PARP Inhibitors in Prostate Cancer–the Preclinical Rationale and Current Clinical Development
Verneri Virtanen 1, Kreetta Paunu 1, Johanna K. Ahlskog 2, Reka Varnai 3,4
, Csilla Sipeky 5 and Maria Sundvall 1,6,*
, Csilla Sipeky 5 and Maria Sundvall 1,6,*
1
Institute of Biomedicine, and Cancer Research Laboratories, Western Cancer Centre FICAN West, University of Turku, FI-20520 Turku, Finland
2
Faculty of Science and Engineering, Åbo Akademi University, and Turku Bioscience, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland
3
Department of Primary Health Care, University of Pécs, H-7623 Pécs, Hungary
4
Faculty of Health Sciences, Doctoral School of Health Sciences, University of Pécs, H-7621 Pécs, Hungary
5
Institute of Biomedicine, University of Turku, FI-20520 Turku, Finland
6
Department of Oncology and Radiotherapy, Turku University Hospital, FI-20521 Turku, Finland
*
Author to whom correspondence should be addressed.
Genes 2019, 10(8), 565; https://doi.org/10.3390/genes10080565
Received: 3 June 2019 / Revised: 22 July 2019 / Accepted: 22 July 2019 / Published: 26 July 2019
(This article belongs to the Special Issue Prostate Cancer Genetics and the Emergence of Targeted Therapies Based on Molecular Profiling)
Abstract
Prostate cancer is globally the second most commonly diagnosed cancer type in men. Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms of prostate cancer and castration resistance. Prostate cancer with DNA repair defects may be vulnerable to therapeutic targeting by Poly(ADP-ribose) polymerase (PARP) inhibitors. PARP enzymes modify target proteins with ADP-ribose in a process called PARylation and are in particular involved in single strand break repair. The rationale behind the clinical trials that led to the current use of PARP inhibitors to treat cancer was to target the dependence of BRCA-mutant cancer cells on the PARP-associated repair pathway due to deficiency in homologous recombination. However, recent studies have proposed therapeutic potential for PARP inhibitors in tumors with a variety of vulnerabilities generating dependence on PARP beyond the synthetic lethal targeting of BRCA1/BRCA2 mutated tumors, suggesting a wider potential than initially thought. Importantly, PARP-associated DNA repair pathways are also closely connected to androgen receptor (AR) signaling, which is a key regulator of tumor growth and a central therapeutic target in prostate cancer. In this review, we provide an extensive overview of published and ongoing trials exploring PARP inhibitors in treatment of prostate cancer and discuss the underlying biology. Several clinical trials are currently studying PARP inhibitor mono-and combination therapies in the treatment of prostate cancer. Integration of drugs targeting DNA repair pathways in prostate cancer treatment modalities allows developing of more personalized care taking also into account the genetic makeup of individual tumors. View Full-TextKeywords:
castration resistant prostate cancer; DNA damage repair; PARP inhibitors; precision medicine
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Virtanen, V.; Paunu, K.; Ahlskog, J.K.; Varnai, R.; Sipeky, C.; Sundvall, M. PARP Inhibitors in Prostate Cancer–the Preclinical Rationale and Current Clinical Development. Genes 2019, 10, 565.
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