Olaparib for the treatment of breast cancer

Abstract

Basal-like breast cancer is characterized by being triple negative and aggressive. Defects in DNA repair is a promising therapeutic target as BRCA alterations are found in 11 to 42% of these tumors, with a frequency varying according to family history and ethnicity. The oral PARP inhibitors exploit this deficiency through a synthetic lethality and are considered as promising anticancer therapies, especially in patients harboring BRCA1 or BRCA 2 mutations. Areas covered: Olaparib is one of the most widely investigated PARP inhibitors. Here, the preclinical data, completed clinical trials and ongoing investigations are discussed. Expert opinion: PARP inhibitors show promising results in breast cancer. However, several issues are raised including the identification of biomarkers to predict treatment response and strategies to counteract emerging resistance. Moreover, the results from ongoing phase III trials of olaparib in breast cancer are still awaited.

Suppression of Canine ATP Binding Cassette ABCB1 in Madin-Darby Canine Kidney Type II Cells Unmasks Human ABCG2-Mediated Efflux of Olaparib

“…Olaparib is an orally active, small molecule inhibitor of poly(ADP-ribose) polymerase. Olaparib was recently approved for the treatment of advanced ovarian cancer and BRCA-mutated metastatic breast cancer, with the possibility of applications to other cancer types as well (Robert et al, 2017). Since olaparib was previously regarded primarily as a substrate for ABCB1, the decrease in intracellular exposure in cancer cells was thought to be entirely mediated by ABCB1 (Vaidyanathan et al, 2016).…”

Electrophilic fatty acids impair RAD51 function and potentiate the effects of DNA-damaging agents on growth of triple-negative breast cells

“…The heightened tumor ␥H2AX levels in vivo and sensitization of TNBC cells to DNA-damaging agents, especially in the context of olaparib-induced responses, led to further exploration of DNA damage repair modulation by OA-NO 2 . As olaparib sensitivity is a hallmark of HR-deficient cells (15), whether OA-NO 2 impacted DNA repair by HR was evaluated. To specifically probe DNA double-strand break repair, MDA-MB-231 cells were challenged with 5 Gy of IR, and RAD51 foci were quantified.…”

Systems-level network modeling of Small Cell Lung Cancer subtypes identifies master regulators and destabilizers

“…These strategies can then be tested in vitro and in vivo.transdifferentiation allows tumors to evade treatment and relapse in a therapy-resistant manner. Characterizing cancer 29 subpopulations, or subtypes, has led to breakthrough targeted treatments that significantly improve patient outcomes, as in 30 the case of melanoma [1], breast [2], and lung cancer [3]. However, approaches to subtype identification suffer from several 31 limitations, including: i) focus on biomarkers, which frequently possess insufficient resolving power; ii) lack of consideration 32 for the system dynamics of the tumor as a whole; and iii) often phenomenological, rather than mechanistic, explanations for 33 subtype sources.…”

“…Given M observations (in our case, each observations is a measurement of gene expression of the N regulator TFs and the 164 target TF in M = 50 cell lines), we want to compute this vector ( V ) describing a probabilistic Boolean function F of N 165 variables (see (5) in Fig 7B). First, we organize the input-output relationship as a binary tree with N layers leading to the 2 N 166 leaves (see (2) in Fig 7B), each of which corresponds to a component of vector V . For instance, given two regulators A and B 167 (N = 2), the leaves of the binary tree correspond to the probabilities that (A ∧ B), (A ∧ B), (A ∧ B), and (A ∧ B).…”