Yannis Minetos

Introduction: Prostate cancer is the second most common cancer worldwide and the fifth leading cause of death which is why it is recommended to screen for this disease starting around age 50.⁶ The progression of prostate cancer starts with a biochemical recurrence of the disease, develops to a nonmetastatic castration-resistant prostate cancer (nmCRPC) and ends with metastatic castration-resistant prostate cancer (mCRPC).⁵ The FDA has approved PARP inhibitors for mCRPC patients with mutations in BRCA genes that mediate DNA repair, but most mCRPC patients do not carry BRCA mutations. Therefore, recent studies have looked into the application of PARP inhibitors in other mCRPC patients such as those with neuroendocrine phenotypes that are present in 25-30% of all mCRPC patients.^2-4  Methods: Research studies looked at the molecular mechanism to better understand the pathogenesis of CRPC with neuroendocrine phenotype (neuroendocrine CRPC). The use of various techniques includes evaluating public data sets with bioinformatics, utilizing mouse xenografts model, and determining the effects of other therapies in combination with PARP inhibition.^2-4   Results: First, new PARP-related pathways including MYCN-PARP-DNA Damage Repair and GR-MYCN-CDK5R1-RB1-E2F1 were proposed as mechanisms in the progression of neuroendocrine CRPC. ^3,4  Second, genes related to DNA Damage Repair including BRCA1, RMI2, and PARP1/2 were upregulated in mouse models of neuroendocrine CRPC. ^3,4 Lastly, the combination of PARP inhibitors and other treatments (eg. cell cycle inhibitors or androgen receptor inhibitors) showed the greatest efficacy in reducing the size and volume of tumors in the mice models.^3,4 Conclusion: Genes associated with DNA repair were upregulated in neuroendocrine CRPC as demonstrated within the mouse model.^3,4 Therapeutic combination of PARP and other treatment illustrated the greatest benefit for this type of CRPC. ^3,4

1. Li L, Karanika S, Yang G, et al. Androgen receptor inhibitor-induced “BRCAness” and PARP inhibition are synthetically lethal for castration-resistant prostate cancer. Sci Signal. 2017;10(480):eaam7479. Published 2017 May 23. doi:10.1126/scisignal.aam7479
2. Hsu EC, Rice MA, Bermudez A, Marques FJG, Aslan M, Liu S, Ghoochani A, Zhang CA, Chen YS, Zlitni A, Kumar S, Nolley R, Habte F, Shen M, Koul K, Peehl DM, Zoubeidi A, Gambhir SS, Kunder CA, Pitteri SJ, Brooks JD, Stoyanova T. Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1. Proc Natl Acad Sci U S A. 2020 Jan 28;117(4):2032-2042. doi: 10.1073/pnas.1905384117. Epub 2020 Jan 13. PMID: 31932422; PMCID: PMC6994991
3. Liu B, Li L, Yang G, Geng C, Luo Y, Wu W, Manyam GC, Korentzelos D, Park S, Tang Z, Wu C, Dong Z, Sigouros M, Sboner A, Beltran H, Chen Y, Corn PG, Tetzlaff MT, Troncoso P, Broom B, Thompson TC. PARP Inhibition Suppresses GR-MYCN-CDK5-RB1-E2F1 Signaling and Neuroendocrine Differentiation in Castration-Resistant Prostate Cancer. Clin Cancer Res. 2019 Nov 15;25(22):6839-6851. doi: 10.1158/1078-0432.CCR-19-0317. Epub 2019 Aug 22. PMID: 31439587; PMCID: PMC6858969
4. Zhang W, Liu B, Wu W, Li L, Broom BM, Basourakos SP, Korentzelos D, Luan Y, Wang J, Yang G, Park S, Azad AK, Cao X, Kim J, Corn PG, Logothetis CJ, Aparicio AM, Chinnaiyan AM, Navone N, Troncoso P, Thompson TC. Targeting the MYCN-PARP-DNA Damage Response Pathway in Neuroendocrine Prostate Cancer. Clin Cancer Res. 2018 Feb 1;24(3):696-707. doi: 10.1158/1078-0432.CCR-17-1872. Epub 2017 Nov 14. PMID: 29138344; PMCID: PMC5823274
5. Cancian M, Renzulli JF 2nd. Nonmetastatic Castration-resistant Prostate Cancer: A Modern Perspective. Urology. 2018 Jun;116:13-16. doi: 10.1016/j.urology.2018.01.010. Epub 2018 Jan 31. PMID: 29357298
6. Kabir Grewal, Kayanaat Grewal and Imad A. Tabbara Anticancer Research PARP Inhibitors inProstate Cancer February 2021, 41 (2) 551-556; DOI:https://doi.org/10.21873/anticanres.1480