Therapeutic targeting of the DNA damage response in prostate cancer

Purpose of review The present article highlights the most common DNA repair gene mutations, using specific examples of individual genes or gene classes, and reviews the epidemiology and treatment implications for each one [with particular emphasis on poly-ADP-ribose polymerase (PARP) inhibition and PD-1 blockade]. Recent findings Genetic and genomic testing have an increasingly important role in the oncology clinic. For patients with prostate cancer, germline genetic testing is now recommended for all men with high-risk and metastatic disease, and somatic multigene tumor testing is recommended for men with metastatic castration-resistant disease. The most common mutations that are present in men with advanced prostate cancer are in genes coordinating DNA repair and the DNA damage response. Summary Although much of what is discussed currently remains investigational, it is clear that genomically-targeted treatments will become increasingly important for patients with prostate cancer in the near future and beyond.
Source: Current Opinion in Oncology - Category: Cancer & Oncology Tags: GENITOURINARY SYSTEM: Edited by Arif Hussain Source Type: research

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Purpose of review The aim of this article is to give an overview of poly(ADP-ribose) polymerase inhibitors (PARPis) trials in prostate cancer and to discuss emerging approaches with potential future clinical implementation in both prostate and urothelial cancer. Recent findings PARPis are a class of drugs that can be applied for the treatment of homologous recombination repair (HRR)-deficient tumors. Tumors are potentially sensitive to PARPi harbor mutations in genes relevant for DNA damage repair, such as BRCA1/2 or ATM, which are present to a significant degree in metastatic prostate and urothelial cancer patients. ...
Source: Current Opinion in Urology - Category: Urology & Nephrology Tags: NOVEL THERAPIES FOR ADVANCED UROLOGIC CANCERS: Edited by Shahrokh F. Shariat Source Type: research
Nature Reviews Clinical Oncology, Published online: 23 May 2020; doi:10.1038/s41571-020-0395-xMature results of the PROfound study demonstrate that the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib prolongs progression-free survival compared with second-generation hormonal therapies in men with metastatic castration-resistant prostate cancer harbouring BRCA1, BRCA2 or ATM mutations. However, a closer look at the efficacy of olaparib on a gene-by-gene basis suggests that its activity is most pronounced in BRCA2-mutant prostate cancers and might not be equally active in all homologous recombination repair-deficient cancers.
Source: Nature Reviews Clinical Oncology - Category: Cancer & Oncology Authors: Source Type: research
20 May 2020 -- AstraZeneca and MSD Inc., Kenilworth, N.J., US (MSD: known as Merck&Co., Inc. inside the US and Canada) today announced that Lynparza (olaparib) has been approved in the US for patients with homologous recombination repair (HRR)...
Source: Drugs.com - New Drug Approvals - Category: Drugs & Pharmacology Source Type: news
(Society of Nuclear Medicine and Molecular Imaging) Prostate cancer patients resistant to PSMA-targeted therapy often have potentially treatable mutations in their DNA damage-repair genes, according to research published in the May issue of The Journal of Nuclear Medicine. In an exploratory study using a relatively new technique--targeted next-generation gene sequencing--researchers found mutations in six out of seven patients with metastatic castration-resistant prostate cancer who did not respond to (PSMA)-targeted radiopharmaceutical therapy despite sufficient PSMA expression in tumors.
Source: EurekAlert! - Medicine and Health - Category: International Medicine & Public Health Source Type: news
The FDA approved olaparib for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair gene-mutated metastatic castration-resistant prostate cancer.
Source: CancerNetwork - Category: Cancer & Oncology Authors: Source Type: news
ew D. Beggs Radiotherapy is routinely used as a neoadjuvant, adjuvant or palliative treatment in various cancers. There is significant variation in clinical response to radiotherapy with or without traditional chemotherapy. Patients with a good response to radiotherapy demonstrate better clinical outcomes universally across different cancers. The PI3K/AKT/mTOR pathway upregulation has been linked to radiotherapy resistance. We reviewed the current literature exploring the role of inhibiting targets along this pathway, in enhancing radiotherapy response. We identified several studies using in vitro cancer cell lines, in...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
The objective is to start treating chronic diseases from the root and not the symptoms of the disease. As we are starting to enroll patients in "senolytics-clinical trials," it will be imperative to assess if senolysis efficiently targets the primary cause of disease or if it works best in combination with other drugs. Additional basic science research is required to address the fundamental role of senescent cells, especially in the established contexts of disease. Notes on Self-Experimentation with Sex Steroid Ablation for Regrowth of the Thymus https://www.fightaging.org/archives/2020/04/notes-on-se...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Recent studies have suggested an increased risk of prostate cancer in men with Lynch syndrome driven by germline mutations in mismatch repair (MMR) genes. However, the incidence and clinical implication of MMR deficiency in sporadic prostate cancers remain poorly understood. We immunohistochemically stained for MLH1, MSH2, MSH6, and PMS2 in a set of tissue microarray consisting of 220 radical prostatectomy specimens and evaluated the relationship between loss of their expression and available clinicopathological features. MLH1, MSH2, MSH6, and PMS2 were lost in 2 (0.9%), 6 (2.7%), 37 (16.8%), and 27 (12.3%) prostate cancer...
Source: Medicine - Category: Internal Medicine Tags: Research Article: Observational Study Source Type: research
Conclusion: Patients with resistance to PSMA-TAT despite PSMA positivity frequently harbor mutations in DNA damage-repair and checkpoint genes. Although the causal role of these alterations in the patient outcome remains to be determined, our findings encourage future studies combining PSMA-TAT and DNA damage-repair–targeting agents such as poly(ADP-ribose)-polymerase inhibitors.
Source: Journal of Nuclear Medicine - Category: Nuclear Medicine Authors: Tags: Clinical Source Type: research
I periodically publish thoughts on self-experiments that seem interesting and relevant to aging. Despite the influence of the quantified self movement, the broader self-experimentation community is largely terrible on matters of research, rigor, reporting, and safety. My motivation is to something to raise the bar on all of these items. For every discussion I've published on a particular self-experiment, there are half a dozen others sitting at some stage of research and interest. Over the past year or so, I've been on and off looking into sex steroid ablation as a mechanism for thymus regrowth. Since my company, Re...
Source: Fight Aging! - Category: Research Authors: Tags: Self-Experimentation Source Type: blogs
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