At the time of diagnosis, most epithelial ovarian cancers (EOCs) are no longer dependent on single genetic determinants for growth and/or survival. Therefore, targeted therapies used as single agents are not likely to be effective in this disease. We hypothesized that focused second site lethality screens performed using a cogently designed siRNA library would help identify critical cooperating oncogenic pathways that could be targeted using combinations of novel biologies. We have used RNAi approaches to identify candidates that selectively enhance killing by EGFR-inhibitors, such as erlotinib and cetuximab, and by the Src-targeting agent, dasatinib (also known as BMS-354825 or Sprycel"). We have used bioinformatics approaches to map the pattern of hits back to a network of interacting signaling proteins. This has already revealed suggestive clusters of very closely interacting proteins, implying we have identified key survival nodes controlling resistance to drug treatment. In two cases, we have been able to exploit this information to develop novel, synergizing combinations of targeted therapeutic agents. The overall objectives going forward are to take the genes obtained through our siRNA screens, continue to map the sensitization network for targeted therapeutics relevant to EOC, and to design meaningful combinations of siRNAs with drugs, or drugs with drugs, that can be rapidly translated to the clinic. The four Aims proposed will systematically develop our preliminary studies to identify productive targets of co- inhibition, with the ultimate goal of identifying new drug combinations that will greatly enhance the treatment of women with EOC. Hence, Aim 1 will complete the initial hit validation process, create a "master plate" of individual hits and use this master plate of siRNAs to evaluate efficacy of the siRNAs in multiple EOC cell lines.
In Aim 2, we will explore the expression patterns of proteins and transcripts for genes identified through hits in patient samples, to assess their clinical relevance.
In Aim 3 we will perform animal-based experiments to further test supersensitizing combinations of drugs and siRNAs.
In Aim 4 we will use the combined results of this analysis both to nominate new targets for drug development and to initiate clinical trials using combined molecular targeted agents. We believe that this cutting-edge approach will yield a paradigm that can subsequently be applied for multiple therapeutic applications.
Future clinical studies will need to explore schedules and combinations of treatments that optimize therapeutic results of existing agents, but at the same time novel druggable targets must also be found. The studies proposed offer an unprecedented opportunity to employ a functional approach to identify critical drug response-modifying genes that can be therapeutically targeted to improve ovarian cancer treatment outcomes with contemporary agents such as dasatinib and cetuximab, with or without the front line chemotherapeutic agents, platinum and paclitaxel.
|Zhong, Qian; Peng, Hong-Ling; Zhao, Xia et al. (2015) Effects of BRCA1- and BRCA2-related mutations on ovarian and breast cancer survival: a meta-analysis. Clin Cancer Res 21:211-20|
|Duraiswamy, Jaikumar; Freeman, Gordon J; Coukos, George (2014) Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors--response. Cancer Res 74:633-4; discussion 635|
|Li, Chunsheng; Wang, Junying; Hu, Jia et al. (2014) Development, optimization, and validation of novel anti-TEM1/CD248 affinity agent for optical imaging in cancer. Oncotarget 5:6994-7012|
|Hu, Xiaowen; Feng, Yi; Zhang, Dongmei et al. (2014) A functional genomic approach identifies FAL1 as an oncogenic long noncoding RNA that associates with BMI1 and represses p21 expression in cancer. Cancer Cell 26:344-57|
|Matthaiou, Efthymia-Iliana; Barar, Jaleh; Sandaltzopoulos, Raphael et al. (2014) Shikonin-loaded antibody-armed nanoparticles for targeted therapy of ovarian cancer. Int J Nanomedicine 9:1855-70|
|Do, T-V; Xiao, F; Bickel, L E et al. (2014) Aurora kinase A mediates epithelial ovarian cancer cell migration and adhesion. Oncogene 33:539-49|
|Zhang, S; Mercado-Uribe, I; Xing, Z et al. (2014) Generation of cancer stem-like cells through the formation of polyploid giant cancer cells. Oncogene 33:116-28|
|Feng, Yi; Hu, Xiaowen; Zhang, Youyou et al. (2014) Methods for the study of long noncoding RNA in cancer cell signaling. Methods Mol Biol 1165:115-43|
|Liu, Hanqing; Beck, Tim N; Golemis, Erica A et al. (2014) Integrating in silico resources to map a signaling network. Methods Mol Biol 1101:197-245|
|Ye, Qunrui; Song, De-Gang; Poussin, Mathilde et al. (2014) CD137 accurately identifies and enriches for naturally occurring tumor-reactive T cells in tumor. Clin Cancer Res 20:44-55|
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