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: Verneri Virtanen Kreetta Paunu Johanna K. Ahlskog Reka Varnai Csilla Sipeky Maria 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 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...
Source: Genes - Category: Genetics & Stem Cells Authors: Tags: Review Source Type: research

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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
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
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(ADPÔÇÉribose) polymerase (PARP) inhibitors. PARPenzymes modify target proteins...
Source: Genes - Category: Genetics & Stem Cells Authors: Tags: Review Source Type: research
Abstract Inter- and intra-patient molecular heterogeneity of primary and metastatic prostate cancer (PCa) confers variable clinical outcome and poses a formidable challenge in disease management. High-throughput integrative genomics and functional approaches have untangled the complexity involved in this disease and revealed a spectrum of diverse aberrations prevalent in various molecular subtypes, including ETS fusion negative. Emerging evidence indicates that SPINK1 upregulation, mutations in epigenetic regulators or chromatin modifiers, and SPOP are associated with the ETS-fusion negative subtype. Additionally,...
Source: Trends in Molecular Medicine - Category: Molecular Biology Authors: Tags: Trends Mol Med Source Type: research
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