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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We present in vitro evidence that HDACi can enhance the radiosensitivity of human thyroid cancer cells.
Source: Molecular and Cellular Endocrinology - Category: Endocrinology Source Type: research
This article provides an overview of AZD1775, based on English peer-reviewed articles on MEDLINE. The authors highlight the data from the published preclinical and clinical studies. Expert opinion: A majority of the current clinical trials focus on AZD1775 combined with chemotherapy or radiation. Treatment with AZD1775 was tolerated and antitumor activity has been observed, especially in patients with advanced malignancies harboring G1 checkpoint aberrations and/or DNA damage repair defects. Thus, identification of the molecular subtypes that benefit most from the treatment with AZD1775 alone or in combination may provide ...
Source: Expert Opinion on Investigational Drugs - Category: Drugs & Pharmacology Tags: Expert Opin Investig Drugs Source Type: research
CONCLUSIONS: Cancer cells with low K-H expression may have exploitable BRCAness properties that greatly expands use of PARP inhibitors beyond BRCA mutations. Our results suggest that aberrant K-H alterations may have vital translational implications in cellular responses/survival to DNA damage, carcinogenesis and personalized medicine. PMID: 30108102 [PubMed - as supplied by publisher]
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research
CONCLUSIONS: HPV-positive HNSCC cells are unresponsive to TGFβ. Abrogated TGFβ signaling compromises homologous recombination and shifts reliance on alt-EJ repair that provides a mechanistic basis for sensitivity to PARP inhibitors. The effect of HPV in HNSCC provides critical validation of TGFβ's role in DNA repair proficiency and further raises the translational potential of TGFβ inhibitors in cancer therapy. PMID: 30087144 [PubMed - as supplied by publisher]
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research
Abstract BMI-1 (B-lymphoma Mo-MLV insertion region 1) is a key protein partner in polycomb repressive complex 1 (PRC1) that helps in maintaining the integrity of the complex. It is also a key player in ubiquitination of histone H2A which affects gene expression pattern involved in various cellular processes such as cell proliferation, growth, DNA repair, apoptosis and senescence. In many cancers, Overexpression of BMI1correlates with advanced stages of disease, aggressive clinicopathological behavior, poor prognosis resistance to radiation and chemotherapy. BMI1 is emerging as a key player in EMT, chemo-resistance...
Source: Gene - Category: Genetics & Stem Cells Authors: Tags: Gene Source Type: research
Publication date: Available online 3 August 2018Source: Seminars in Cancer BiologyAuthor(s): Gwenola Manic, Antonella Sistigu, Francesca Corradi, Martina Musella, Ruggero De Maria, Ilio VitaleAbstractCancer stem cells (CSCs) are subpopulations of multipotent stem cells (SCs) responsible for the initiation, long-term clonal maintenance, growth and spreading of most human neoplasms. Reportedly, CSCs share a very robust DNA damage response (DDR) with embryonic and adult SCs, which allows them to survive endogenous and exogenous genotoxins. A range of experimental evidence indicates that CSCs have high but heterogeneous levels...
Source: Seminars in Cancer Biology - Category: Cancer & Oncology Source Type: research
Abstract Human KIF4 is a member of Kinesin-4 kinesin family. The highly conserved structure contains an N-terminal motor region, coiled-coil region and C-terminal loading region. KIF4 plays important roles in DNA repair and DNA replication, which maintains genetic stability. KIF4 is also essential for regulation of mitosis and meiosis. KIF4 cooperates with condensin I and TopoIIα to help with chromosomal condensation, and binds to a plethora of cell-cycle proteins to regulate spindle organization and cytokinesis. Additionally, KIF4 plays roles in germ plasm aggregation and radial order in germ cells. In neur...
Source: Gene - Category: Genetics & Stem Cells Authors: Tags: Gene Source Type: research
Abstract Defining mechanisms that maintain tissue stem cells during homeostasis, stress, and aging is important for improving tissue regeneration and repair and enhancing cancer therapies. Here, we show that Id1 is induced in hematopoietic stem cells (HSCs) by cytokines that promote HSC proliferation and differentiation, suggesting that it functions in stress hematopoiesis. Genetic ablation of Id1 increases HSC self-renewal in serial bone marrow transplantation (BMT) assays, correlating with decreases in HSC proliferation, mitochondrial biogenesis, and reactive oxygen species (ROS) production. Id1-/- HSCs have a q...
Source: Cell Stem Cell - Category: Stem Cells Authors: Tags: Cell Stem Cell Source Type: research
Abstract Matching unique features of cancer types with effective therapies is a cornerstone of precision medicine. Clinical success has been seen in inhibiting specific molecular alterations that drive the growth of cancer cells and targeting molecules whose elevated expression is confined to cancer cells. In addition, cancer cells can have vulnerabilities induced by somatic mutations they carry; attacks on these vulnerabilities range from specific molecular alterations pointing to direct drug strategies to harnessing immune recognition of genetically altered epitopes produced by the cancer cells. Recent advances ...
Source: Annals of Internal Medicine - Category: Internal Medicine Authors: Tags: Ann Intern Med 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
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