PARP Inhibition in Cancer: An Update on Clinical Development

AbstractPARP (poly(ADP-ribose) polymerase) inhibitors represent a novel class of anti-cancer therapy; they take advantage of synthetic lethality and induce cell death by exploiting a defect in DNA repair. This class of medication was initially evaluated in patients with BRCA-associated tumors, but efficacy was also demonstrated in other populations. Since 2014, four PARP inhibitors have been approved in various indications: olaparib, niraparib, and rucaparib in high-grade serous ovarian cancer, and olaparib and talazoparib in metastatic breast cancer. The exact indications and study populations vary slightly between the different approvals in both disease states but there is significant overlap. PARP inhibitors continue to be investigated in ongoing clinical trials. In line with other targeted therapies, benefit appears to be strongest in a distinct population of patients with BRCA mutations or other defects in homologous recombination repair. Combination therapies, which include anti-angiogenesis agents and immunotherapy, show promise as a strategy to broaden efficacy for unselected patients. Initial studies of PARP inhibitors in combination with chemotherapy were limited by toxicity, but further studies are underway. To date, head-to-head trials comparing various PARP inhibitors have not been conducted, so questions remain in terms of choosing a PARP inhibitor to administer when indications overlap, as well as how to sequence these medications. Here we review both completed...
Source: Targeted Oncology - Category: Cancer & Oncology Source Type: research

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RAS protein activator like 2 (RASAL2) belongs to the RAS GTPase-activating protein family and plays an important role in several cancers, including ovarian cancer, nasopharyngeal carcinoma, malignant astrocytoma, renal cell carcinoma, bladder cancer, colorectal cancer, liver cancer, triple-negative breast cancer, lung adenocarcinoma, and pancreatic ductal adenocarcinoma. Traditionally, RASAL2 has been regarded as a tumor suppressor but recent studies have found that it is an oncogene in specific types of cancer, such as colorectal cancer, liver cancer, triple-negative breast cancer, triple-negative/estrogen receptor-negati...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
In this study, consequences of deficiency and overexpression of INPP4B on cellular transformation was investigated using a mouse embryonic fibroblast (MEF) model of cellular transformation. We observed that neither deficiency nor overexpression of INPP4B was sufficient to induce neoplastic transformation, alone or in combination with H-Ras V12 or E1A overexpression. However, Inpp4b-deficiency did cooperate with SV40 T-Large-mediated cellular transformation, a finding which was associated with increased phosphorylated-Akt levels. Transformation and phosphorylated-Akt levels were dampened upon overexpression of INPP4B in SV4...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research
Abstract Several papers have reported that calcium channel blocking drugs were associated with increased breast cancer risk and worsened prognosis. One of the most common signs of breast tumors is the presence of small deposits of calcium, known as microcalcifications. Therefore, we studied the effect of dihydropyridine nifedipine on selected calcium transport systems in MDA-MB-231 cells, originating from triple negative breast tumor and JIMT1 cells that represent a model of HER2-positive breast cancer, which possesses amplification of HER2 receptor, but cells do not response to HER2 inhibition treatment with tras...
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Biochem Pharmacol Source Type: research
e;s C Abstract In France, breast cancer is the most common cancer among women and the leading cause of cancer deaths. Identifying women with a "high" or "very high" breast cancer risk, according the terminology of the Haute Autorité de Santé 2014 guidelines, is essential to offer them special cares in term of screening and prevention. Women genetically predisposed have a very high risk of breast cancer. During the oncogenetic specialist consultation, familial and personal history of cancer is taken into account to evaluate the risk of hereditary Breast/Ovarian syndrome and th...
Source: Presse Medicale - Category: General Medicine Authors: Tags: Presse Med Source Type: research
Purpose of review To delineate the current state of evidence on the impact of night shift work on age at natural menopause. Recent findings The only direct evidence is from a single observational study, which indicates that women who work night shifts are at moderately higher risk for earlier menopause and that this risk is more pronounced among younger women. Underlying biological mechanisms have yet to be sufficiently substantiated. A long-held line of inquiry, most strongly propagated by the observed link between night shift work and female breast cancer, is the ‘Light at Night’ hypothesis, which sugges...
