The clinical development of PARP inhibitors for the treatment of tumors deficient in BRCA1 or BRCA2 is based on the concept of synthetic lethality. From the initial proof of concept study with the PARP1 inhibitor olaparib (AZD2281) in BRCA mutation carriers, in which 28% of ovarian cancer patients achieved an objective response, the target population of ovarian patients potentially sensitive to treatment with PARP inhibitors has greatly increased. Objective responses have been observed in both platinum-sensitive and platinum-resistant BRCA mutation carriers but, more recently, also in BRCA negative 'BRCAness' patients, those with no BRCA mutations but with a dysfunction of the homologous recombination (HR) system, which makes them more sensitive to the antitumor agents which cause double strand breaks of DNA. The recent results achieved with olaparib, given as maintenance in platinum sensitive recurrent high grade serous ovarian cancer, in response after reinduction with platinum, confirm the antitumor effect of single agent olaparib in BRCAness patients. Main topics of investigations in this field are the identification of BRCAness phenotype and the definition of tests to identify BRCAness patients. More in general, additional preclinical studies are needed to further improve clinical results in order to define the optimal regimen of combination with PARP1 inhibitor and cytotoxics or molecular targeted agents (sequence of administration, interval between dosing of the agents, duration of treatment).
"ily targeting appropriate cellular receptors, e. g. receptors of the vascular endothelial growth factor, the platelet-derived growth factor , and the tyrosine kinase receptor c-kit (Cannistra et al., 2007; Raja et al., 2011; Du Bios et al., 2013). Another treatment approach in women with BRCA 1or BRCA 2 mutations is based on suppressing cancer cell DNA repair machinery by olaparib, a compound binding to and subsequently inhibiting the poly-(ADP-ribose) polymerase (Sessa, 2011). Finally, the tetrahydroisoquinoline alkaloid trabectedin affect DNA integrity by direct binding to the chromosomal DNA and followed by promoting nucleic acid restriction and apoptosis initiation (D'Incalci and Galmarini, 2010). "
"The clinical relevance of synthetic lethality has been rapidly recognized. Multiple phase II and III clinical trials of PARP inhibitors were conducted for breast and ovarian cancer patients with BRCA1 or BRCA2 mutation  .Over the last few years, genes having SL interactions (SLs) in cancers have been actively studied using individual RNAi experiments, or by large scale RNAi screenings that uncover multiple SL gene pairs   , which in general were centered on one gene. Astsaturov and colleagues identified SLs in human by combining both computational and experimental approaches .They first combined pathway maps, protein-protein interactions, gene expression data and human orthologs of Drosophila Egfr genetic interaction partners, to predict 2689 SL candidates of EGFR. "
[Show abstract][Hide abstract] ABSTRACT: Two genes are called synthetic lethal (SL) if their simultaneous mutations lead to cell death, but each individual mutation does not. Targeting SL partners of mutated cancer genes can kill cancer cells specifically, but leave normal cells intact. We present an integrated approach to uncovering SL pairs in colorectal cancer (CRC). Screening verified SL pairs using microarray gene expression data of cancerous and normal tissues, we first identified potential functionally relevant (simultaneously differentially expressed) gene pairs. From the top-ranked pairs, ~ 20 genes were chosen for immunohistochemistry (IHC) staining in 171 CRC patients. To find novel SL pairs, all 169 combined pairs from the individual IHC were synergistically correlated to five clinicopathological features, e.g. overall survival. Of the 11 predicted SL pairs, MSH2-POLB and CSNK1E-MYC were consistent with literature, and we validated the top two pairs, CSNK1E-TP53 and CTNNB1-TP53 using RNAi knockdown and small molecule inhibitors of CSNK1E in isogenic HCT-116 and RKO cells. Furthermore, synthetic lethality of CSNK1E and TP53 was verified in mouse model. Importantly, multivariate analysis revealed that CSNK1E-P53, CTNNB1-P53, MSH2-RB1, and BRCA1-WNT5A were independent prognosis markers from stage, with CSNK1E-P53 applicable to early-stage and the remaining three throughout all stages. Our findings suggest that CSNK1E is a promising target for TP53-mutant CRC patients which constitute ~ 40% to 50% of patients, while to date safety regarding inhibition of TP53 is controversial. Thus the integrated approach is useful in finding novel SL pairs for cancer therapeutics, and it is readily accessible and applicable to other cancers.
"Thus, PARP inhibitors are suitable for the treatment of tumors with dysfunctional DNA repair. Three phase II studies with the PARP inhibitors olaparib and iniparib have demonstrated activity in platinum-sensitive ovarian carcinoma [78–81]. A preliminary study has demonstrated that ovarian carcinoma patients with BRCA1 or 2 mutations respond better to olaparib than those without mutations . "
[Show abstract][Hide abstract] ABSTRACT: Ovarian carcinoma (OC) is the most lethal gynecological malignancy. Response to platinum-based chemotherapy is poor in some patients and, thus, current research is focusing on new therapy options. The various histological types of OC are characterized by distinctive molecular genetic alterations that are relevant for ovarian tumorigenesis. The understanding of these molecular pathways is essential for the development of novel therapeutic strategies.
We want to give an overview on the molecular genetic changes of the histopathological types of OC and their role as putative therapeutic targets.
In Depth Review of Existing Data
In 2012, the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, was approved for OC treatment. Bevacizumab has shown promising results as single agent and in combination with conventional chemotherapy, but its target is not distinctive when analyzed before treatment. At present, mammalian target of rapamycin (mTOR) inhibitors, poly-ADP-ribose polymerase (PARP) inhibitors and components of the EGFR pathway are in the focus of clinical research. Interestingly, some phytochemical substances show good synergistic effects when used in combination with chemotherapy.
Ongoing studies of targeted agents in conjunction with chemotherapy will show whether there are alternative options to bevacizumab available for OC patients. Novel targets which can be assessed before therapy to predict efficacy are needed. The assessment of therapeutic targets is continuously improved by molecular pathological analyses on tumor tissue. A careful selection of patients for personalized treatment will help to reduce putative side effects and toxicity.
International Journal of Molecular Sciences 05/2013; 14(5):9536-55. DOI:10.3390/ijms14059536 · 2.86 Impact Factor
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