Citations

Abstract Metastatic malignant melanoma is an incurable disease with average 5-year survival rates for patients with disseminated disease ranging from 5-18%. Despite the recent development of promising targeted and immunological approaches for treatment of melanoma patients, there remains an urgent need to improve the effectiveness of conventional chemotherapeutics such as TMZ treatment for those patients ineligible or unresponsive to these approaches. We hypothesized that genetic alterations or contexts of vulnerability (COVs) exist in melanoma cells that mediate sensitivity to TMZ, and thus developed RNA-interference-based (RNAi) TMZ chemosensitization assays in melanoma cell lines in order to better understand how to pharmacologically augment TMZ response. First, we extensively developed RNAi sensitization assay in 17 melanoma cell lines followed by screening siRNA kinome library in these cell lines. This screening result, combined with our previous melanoma genomic data (gene expression, aCGH, SNP, and gene mutations), would prioritize the critical essential genes in melanoma. In addition, we profiled 17 melanoma cell lines for TMZ sensitivity and subsequently optimized RNAi screening parameters for detection of TMZ sensitization in one sensitive (UACC903) and four resistant (UACC647, UACC1308, UACC91 and UACC1940) cell lines. We then performed high-throughput RNAi screens with a 7,000 gene siRNA library targeting the druggable genome in these five cell lines. The data from the screens were rigorously evaluated and top TMZ-sensitizing hits were identified and confirmed. Based on these data, we prioritized the ATR/ATM/Chk1 pathway for further evaluation. We tested two Chk1 inhibitors for synergistic effects when combined with TMZ. Notably, both Chk1 inhibitors demonstrated good synergistic effects in the TMZ-resistant cell lines, with moderate/marginal effects in the sensitive line UACC903. These data are consistent with previous reports that inhibition of Chk1 can sensitize TMZ-induced cytotoxicity in glioma cells, and suggest that targeting this pathway in melanoma may augment TMZ response in melanoma. We are presently following up these results across a larger panel of melanoma cell lines, as well as evaluating pharmacological inhibitors of additional TMZ-sensitizing siRNA hits and pathways with the hope that these results may serve as a starting point for the development of novel combination therapies for melanoma patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5457. doi:10.1158/1538-7445.AM2011-5457

Abstract Background Surgical planning and local-regional treatment of breast cancer relies on accurate assessment of disease extent including the primary tumor size and the presence/absence of multiple tumor foci. As a staging modality for breast cancer, MRI has shown high sensitivity for detection of additional foci of diseases within the index breast. However, the impact of preoperative breast MRI on reducing re-excision rates and improving local control is less clear. Data from the COMICE trial in the UK suggested that routine use of pre-operative breast MRI did not alter rates of re-excision; however issues have been raised about the lack of quality standards for the MR imaging that may have resulted in the negative results of this trial. Retrospective data suggest that local recurrence is not impacted by use of breast MRI. In concert with data showing no improvement in clinical outcomes of breast cancer patients, concerns have been raised that routine use of preoperative breast MRI is associated with increased rates of mastectomy and delays to surgery. Therefore, the application of MRI for preoperative surgical staging remains controversial. In order to address this ongoing controversy, a joint effort has been launched by ACOSOG and ACRIN for a prospective clinical trial focused on evaluating the impact of preoperative breast MRI on clinically relevant patient outcomes. An important part of this collaboration is implementation of standards of how MRI findings should be clinically managed and used to direct localization methods and surgical planning, thereby creating guidelines for subsequent patient intervention. Trial design/eligibility criteria: A prospective multicenter trial will include women eligible for BCT by standard criteria and randomized between current standard of care, clinical examination and mammography (+/− ultrasound) and the same plus preoperative breast MRI. The study will focus on women at the highest risk of local recurrence: ER/PR/HER-2 negative (triple negative) and HER-2 amplified breast cancers. Specific aims: To compare the rates of local recurrence following breast conserving therapy in a cohort randomized to preoperative staging with mammography or mammography plus breast MRI. Additionally, a comparison of rates of re-operation, time to local recurrence, survival outcomes, contralateral breast cancer rates, rates of multicentric disease and other secondary aims will be performed. Costs and quality of life measures will also be investigated. Statistical methods: A stratified logrank test and Cox partial likelihood score test will be used to assess whether the distribution of LR times differs with respect to diagnostic work-up approach having adjusted for tumor stage. Cox modeling with the Cox partial likelihood score test will be used to examine the strength of association between these time to event distributions and such additional potential prognostic factors as menopausal status, chemotherapy, radiation therapy, ER, PR, number of positive lymph nodes, HER-2/neu expression, Nottingham grade, and Ki-67 expression. Target Accrual: 556 patients Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-05-06.

Abstract Background: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Methods: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. Results: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07–1.27; P = 7.42 × 10−4] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73–0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94–1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05–1.29; P = 3.8 × 10−4) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10–1.52; P = 1.8 × 10−3). Conclusions: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(4); 645–57. ©2012 AACR.