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 reported a dual HDAC and DNMT inhibitor 208 and found it induced G1 cell cycle arrest and apoptosis in U937 cells. Proteome and bioinformatic analyses revealed that the combined inhibition of DNMT1 and HDAC by 208 affected the expression of a series of proteins involved in many biological processes. We observed that several proteins associated with G1 cell cycle arrest and apoptosis were down regulated after 208 treatment, including p85α, MEK, and CDK4, suggesting that 208 induces cell cycle arrest and apoptosis through the p85α/MEK-mediated pathway in U937 cells. Moreover, biological function...
Source: Chinese Chemical Letters - Category: Chemistry Source Type: research
AbstractPurpose of ReviewCellular therapy started in the early twentieth century with the development of blood transfusion and later bone marrow transplantation. This review describes the historical origins and major milestones in the field of cellular therapy. We discuss ethical concerns associated with certain cell sources and how they influenced therapy strategies. A focus of this article is on the use of stem cells to understand regenerative repair after kidney injury. In addition, we give an overview over past and current kidney-related cellular therapy trials.Recent FindingsThe number of kidney-related cellular thera...
Source: Current Transplantation Reports - Category: Transplant Surgery Source Type: research
Abstract SWI/SNF complexes are among the most studied ATP-dependent chromatin remodeling complexes, mostly due to their critical role in coordinating chromatin architecture and gene expression. Mutations in genes encoding SWI/SNF subunits are frequently observed in a large variety of human cancers, suggesting that one or more of the multiple SWI/SNF functions protect against tumorigenesis. Chromatin remodeling is an integral component of the DNA damage response (DDR), which safeguards against DNA damage-induced genome instability and tumorigenesis by removing DNA damage through interconnected DNA repair and signal...
Source: DNA Repair - Category: Genetics & Stem Cells Authors: Tags: DNA Repair (Amst) Source Type: research
Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more. This content is...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Date: Wednesday, 03 20, 2019; Speaker: Dipanjan Chowdhury , Ph.D., Chief Division of Radiation and Genomic Stability, Dana-Farber Cancer Institute; Building: Building 37; 4041
Source: NIH Calendar of Events - Category: American Health Source Type: events
Jim Mellon's Juvenescence venture is at present one of the few major venture organizations focused on approaches to treat aging as a medical condition. Mellon and his colleagues outlined their take on the field in a 2017 book, also called Juvenescence. We are fortunate in that he is among the first few high net worth individuals to both agree with the SENS philosophy of damage repair, and then, much more importantly, follow through in action as well as word. He is not just seeing a massive market opportunity in treating aging, though that is certainly there, but is doing this because he wishes to achieve the goal of radica...
Source: Fight Aging! - Category: Research Authors: Tags: Healthy Life Extension Community Source Type: blogs
Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more. This content is...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
I am a little late with the 2019 list of projects in rejuvenation biotechnology that I'd like to see startups tackling sometime soon. In my defense, this year I have a startup of my own to keep up with, and the first part of 2019 was a wall to wall series of conferences alternating between the US and Europe. It continues to be the case that this is a new industry of near endless potential, yet little of that potential is under active development. This is the state of affairs despite the arrival of hundreds of millions of dollars in venture funds managed by the like of Juvenescence, Life Biosciences, and so on. The research...
Source: Fight Aging! - Category: Research Authors: Tags: Investment Source Type: blogs
Conclusions: These results underscore the combinatorial treatment using TMZ and L189 to bring desirable cancer cell growth arrest and future molecular study to dissect out the participating pathways.
Source: Current Cancer Therapy Reviews - Category: Cancer & Oncology Source Type: research
Abstract During the last decade, advances of radiotherapy (RT) have been made in the clinical practice of cancer treatment. RT exerts its anticancer effect mainly via leading to the DNA double-strand break (DSB), which is one of the most toxic DNA damages. Non-homologous end joining (NHEJ) and homologous recombination (HR) are two major DSB repair pathways in human cells. It is known that dysregulations of DSB repair elicit a predisposition to cancer and probably result in resistance to cancer therapies including RT. Therefore, targeting the DSB repair presents an attractive strategy to counteract radio- resistanc...
Source: Current Drug Targets - Category: Drugs & Pharmacology Authors: Tags: Curr Drug Targets Source Type: research
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