Source: Current Opinion in Endocrinology, Diabetes and Obesity - Category: Endocrinology Tags: REPRODUCTIVE ENDOCRINOLOGY: Edited by Wendy Kuohung Source Type: research
lessandro Weisz Although a large fraction of high-grade serous epithelial ovarian cancers (OCs) expresses Estrogen Receptor alpha (ERα), anti-estrogen-based therapies are still not widely used against these tumors due to a lack of sufficient evidence. The histone methyltransferase Disruptor of telomeric silencing-1-like (DOT1L), which is a modulator of ERα transcriptional activity in breast cancer, controls chromatin functions involved in tumor initiation and progression and has been proposed as a prognostic OC biomarker. As molecular and clinico-pathological data from TCGA suggest a correlation bet...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
Abstract The tyrosine kinase receptor ErbB2 is frequently found to be overexpressed in multiple cancer types. Targeted therapeutic approaches against ErbB2 have shown promising results and received FDA approvals in the treatment of breast cancer. However, this approach has not been granted in ovarian cancers till now. In order to assess the validity of ErbB2-targeted therapy in ovarian cancer, we investigated the effectiveness of two FDA-approved tyrosine kinase inhibitors of ErbB2, lapatinib and neratinib, on the growth of ovarian cancers. We observed that both lapatinib and neratinib displayed inhibitory effects...
Source: The International Journal of Biochemistry and Cell Biology - Category: Biochemistry Authors: Tags: Int J Biochem Cell Biol Source Type: research
Genes, Vol. 10, Pages 882: The BRCA1 c.4096+3A>G Variant Displays Classical Characteristics of Pathogenic BRCA1 Mutations in Hereditary Breast and Ovarian Cancers, But Still Allows Homozygous Viability Genes doi: 10.3390/genes10110882 Authors: Arason Agnarsson Johannesdottir Johannsson Hilmarsdottir Reynisdottir Barkardottir Mutations in BRCA1 result in predisposal to breast and ovarian cancers, but many variants exist with unknown clinical significance (VUS). One is BRCA1 c.4096+3A>G, which affects production of the full-length BRCA1 transcript, while augmenting transcripts lacking mos...
Source: Genes - Category: Genetics & Stem Cells Authors: Tags: Article Source Type: research
Abstract Cancer incidence rate has increased so much that it is the second leading cause of deaths worldwide after cardiovascular diseases. Sensitive and specific biomarkers are needed for an early diagnosis of cancer and in-time treatment. Recent studies have found that long non-coding RNAs (lncRNAs) participate in cancer tumorigenesis. LncRNA P73 antisense RNA 1T (TP73-AS1), also known as KIAA0495 and p53-dependent apoptosis modulator (PDAM), is located in human chromosomal band 1p36.32 and plays a crucial role in many different carcinomas. This review summarizes current findings on the role of TP73-AS1 and its ...
Source: Bioscience Reports - Category: Biomedical Science Authors: Tags: Biosci Rep Source Type: research
Authors: Lee A, Moon BI, Kim TH Abstract Hereditary breast cancer is known for its strong tendency of inheritance. Most hereditary breast cancers are related to BRCA1/BRCA2 pathogenic variants. The lifelong risk of breast cancer in pathogenic BRCA1 and BRCA2 variant carriers is approximately 65% and 45%, respectively, whereas that of ovarian cancer is estimated to be 39% and 11%, respectively. Therefore, understanding these variants and clinical knowledge on their occurrence in breast cancers and carriers are important. BRCA1 pathogenic variant breast cancer shows more aggressive clinicopathological features than t...
Source: Annals of Laboratory Medicine - Category: Laboratory Medicine Tags: Ann Lab Med Source Type: research
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