DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Identifying Genomic Drivers of Prostate Cancer Progression

Posted November 27, 2020

Wassim Abida, M.D., Ph.D., Memorial Sloan Kettering Cancer Center

 Dr. Wassim Abida Dr. Wassim Abida

Despite significant advances in therapy, metastatic prostate cancer (PCa) remains a lethal disease. A better understanding of the biological basis of PCa is needed in order to develop new treatment approaches and improve outcomes for patients. Recently, large studies have reported DNA changes, known as genomic alterations, which occur in early and advanced PCa. Some genomic alterations drive the clinical progression of prostate cancer and may serve as clinical targets. An important group of genomic drivers are genes that are involved in DNA repair, which are altered in up to 25% of PCa. Dr. Wassim Abida at Memorial Sloan Kettering Cancer Center studies tumors that harbor alterations in DNA repair genes. His approach has been to focus on molecularly defined subsets of PCa, determine their clinical behavior, and bring these findings into the clinic through exploring new therapies that may target their specific vulnerabilities.

With funding from an FY16 Physician Research Award, Dr. Abida and his research team studied matched primary and metastatic tumors from PCa patients to identify drivers of disease progression. Through this, they found that 3-4% of PCa tumors harbor deficiencies in DNA mismatch repair and display a feature called microsatellite instability. In some cases, microsatellite instability is identified only in the tumor obtained later in the course of disease. Approximately half of prostate cancers with microsatellite instability responded to a class of drugs called immune checkpoint inhibitors. They next explored the association of genomic alterations in several genes associated with DNA damage repair with the response to inhibitors of the PARP protein, which have been shown to effectively kill PCa cells with mutations in the DNA repair genes BRCA1 and BRCA2. Additional studies of BRCA1 and BRCA2 found that unlike other solid tumors, alterations in these genes in PCa occur evenly as inherited and somatic (tumor acquired) alterations and about 40-50% respond to PARP inhibition. Furthermore, they were able to identify positive response rates to PARP inhibition in patients with other altered DNA repair genes, such as PALB2 and FANCA.

Dr. Abida has provided insight into the genes that drive the progression of PCa and has identified drugs that can specifically target these tumors. His research on BRCA1 and BRCA2 genes, helped contribute to the clinical trial which led to the FDA approval of PARP inhibitor rucaparib for metastatic PCa in May, 2020. He hopes that his work will help to identify additional drug targets and lead to approval of more therapeutic options for men with PCa.

 Dr. Wassim Abida Figure Response to immunotherapy (PSA and radiographic) in a patient with microsatellite instability-high (MSI-H) prostate cancer treated with immune checkpoint blockade. (Adapted from Abida et al, JAMA Oncology 2019)

Publications:

Abida W, Armenia J, Gopalan A, et al. 2017. Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations that May Affect Clinical Decision Making. JCO Precision Oncol. 1: 1-17. doi: 10.1200/PO.17.00029.

Abida W, Cheng ML, Armenia J, Middha S, Autio KA, Vargas HA, Rathkopf D, Morris MJ, Danila DC, Slovin SF, et al.Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. JAMA Oncol. 2019 Apr 1;5(4):471-478. doi: 10.1001/jamaoncol.2018.5801. PubMed PMID: 30589920; PubMed Central PMCID: PMC6459218.

Nguyen B, Mota JM, Nandakumar S, Stopsack KH, Weg E, Rathkopf D, Morris MJ, Scher HI, Kantoff PW, Gopalan A, Zamarin D, Solit DB, Schultz N, Abida W*. Pan-cancer Analysis of CDK12 Alterations Identifies a Subset of Prostate Cancers with Distinct Genomic and Clinical Characteristics. Eur Urol. 2020 Apr 19;. doi: 10.1016/j.eururo.2020.03.024. [Epub ahead of print] PubMed PMID: 32317181. *Corresponding author

Stopsack KH, Nandakumar S, Wibmer AG, Haywood S, Weg ES, Barnett ES, Kim CJ, Carbone EA, Vasselman SE, Nguyen B, Hullings MA, Scher HI, Morris MJ, Solit DB, Schultz N, Kantoff PW, Abida W*. Oncogenic Genomic Alterations, Clinical Phenotypes, and Outcomes in Metastatic Castration-Sensitive Prostate Cancer. Clin Cancer Res. 2020 Jul 1;26(13):3230-3238. doi: 10.1158/1078-0432.CCR-20-0168. Epub 2020 Mar 27. PubMed PMID: 32220891; PubMed Central PMCID: PMC7334067. *Corresponding author

Abida W*, Campbell D, Patnaik A, Shapiro JD, Sautois B, Vogelzang NJ, Voog EG, Bryce AH, McDermott R, Ricci F, Rowe J, Zhang J, Piulats JM, Fizazi K, Merseburger AS, Higano CS, Krieger LE, Ryan CJ, Feng FY, Simmons AD, Loehr A, Despain D, Dowson M, Green F, Watkins SP, Golsorkhi T, Chowdhury S. Non-BRCA DNA Damage Repair Gene Alterations and Response to the PARP Inhibitor Rucaparib in Metastatic Castration-Resistant Prostate Cancer: Analysis From the Phase II TRITON2 Study. Clin Cancer Res. 2020 Jun 1;26(11):2487- 2496. doi: 10.1158/1078-0432.CCR-20-0394. Epub 2020 Feb 21. PubMed PMID: 32086346.

Link:

Identifying Genomic Drivers of Prostate Cancer Progression and Drug Resistance in Tumors and Circulating DNA

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Last updated Friday, November 27, 2020