Genes, Vol. 10, Pages 565: PARP Inhibitors in Prostate Cancer —The Preclinical Rationale and Current Clinical Development

Genes, Vol. 10, Pages 565: PARP Inhibitors in Prostate Cancer—The Preclinical Rationale and Current Clinical Development Genes doi: 10.3390/genes10080565 Authors: Virtanen Paunu Ahlskog Varnai Sipeky Sundvall 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 ofprostate cancer and castration resistance. Prostate cancer with DNA repair defects may bevulnerable to therapeutic targeting by Poly(ADP‐ribose) polymerase (PARP) inhibitors. PARPenzymes modify target proteins with ADP‐ribose in a process called PARylation and are inparticular involved in single strand break repair. The rationale behind the clinical trials that led tothe current use of PARP inhibitors to treat cancer was to target the dependence of BRCA‐mutantcancer cells on the PARP‐associated repair pathway due to deficiency in homologousrecombination. However, recent studies have proposed therapeutic potential for PARP inhibitorsin tumors with a variety of vulnerabilities generating dependence on PARP beyond the syntheticlethal targeting of BRCA1/BRCA2 mutated tumors, suggesting a wider potential than initiallythought. Importantly, PARP‐associated DNA repair pathways are also closely connected toandrogen receptor (AR) signaling, which is a key regulator of tumor growth and a centraltherapeutic target in prostate cancer. In this review, we provide an ex...
Source: Genes - Category: Genetics & Stem Cells Authors: Tags: Review Source Type: research

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Second interim analysis from the Phase 3 SPARTAN study reporting updated overall survival results in patients with non-metastatic castration-resistant prostate cancer treated with ERLEADA ® (apalutamide)Patient-reported outcomes from the Phase 3 TITAN study evaluating ERLEADA® in patients with metastatic castration-sensitive prostate cancer Interim analysis from the Phase 2 GALAHAD study evaluating niraparib in the treatment of patients with metastatic castration-resistant prostate cancer and biallelic DNA-repair gene defects, featured as late-breaking abstract
Source: Johnson and Johnson - Category: Pharmaceuticals Source Type: news
This study identifies novel mechanistic targets of WA in prostate cancer.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research
This study aims to clarify the potential role and molecular mechanisms of GRIM-19 on the response of PC cells to chemical drug docetaxel. mRNA and protein level of GRIM-19 expression in cells and tissues of PC were measured by quantitative real-time PCR and western blot, respectively. Knock-down of GRIM-19 in PC cells was performed using siRNA. Cell apoptosis was determined by flow cytometric analysis. DNA damage in PC cells was detected by γ-H2AX staining. GRIM-19 was downregulated in PC tissues and cell lines. Knockdown of GRIM-19 increased the resistance of PC cells to docetaxel, and overexpression of GRIM-19 prom...
Source: Clinical and Experimental Pharmacology and Physiology - Category: Drugs & Pharmacology Authors: Tags: Clin Exp Pharmacol Physiol Source Type: research
CONCLUSIONS: Leveraging large-scale transcriptomic data allowed the identification of an aggressive subtype of treatment-naïve primary prostate cancer that harbors molecular features more analogous to mCRPC. This suggests that a pre-existing subgroup of patients may have tumors that are predisposed to fail multiple current standard of care therapies and warrant dedicated therapeutic investigation. PMID: 31515456 [PubMed - as supplied by publisher]
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research
Prostate cancer (PC) initially depends on androgen receptor (AR) signaling for survival and growth. Therapeutics designed to suppress AR activity serve as the primary intervention for advanced disease. However, supraphysiological androgen (SPA) concentrations can produce paradoxical responses leading to PC growth inhibition. We sought to discern the mechanisms by which SPA inhibits PC and to determine if molecular context associates with antitumor activity. SPA produced an AR-mediated, dose-dependent induction of DNA double-strand breaks, G0/G1 cell-cycle arrest, and cellular senescence. SPA repressed genes involved in DNA...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
In conclusion, our data show how oncogenic and tumor-suppressive drivers of cellular senescence act to regulate surveillance processes that can be circumvented to enable SnCs to elude immune recognition but can be reversed by cell surface-targeted interventions to purge the SnCs that persist in vitro and in patients. Since eliminating SnCs can prevent tumor progression, delay the onset of degenerative diseases, and restore fitness; since NKG2D-Ls are not widely expressed in healthy human tissues and NKG2D-L shedding is an evasion mechanism also employed by tumor cells; and since increasing numbers of B cells express NKG2D ...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
In conclusion, our data show how oncogenic and tumor-suppressive drivers of cellular senescence regulate surveillance processes that can be circumvented to enable SnCs to elude immune recognition but can be reversed by cell surface-targeted interventions to purge the SnCs that persist in vitro and in patients. Since eliminating SnCs can prevent tumor progression, delay the onset of degenerative diseases, and restore fitness; since NKG2D-Ls are not widely expressed in healthy human tissues and NKG2D-L shedding is an evasion mechanism also employed by tumor cells; and since increasing numbers of B cells express NKG2D ligands...
Source: Fight Aging! - Category: Research Authors: Tags: Medicine, Biotech, Research Source Type: blogs
CONCLUSION: Our findings indicate that the number of γH2AX foci per cell was not changed in dependence on the Ra-223 therapy cycles. The ability of patient's lymphocytes to repair ex vivo induced DSB remained unaffected throughout the entire therapy course. PMID: 31387125 [PubMed - as supplied by publisher]
Source: Nuklearmedizin - Category: Radiology Authors: Tags: Nuklearmedizin Source Type: research
Conclusion: PC patients carrying ≥1 pathogenic DNA instability mutation, and DRD mutation carriers specifically, had higher clinical burden than non-mutation carriers. Targeted therapies for these patients are needed to reduce clinical burden and associated healthcare resource utilization. PMID: 31352849 [PubMed - as supplied by publisher]
Source: Journal of Medical Economics - Category: Health Management Tags: J Med Econ Source Type: research
Publication date: Available online 26 July 2019Source: European UrologyAuthor(s): Daniel McLennan, Niranjan Sathianathen, Omar Alghazo, Arun Azad, Declan G. Murphy
Source: European Urology - Category: Urology & Nephrology Source Type: research
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