At the fime of diagnosis, most epithelial ovarian cancers (EOCs) are no longer dependent on single genefic 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 erlofinib and cetuximab, and by the Src-targefing agent, dasafinib (also known as BMS-354825 or Sprycel"). We have used bioinformafics approaches to map the pattern of hits back to a network of interacting signaling proteins. This has already revealed suggesfive 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 objecfives 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 combinafions of siRNAs with drugs, or drugs with drugs, that can be rapidly translated to the clinic. The four Aims proposed will systemafically develop our preliminary studies to identify productive targets of co- inhibifion, with the ulfimate goal of identifying new drug combinations that will greatly enhance the treatment of women with EOC. Hence, Aim 1 will complete the inifial hit validafion process, create a "master plate" of individual hits and use this master plate of siRNAs to evaluate efficacy of the siRNAs in mulfiple EOC cell lines. In Ainfi 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 combinafions 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 inifiate clinical trials using combined molecular targeted agents. We believe that this cutfing-edge approach will yield a paradigm that can subsequently be applied for mulfiple therapeutic applicafions.

Public Health Relevance

Future clinical studies will need to explore schedules and combinafions of treatments that opfimize therapeufic results of existing agents, but at the same fime novel druggable targets must also be found. The studies proposed offer an unprecedented opportunity to employ a functional approach to identify crifical drug response-modifying genes that can be therapeufically targeted to improve ovarian cancer treatment outcomes with contemporary agents such as dasafinib and cetuximab, with or without the front line chemotherapeutic agents, plafinum and paclitaxel.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA083638-14
Application #
8380820
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
Project End
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
14
Fiscal Year
2012
Total Cost
$242,445
Indirect Cost
$57,762
Name
Fox Chase Cancer Center
Department
Type
DUNS #
073724262
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Xiao, Xue; Yang, Gong; Bai, Peng et al. (2016) Inhibition of nuclear factor-kappa B enhances the tumor growth of ovarian cancer cell line derived from a low-grade papillary serous carcinoma in p53-independent pathway. BMC Cancer 16:582
Prudnikova, T Y; Villamar-Cruz, O; Rawat, S J et al. (2016) Effects of p21-activated kinase 1 inhibition on 11q13-amplified ovarian cancer cells. Oncogene 35:2178-85
Tan, Yinfei; Xin, Xiaoban; Coffey, Francis J et al. (2016) Appl1 and Appl2 are Expendable for Mouse Development But Are Essential for HGF-Induced Akt Activation and Migration in Mouse Embryonic Fibroblasts. J Cell Physiol 231:1142-50
Wang, Yifan; Bernhardy, Andrea J; Cruz, Cristina et al. (2016) The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin. Cancer Res 76:2778-90
Zhang, Youyou; Feng, Yi; Hu, Zhongyi et al. (2016) Characterization of Long Noncoding RNA-Associated Proteins by RNA-Immunoprecipitation. Methods Mol Biol 1402:19-26
Hu, Xiaowen; Feng, Yi; Hu, Zhongyi et al. (2016) Detection of Long Noncoding RNA Expression by Nonradioactive Northern Blots. Methods Mol Biol 1402:177-88
Zhang, Youyou; He, Qun; Hu, Zhongyi et al. (2016) Long noncoding RNA LINP1 regulates repair of DNA double-strand breaks in triple-negative breast cancer. Nat Struct Mol Biol 23:522-30
Beck, Tim N; Korobeynikov, Vladislav A; Kudinov, Alexander E et al. (2016) Anti-Müllerian Hormone Signaling Regulates Epithelial Plasticity and Chemoresistance in Lung Cancer. Cell Rep 16:657-71
Zhang, Shiwu; Mercado-Uribe, Imelda; Sood, Anil et al. (2016) Coevolution of neoplastic epithelial cells and multilineage stroma via polyploid giant cells during immortalization and transformation of mullerian epithelial cells. Genes Cancer 7:60-72
Daly, Mary B; Dresher, Charles W; Yates, Melinda S et al. (2015) Salpingectomy as a means to reduce ovarian cancer risk. Cancer Prev Res (Phila) 8:342-8

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