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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
7P50CA083638-15
Application #
8474624
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
15
Fiscal Year
2013
Total Cost
$307,010
Indirect Cost
$74,010
Name
Research Institute of Fox Chase Cancer Center
Department
Type
DUNS #
064367329
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Nacson, Joseph; Krais, John J; Bernhardy, Andrea J et al. (2018) BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance. Cell Rep 25:1384
Gabbasov, Rashid; Xiao, Fang; Howe, Caitlin G et al. (2018) NEDD9 promotes oncogenic signaling, a stem/mesenchymal gene signature, and aggressive ovarian cancer growth in mice. Oncogene 37:4854-4870
Chiang, Cheryl Lai-Lai; Kandalaft, Lana E (2018) In vivo cancer vaccination: Which dendritic cells to target and how? Cancer Treat Rev 71:88-101
Hu, Xiaowen; Sood, Anil K; Dang, Chi V et al. (2018) The role of long noncoding RNAs in cancer: the dark matter matters. Curr Opin Genet Dev 48:8-15
Nacson, Joseph; Krais, John J; Bernhardy, Andrea J et al. (2018) BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance. Cell Rep 24:3513-3527.e7
Beck, Tim N; Smith, Chad H; Flieder, Douglas B et al. (2017) Head and neck squamous cell carcinoma: Ambiguous human papillomavirus status, elevated p16, and deleted retinoblastoma 1. Head Neck 39:E34-E39
Yang, Lu; Zhang, Youyou; Shan, Weiwei et al. (2017) Repression of BET activity sensitizes homologous recombination-proficient cancers to PARP inhibition. Sci Transl Med 9:
Skates, Steven J; Greene, Mark H; Buys, Saundra S et al. (2017) Early Detection of Ovarian Cancer using the Risk of Ovarian Cancer Algorithm with Frequent CA125 Testing in Women at Increased Familial Risk - Combined Results from Two Screening Trials. Clin Cancer Res 23:3628-3637
Zhang, Dongmei; Zhang, Gao; Hu, Xiaowen et al. (2017) Oncogenic RAS Regulates Long Noncoding RNA Orilnc1 in Human Cancer. Cancer Res 77:3745-3757
Prudnikova, Tatiana Y; Chernoff, Jonathan (2017) The Group I Pak inhibitor Frax-1036 sensitizes 11q13-amplified ovarian cancer cells to the cytotoxic effects of Rottlerin. Small GTPases 8:193-198

Showing the most recent 10 out of 323 publications