Arun, Banu

Abstract Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis. Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.

Abstract Purpose: We aimed to establish the MTD of the poly (ADP-ribose) (PAR) polymerase inhibitor, veliparib, in combination with carboplatin in germline BRCA1- and BRCA2- (BRCA)-associated metastatic breast cancer (MBC), to assess the efficacy of single-agent veliparib, and of the combination treatment after progression, and to correlate PAR levels with clinical outcome. Experimental Design: Phase I patients received carboplatin (AUC of 5–6, every 21 days), with escalating doses (50-20 mg) of oral twice-daily (BID) veliparib. In a companion phase II trial, patients received single-agent veliparib (400 mg BID), and upon progression, received the combination at MTD. Peripheral blood mononuclear cell PAR and serum veliparib levels were assessed and correlated with outcome. Results: Twenty-seven phase I trial patients were evaluable. Dose-limiting toxicities were nausea, dehydration, and thrombocytopenia [MTD: veliparib 150 mg po BID and carboplatin (AUC of 5)]. Response rate (RR) was 56%; 3 patients remain in complete response (CR) beyond 3 years. Progression-free survival (PFS) and overall survival (OS) were 8.7 and 18.8 months. The PFS and OS were 5.2 and 14.5 months in the 44 patients in the phase II trial, with a 14% RR in BRCA1 (n = 22) and 36% in BRCA2 (n = 22). One of 30 patients responded to the combination therapy after progression on veliparib. Higher baseline PAR was associated with clinical benefit. Conclusions: Safety and efficacy are encouraging with veliparib alone and in combination with carboplatin in BRCA-associated MBC. Lasting CRs were observed when the combination was administered first in the phase I trial. Further investigation of PAR level association with clinical outcomes is warranted. Clin Cancer Res; 23(15); 4066–76. ©2017 AACR.

Abstract Background: The potential for exploiting BRCA deficiencies with DNA repair inhibitors has both pre-clinical and clinical support. ABT-888 (veliparib), a DNA repair inhibitor initially thought to target Poly(ADP-Ribose) Polymerases (PARP), has demonstrated in vitro inhibition of BRCA1 and BRCA2 deficient mouse embryonic stell cells, with a larger effect on BRCA1 cells. We report on the pre-planned interim analysis of the efficacy of single agent veliparib in patients with either BRCA1 or BRCA2-associated stage IV breast cancer. Methods: BRCA 1 or 2 carrier patients with stage IV breast cancer, with measurable disease, without prior exposure to a PARP inhibitor or a platinum compound in the metastatic setting, were eligible. Velapirib was administered orally, at doses of 400 mg twice daily. Dose adjustments based on toxicity were permitted. Patients progressing on velapirib alone received carboplatin at an AUC of 5, IV, given Q 21 days, and velapirib 150 mg twice daily (the maximum tolerated dose [MTD] of the combination from our completed Phase I study: J Clin Oncol 30, 2012 [suppl; abstr 1024]). Patients were to be accrued from 7 NCI NO1- supported consortia. Initially 10 patients were to be accrued to each stratum (BRCA1 and BRCA2) to provide evidence of single agent activity. If there was sufficient activity to warrant consideration of velapirib as single agent therapy (defined as 2 or more confirmed partial [PR] or better responses out of 10 per stratum), an additional 12 patients would be accrued per stratum. Results: 20 evaluable patients (11 BRCA1 and 9 BRCA2 [1 in screening]) have been accrued, the majority with lung or liver as visceral metastatic sites of disease. Median age (range) is 46 (29-68) years. Tumors from 9 patients were hormone receptor positive. BRCA1 cohort: 4 of 11 patients are off treatment at a median of 2 months (1-4); 1 patient stopped velapirib due to toxicity (grade 2 rash/pruritus, grade 2 vomiting), 3 stopped for progressive disease (one with an unconfirmed PR). Seven patients are still on single agent veliparib with 1 unconfirmed PR, and 1 patient with two evaluations showing stable disease. BRCA2 cohort: 2 patients are off treatment at 2 months for progressive disease, 7 are still on treatment with 1 confirmed PR, and 3 unconfirmed PRs. Data on patients receiving combination of velapirib and carboplatin after progression is too early. Treatment-related toxicity is being updated and has so far been reported from 14 patients: 1 patient had grade 3 fatigue, 1 patient with liver metastasis had both grade 3 alanine aminotransferase elevation and grade 3 abdominal pain. Grade 2 toxicities occurring in more than 1 patient included nausea/vomiting (6 patients), chills (2 patients), and fatigue (2 patients). Conclusion: Velapirib has single agent activity in both BRCA1 and BRCA2-associated stage IV breast cancer patients, and is well-tolerated. Mature response, treatment, and toxicity data will be presented. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-05.

AbstractThis article reviews progress in chemopreventive drug development, especially data and concepts that are new since the 2002 AACR report on treatment and prevention of intraepithelial neoplasia. Molecular biomarker expressions involved in mechanisms of carcinogenesis and genetic progression models of intraepithelial neoplasia are discussed and analyzed for how they can inform mechanism-based, molecularly targeted drug development as well as risk stratification, cohort selection, and end-point selection for clinical trials. We outline the concept of augmenting the risk, mechanistic, and disease data from histopathologic intraepithelial neoplasia assessments with molecular biomarker data. Updates of work in 10 clinical target organ sites include new data on molecular progression, significant completed trials, new agents of interest, and promising directions for future clinical studies. This overview concludes with strategies for accelerating chemopreventive drug development, such as integrating the best science into chemopreventive strategies and regulatory policy, providing incentives for industry to accelerate preventive drugs, fostering multisector cooperation in sharing clinical samples and data, and creating public-private partnerships to foster new regulatory policies and public education.