Prostate cancer and PARP inhibitors: progress and challenges.
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ABSTRACT:
SUBMITTER: Teyssonneau D
PROVIDER: S-EPMC8008655 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:INTRODUCTION:Prostate adenocarcinoma represents a leading cause of cancer-related mortality. Increased emphasis on understanding the molecular basis of prostate cancer has identified a substantial burden of homologous recombination (HR) pathway mutations, which are enriched in castrate-resistant disease. This discovery has yielded novel therapeutic opportunities. Areas covered: We will discuss the treatment of castrate-resistant prostate cancer (CRPC), with a focus on the use of poly (ADP-ribose) polymerase (PARP) inhibitors in this space. Evidence for use in HR-deficient patients will be outlined with discussion of the mechanism of action for this drug class, pathways of resistance, and approaches for expanding PARP inhibitor use to non-HR-deficient prostate cancer subgroups. Expert opinion: PARP inhibition represents an exciting tool for management of HR-inactivated CRPC. With rapid adoption of next-generation sequencing technologies and other molecular techniques, the number of patients in this category is likely to increase. Ongoing and future investigations will be critical for improved understanding of the promise and appropriate treatment sequencing of PARP inhibition and optimal options for HR-proficient and -deficient prostate cancer populations. Questions remain about the clinical significance of monoallelic vs. biallelic HR mutations, the relevance of germline vs. somatic-only mutations, and the importance of mutations in non-canonical HR genes.
| S-EPMC6088797 | biostudies-literature
Project description:Poly (ADP-ribose) polymerase inhibitors (PARPi) are a unique class of antineoplastic agents that function by inducing synthetic lethality. Synthetic lethality occurs when PARPi and either another agent or an underlying genetic alteration together lead to overwhelming DNA damage and ultimately cell death. PARPi first showed promise as a cancer therapy in patients with BRCA1/2 mutations and have become part of standard treatment for breast and ovarian cancer. In prostate cancer, two PARPi, rucaparib and olaparib, have been FDA approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). While both agents are approved for tumors with BRCA1/2 alterations, for olaparib the indication is also expanded to patients with 12 other homologous recombination deficiency (HRD) gene alterations including ATM and PALB2. PARPi differ in their pharmacokinetics and pharmacodynamics, and additional studies are being conducted with niraparib, veliparib, and talazoparib in prostate cancer. While PARPi are fairly well tolerated, common toxicities include hematologic (anemia/thrombocytopenia) and gastrointestinal effects (nausea/vomiting). Ongoing studies are being conducted combining PARPi with other agents in patients with and without HRD alterations. Early data are promising for the combination of PARPi with second-generation antiandrogens and with immunotherapy. As additional trials are developed and reported, the hope is that the patient population who may benefit from PARPi will continue to expand.
| S-EPMC7489946 | biostudies-literature
Project description:In our previous studies of the molecular mechanisms of poly(ADP-ribose) polymerase 1 (PARP-1)-mediated transcriptional regulation we identified a novel class of PARP-1 inhibitors targeting the histone-dependent route of PARP-1 activation. Because histone-dependent activation is unique to PARP-1, non-NAD-like PARP-1 inhibitors have the potential to bypass the off-target effects of classical NAD-dependent PARP-1 inhibitors, such as olaparib, veliparib, and rucaparib. Furthermore, our recently published studies demonstrate that, compared to NAD-like PARP-1 inhibitors that are used clinically, the non-NAD-like PARP-1 inhibitor 5F02 exhibited superior antitumor activity in cell and animal models of human prostate cancer (PC). In this study, we further evaluated the antitumor activity of 5F02 and several of its novel analogues against PC cells. In contrast to NAD-like PARP-1 inhibitors, non-NAD-like PARP-1 inhibitors demonstrated efficacy against androgen-dependent and -independent routes of androgen receptor signaling activation. Our experiments reveal that methylation of the quaternary ammonium salt and the presence of esters were critical for the antitumor activity of 5F02 against PC cells. In addition, we examined the role of a related regulatory protein of PARP-1, called Poly(ADP-ribose) glycohydrolase (PARG), in prostate carcinogenesis. Our study reveals that PARG expression is severely disrupted in PC cells, which is associated with decreased integrity and localization of Cajal bodies (CB). Overall, the results of our study strengthen the justification for using non-NAD-like PARP-1 inhibitors as a novel therapeutic strategy for the treatment of advanced prostate cancer.
| S-EPMC6702078 | biostudies-literature
Project description:The U.S. Food and Drug Administration recently approved two poly-adenosine diphosphate-ribose polymerase (PARP) inhibitors, olaparib and rucaparib, for treatment of biomarker-positive metastatic castrate resistant prostate cancer. The benefits of PARP inhibition have been well characterized in patients who have BRCA1 and BRCA2 mutations in several forms of cancer. BRCA1 and BRCA2 occupy key roles in DNA damage repair, which is comprised of several different pathways with numerous participants. Patients with mutations in other key genes within the DNA damage repair pathway may also respond to treatment with PARP inhibitors, and identification of these alterations could significantly increase the percentage of patients that may benefit from PARP inhibition. This review focuses on the potential for synthetically lethal interactions between PARP inhibitors and non-BRCA DNA damage repair genes. IMPLICATIONS FOR PRACTICE: The treatment potential of PARP inhibition has been well characterized in patients with BRCA1 and BRCA2 mutations, but there is compelling evidence for expanding the use of PARP inhibitors to mutations of other non-BRCA DNA damage repair (DDR) genes. This could increase the percentage of patients that may benefit from treatment with PARP inhibitors alone or in combination with other therapies. Understanding the significance of PARP inhibitor-sensitizing alterations in other common non-BRCA DDR genes will help guide clinical decisions to provide targeted treatment options to a wider population of patients.
