 191015, Russia.
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Paterniti I, Scuderi SA, Casili G, Lanza M, Mare M, Giuffrida R, Colarossi C, Portelli M, Cuzzocrea S, Esposito E. Poly (ADP-Ribose) Polymerase Inhibitor, ABT888, Improved Cisplatin Effect in Human Oral Cell Carcinoma. Biomedicines 2021; 9:biomedicines9070771. [PMID: 34356835 PMCID: PMC8301366 DOI: 10.3390/biomedicines9070771] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 06/16/2021] [Accepted: 06/28/2021] [Indexed: 11/16/2022] Open
Abstract
Cisplatin is one of the chemotherapeutic drugs used for the management of oral carcinoma, in which combined therapies are estimated to exert superior therapeutic efficacy compared with monotherapy. It is known that poly(ADP-ribosyl)ation is implicated in a multiplicity of cellular activities, such as DNA repair and cell death. Based on these, PARP inhibitors are used for the treatment of cancers; however, the capacity of PARP inhibitors associated to anti-cancer drugs have not been completely assessed in oral carcinoma. Here, we evaluated the effects of PARPi veliparib (ABT888) in combination with cisplatin on the survival of three human oral cancer cell lines HSC-2, Ca9-22 and CAL27 and we observed the effects of ABT888 alone or in combination with cisplatin on apoptosis and DNA damage repair mechanism. The results obtained showed that ABT888 induces a cytotoxicity effect on cell viability increasing the apoptotic pathway as well as DNA strand break; moreover, our results displayed the effects with cisplatin in a dose-dependent manner. Therefore, our results indicate PARP inhibitors as adjuvants for therapeutic strategy of oral cancer.
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Affiliation(s)
- Irene Paterniti
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31-98166 Messina, ME, Italy; (I.P.); (S.A.S.); (G.C.); (M.L.); (S.C.)
| | - Sarah Adriana Scuderi
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31-98166 Messina, ME, Italy; (I.P.); (S.A.S.); (G.C.); (M.L.); (S.C.)
| | - Giovanna Casili
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31-98166 Messina, ME, Italy; (I.P.); (S.A.S.); (G.C.); (M.L.); (S.C.)
| | - Marika Lanza
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31-98166 Messina, ME, Italy; (I.P.); (S.A.S.); (G.C.); (M.L.); (S.C.)
| | - Marzia Mare
- Istituto Oncologico del Mediterraneo, via Penninazzo 7, 95029 Viagrande, CT, Italy; (M.M.); (C.C.)
- IOM Ricerca Srl, via Penninazzo 11, 95029 Viagrande, CT, Italy;
| | | | - Cristina Colarossi
- Istituto Oncologico del Mediterraneo, via Penninazzo 7, 95029 Viagrande, CT, Italy; (M.M.); (C.C.)
| | - Marco Portelli
- Department of Biomedical and Dental Science, Morphological and Functional Images, University of Messina, via Consolare Valeria, 98125 Messina, ME, Italy;
| | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31-98166 Messina, ME, Italy; (I.P.); (S.A.S.); (G.C.); (M.L.); (S.C.)
| | - Emanuela Esposito
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31-98166 Messina, ME, Italy; (I.P.); (S.A.S.); (G.C.); (M.L.); (S.C.)
- Correspondence: ; Tel.: +39-090-676-5208
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Leung DKW, Chiu PKF, Ng CF, Teoh JYC. Novel Strategies for Treating Castration-Resistant Prostate Cancer. Biomedicines 2021; 9:biomedicines9040339. [PMID: 33801751 PMCID: PMC8066514 DOI: 10.3390/biomedicines9040339] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 03/23/2021] [Accepted: 03/23/2021] [Indexed: 01/06/2023] Open
Abstract
The development of castration resistance is an inevitable pathway for the vast majority of patients with advanced prostate cancer. Recently, there have been significant breakthroughs in the understanding and management options of castration-resistant prostate cancer. Three novel hormonal agents showed survival benefits in non-metastatic patients. As for metastatic disease, there was an even wider range of management options being investigated. This review summarized advances in the management of castration-resistant prostate cancer (CRPC) including emerging data on novel imaging techniques and treatment strategies.
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46
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Stopsack KH. Reply to Johann S. de Bono, Maha Hussain, and Jinyu Kang's Letter to the Editor re: Konrad H. Stopsack. Efficacy of PARP Inhibition in Metastatic Castration-resistant Prostate Cancer is Very Different with Non-BRCA DNA Repair Alterations: Reconstructing Prespecified Endpoints for Cohort B from the Phase 3 PROfound Trial of Olaparib. Eur Urol. In press. https://doi.org/ 10.1016/j.eururo.2020.09.024. Eur Urol 2020; 79:e81-e82. [PMID: 33358233 DOI: 10.1016/j.eururo.2020.12.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 12/10/2020] [Indexed: 11/19/2022]
Affiliation(s)
- Konrad H Stopsack
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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de Bono J, Hussain M, Kang J. Re: Konrad H. Stopsack. Efficacy of PARP Inhibition in Metastatic Castration-resistant Prostate Cancer is Very Different with Non-BRCA DNA Repair Alterations: Reconstructing Prespecified Endpoints for Cohort B from the Phase 3 PROfound Trial of Olaparib. Eur Urol. In press. https://doi.org/ 10.1016/j.eururo.2020.09.024. Eur Urol 2020; 79:e83-e84. [PMID: 33358234 DOI: 10.1016/j.eururo.2020.12.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 12/10/2020] [Indexed: 10/22/2022]
Affiliation(s)
- Johann de Bono
- The Institute of Cancer Research and Royal Marsden Hospital, Sutton, UK.
| | - Maha Hussain
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Jinyu Kang
- Global Medicines Development, Oncology, AstraZeneca, Gaithersburg, MD,USA
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