Special Issue Review PARP inhibitors: Synthetic lethality in the clinic

PARP inhibitors (PARPi), a cancer therapy targeting poly(ADP-ribose) polymerase, are the first clinically approved drugs designed to exploit synthetic lethality, a genetic concept proposed nearly a century ago. Tumors arising in patients who carry germline mutations in either BRCA1 or BRCA2 are sensitive to PARPi because they have a specific type of DNA repair defect. PARPi also show promising activity in more common cancers that share this repair defect. However, as with other targeted therapies, resistance to PARPi arises in advanced disease. In addition, determining the optimal use of PARPi within drug combination approaches has been challenging. Nevertheless, the preclinical discovery of PARPi synthetic lethality and the route to clinical approval provide interesting lessons for the development of other therapies. Here, we discuss current knowledge of PARP inhibitors and potential ways to maximize their clinical effectiveness. Authors: Christopher J. Lord, Alan Ashworth
Source: ScienceNOW - Category: Science Authors: Tags: Frontiers in Cancer Therapy Source Type: news

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In this study, we analyzed the combination of ionizing radiation (IR) along with microRNA-mediated targeting of genes involved in DSB repair to sensitize human non-small cell lung cancer (NSCLC) cells. MicroRNAs are natural occurring modulators of gene expression and therefore represent an attractive strategy to affect the expression of DSB repair genes. As possible IR-sensitizing targets genes we selected genes of homologous recombination (HR) and non-homologous end joining (NHEJ) pathway (i.e. RAD51, BRCA2, PRKDC, XRCC5, LIG1). We examined these genes to determine whether they may be real targets of selected miRNAs by fu...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Non-coding RNA profiling by array Homo sapiens Source Type: research
ConclusionApplication of cytostatic drugs in combination with adaptogenic plant extracts induced significant changes in transcriptome-wide microarray profiles of neuroglial cells. These changes indicate on potential beneficial effects of adaptogens on FEC induced adverse events in cancer chemotherapy.Graphical abstract
Source: Phytomedicine - Category: Drugs & Pharmacology Source Type: research
Publication date: January 2019Source: Biomedicine &Pharmacotherapy, Volume 109Author(s): Chenxi Hu, Xiaodong JiangAbstractAbnormalities in the small ubiquitin-related modifier (SUMO) pathway and the SUMO-specific proteases (SENPs) pathway are frequently observed in cancer. SUMOylation and deSUMOylation are dynamic processes in cells. SUMOylation of cancer-associated proteins may serve as a biomarker for cancer diagnosis and a target for cancer therapy. In recent years, an increasing number of studies have focused on the role of SENPs in the radiosensitivity of cancer cells. SENPs regulate cancer cell radiosensitivity b...
Source: Biomedicine and Pharmacotherapy - Category: Drugs & Pharmacology Source Type: research
Abstract Abnormalities in the small ubiquitin-related modifier (SUMO) pathway and the SUMO-specific proteases (SENPs) pathway are frequently observed in cancer. SUMOylation and deSUMOylation are dynamic processes in cells. SUMOylation of cancer-associated proteins may serve as a biomarker for cancer diagnosis and a target for cancer therapy. In recent years, an increasing number of studies have focused on the role of SENPs in the radiosensitivity of cancer cells. SENPs regulate cancer cell radiosensitivity by mediating DNA damage repair, apoptosis, the cell cycle, and tumor angiogenesis. Here, we review the curren...
Source: Biomedicine and pharmacotherapy = Biomedecine and pharmacotherapie - Category: Drugs & Pharmacology Authors: Tags: Biomed Pharmacother Source Type: research
In this study, we analyzed the combination of ionizing radiation (IR) along with microRNA-mediated targeting of genes involved in DSB repair to sensitize human non-small cell lung cancer (NSCLC) cells. MicroRNAs are natural occurring modulators of gene expression and therefore represent an attractive strategy to affect the expression of DSB repair genes. As possible IR-sensitizing targets genes we selected genes of homologous recombination (HR) and non-homologous end joining (NHEJ) pathway (i.e. RAD51, BRCA2, PRKDC, XRCC5, LIG1). We examined these genes to determine whether they may be real targets of selected miRNAs by fu...
Source: Biochimica et Biophysica Acta (BBA) Gene Regulatory Mechanisms - Category: Genetics & Stem Cells Source Type: research
In this report, we propose that the molecular mechanisms of beneficial actions of CR should be classified and discussed according to whether they operate under rich or insufficient energy resource conditions. Future studies of the molecular mechanisms of the beneficial actions of CR should also consider the extent to which the signals/factors involved contribute to the anti-oxidative, anti-inflammatory, anti-tumor and other CR actions in each tissue or organ, and thereby lead to anti-aging and prolongevity. RNA Interference of ATP Synthase Subunits Slows Aging in Nematodes https://www.fightaging.org/archives/...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
I think it is entirely appropriate to greet the advent of senolytics with enthusiasm. These treatments are the first legitimate rejuvenation therapies to successfully target one of the root causes of aging, the accumulation of lingering senescent cells in old tissues. The first human trial data is approaching publication, but even before it arrives, the evidence to date strongly suggests that meaningful levels of rejuvenation can be achieved in old people at a very low cost. The first senolytic drugs (such as dasatinib and navitoclax) and plant extracts (such as fisetin and piperlongumine) cost very little, and remove only...
Source: Fight Aging! - Category: Research Authors: Tags: Daily News Source Type: blogs
AbstractComprehensive genomic cancer risk assessment (GCRA) helps patients, family members, and providers make informed choices about cancer screening, surgical and chemotherapeutic risk reduction, and genetically targeted cancer therapies. The increasing availability of multigene panel tests for clinical applications allows testing of well-defined high-risk genes, as well as moderate-risk genes, for which the penetrance and spectrum of cancer risk are less well characterized. Moderate-risk genes are defined as genes that, when altered by a pathogenic variant, confer a 2 to fivefold relative risk of cancer. Two such genes ...
Source: Familial Cancer - Category: Cancer & Oncology Source Type: research
International Journal of Cancer,Volume 0, Issue ja, -Not available-.
Source: International Journal of Cancer - Category: Cancer & Oncology Authors: Source Type: research
Authors: Li J, Svilar D, McClellan S, Kim JH, Ahn EE, Vens C, Wilson DM, Sobol RW Abstract Numerous studies have shown that select DNA repair enzyme activities impact response and/or toxicity of genotoxins, suggesting a requirement for enzyme functional analyses to bolster precision medicine or prevention. To address this need, we developed a DNA Repair Molecular Beacon (DRMB) platform that rapidly measures DNA repair enzyme activity in real-time. The DRMB assay is applicable for discovery of DNA repair enzyme inhibitors, for the quantification of enzyme rates and is sufficiently sensitive to differentiate cellular...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research
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