| S-EPMC7794174 | biostudies-literature
Project description:The prognosis for metastatic castration-resistant prostate cancer is unfavorable, and although Poly(ADP)-ribose polymerase-1 (PARP-1) inhibitors have shown efficacy in the treatment of androgen-receptor dependent malignancies, the limited number of options present obstacles for patients that are not responsive to these treatments. Here we utilize an integrated screening strategy that combines cellular screening assays, informatics, in silico computational approaches, and dose-response testing for reducing a compound library of confirmed PARP-1 inhibitors. Six hundred and sixty-four validated PARP-1 inhibitors were reduced to 9 small molecules with favorable physicochemical/ADME properties, unique chemical fingerprints, high dissimilarity to existing drugs, few off-target effects, and dose-responsivity in the 1 µmol/L - 20 µmol/L range. The top 9 unique molecules identified by our integrated screening strategy will be selected for further preclinical development including cytotoxicity testing, effects on mitosis, structure-activity relationship, physicochemical/ADME studies, and in vivo testing.
| S-EPMC7186898 | biostudies-literature
Project description:Poly(ADP-ribose) polymerase (PARP) inhibitors targeting DNA repair gene mutations have shown significant clinical benefit in patients with ovarian and breast cancers. In metastatic prostate cancers, the prevalence of DNA repair gene mutations is up to 20%, and early phase studies have shown clinical activity of PARP inhibitors. Numerous clinical trials with either PARP monotherapy or in combination with other therapeutic agents are ongoing in prostate cancer. In this comprehensive review, we provide the rationale, efficacy, and safety data of PARP inhibitors in prostate as well as urothelial cancers.
| S-EPMC7020773 | biostudies-literature
Project description:p53 is the major tumor suppressor and the most frequently inactivated gene in cancer. p53 could be disabled either by mutations or by upstream negative regulators, including, but not limited to MDM2 and MDMX. p53 activity is required for the prevention as well as for the eradication of cancers. Restoration of p53 activity in mouse models leads to the suppression of established tumors of different origin. These findings provide a strong support to the anti-cancer strategy aimed for p53 reactivation. In this review, we summarize recent progress in the development of small molecules, which restore the tumor suppressor function of wild-type p53 and discuss their clinical advance. We discuss different aspects of p53-mediated response, which contribute to suppression of tumors, including non-canonical p53 activities, such as regulation of immune response. While targeting p53 inhibitors is a very promising approach, there are certain limitations and concerns that the intensive research and clinical evaluation of compounds will hopefully help to overcome.
| S-EPMC6735775 | biostudies-literature
Project description:PARP inhibitors (PARPi) gained major interest among prostate cancer researchers in the last few years, thanks to the outstanding results coming from the PROfound an TRITON2 studies. Following that, PARPi gained approval also in metastatic, castration-resistant prostate cancer (mCRPC) with mutations in homologous repair (HR) - related genes. Nevertheless, some questions still remain unanswered concerning the management of drug resistance and PARPi-sensitivity in patients harboring alterations in various DNA damage response (DDR) related genes, not only BRCA1 and BRCA2. In this perspective article we focus on the key issues concerning PARPi in mCRPC, specifically those related to drug sensitivity and resistance mechanisms, exploring the possible role of combination therapeutic approaches and trying to depict potential future addresses in translational oncology research.
| S-EPMC8591349 | biostudies-literature
Project description:The approval of upfront abiraterone for castration-sensitive prostate cancer and the approval of enzalutamide and apalutamide for non-metastatic castration-resistant prostate cancer have led to early utilization of potent androgen receptor (AR) signaling inhibitors in treating advanced prostate cancer. There is an unmet need to develop novel therapies beyond targeting AR signaling for metastatic castration-resistant prostate cancer (mCRPC). Poly (ADP-ribose) polymerase inhibitors (PARPi) belong to a class of targeted agents being developed for the treatment of homologous recombination repair (HRR) deficient tumors. Olaparib, rucaparib, niraparib, veliparib, and talazoparib were evaluated in early phase trials as a monotherapy for HRR-deficient mCRPC. Among them, olaparib and rucaparib have breakthrough designations for BRCA1/2-mutated mCRPC. Phase II studies also reported clinical activity of the PARPi and abiraterone combination and the PARPi checkpoint inhibitor combination in HRR-intact mCRPC. Ongoing phase III trials are testing these combinations as frontline or later line treatments for mCRPC. This review summarizes the critical clinical data as well as ongoing clinical trials for developing PARPi in treating mCRPC.
| S-EPMC6721701 | biostudies-literature
Project description: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.
| S-EPMC6723995 | biostudies-literature