This research proposal is intended to provide predoctoral and postdoctoral training to develop necessary skills for a career as an independent investigator in cancer biology. The long-term research focus is in cancer genetics, particularly to 1) identify genetic interactions with coordinated function in human cancer, 2) develop diagnostic and prognostic markers, and 3) develop novel therapeutics based on alterations within the cancer genome. The proposed dissertation research during the F99 training phase is to investigate FOXM1?s oncogenic role in HGSC and to foster its development as a therapeutic target. It remains unclear how FOXM1 cooperates with other genes to exert its oncogenic effects. Knowledge of these interactions is critical, e.g. to allow development of synthetic lethal therapeutic approaches that capitalize on FOXM1 overexpression. We have recently made several discoveries relevant to this concept. First, the FOXM1 genomic locus is amplified in HGSC, in conjunction with increased FOXM1 expression. Notably, FOXM1 amplification showed better correlation with poor prognosis than FOXM1 mRNA expression, suggesting that other genes at the amplified locus (12p13.33) cooperate with FOXM1 to exert oncogenic function. Subsequent analysis of 12p13.33 revealed that FOXM1 is arranged in a head-to-head orientation with RHNO1. Genes sharing this genomic arrangement frequently have dependent functions and regulate DNA repair. Consistently, RHNO1 is a component of the 9-1-1 DNA damage complex, and is required for full activation of ataxia telangiectasia and Rad3-related (ATR). Based on these and additional data, we hypothesize that FOXM1-RHNO1 constitutes a novel oncogenic axis in HGSC. As a corollary, we hypothesize that targeting RHNO1 or ATR in FOXM1 overexpressing HGSC will cause synthetic lethality. Our research will utilize inducible overexpression and knockdown approaches to define the independent and cooperative roles of FOXM1 and RHNO1 in cell cycle, replication stress, genomic instability, and cell fitness. We will utilize FTE and OSE cell models and genomically validated HGSC cell lines. We will determine the therapeutic activity of RHNO1 knockdown and pharmacological inhibition of ATR in HGSC cells with or without 12p13.33 amplification and FOXM1 overexpression. To expand upon the Ph.D. research direction, postdoctoral training will be obtained in cancer genetics. The goal of this proposed K00 postdoctoral training is to gain expertise to analyze the cancer genome to identify biologically significant gene alterations and genetic interactions, functionally validate these findings with high-throughput approaches, and finally model the desired genetics in vitro and vivo to further understand cancer biology and develop novel therapeutics. This will provide a systematic approach for translating cancer genomics into molecular diagnostics. Ultimately, the proposed F99/K00 training will foster my growth for transition into a challenging and rewarding career as an independent cancer investigator.
This research proposal provides a training plan to become an independent cancer researcher with a focus in cancer genetics. The long term goals of this program are to 1) identify genetic interactions with coordinated function in human cancer, 2) develop diagnostic and prognostic markers for cancer, and, 3) develop novel cancer therapeutics based on alterations within the cancer genome. This research has potential to benefit public health because it will improve our understanding of cancer biology and will lead to the development of new cancer therapeutic targets.
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|Robb, Caroline M; Kour, Smit; Contreras, Jacob I et al. (2018) Characterization of CDK(5) inhibitor, 20-223 (aka CP668863) for colorectal cancer therapy. Oncotarget 9:5216-5232|