Abstract IA20: Framing therapeutic opportunities in tumor-activated gametogenic programs

Abstract

Abstract Tumors frequently activate genes whose expression is otherwise restricted to gametogenic tissues. These genes, the Cancer/Testes-antigens (CTA, CT-antigens), were originally identified by virtue of the humoral immune response they invoked in cancer patients. Given their germ line biased expression pattern, CT-antigens may afford the potential for an extraordinary therapeutic window, if they are required for tumor cell proliferation and survival. However, functional roles for CT-antigens in tumorigenesis and any efficacy as therapeutic intervention points have not been extensively investigated. Recently, our group and others have implicated CT-antigens in supporting mitotic fidelity, p53 silencing and retinoic acid signaling to promote tumorigenesis. This data indicates that gametogenic genes anomalously expressed in tumors can functionally buttress neoplastic phenotypes. To generate a more comprehensive understanding of the functional roles of CTAs in the tumorigenic setting, we have employed an unbiased, multi-dimensional, loss of function discovery platform to systematically assess the contribution of CT-antigens to a range of oncogenic signaling pathways and phenotypes. This effort has revealed that distinct CTA's can support many of the hallmarks of cancer, including: 1) enhanced energy production 2) hijacking developmental programs that promote self-renewal and metastases 3) modulation of cell-fate programs that support proliferation 4) adaption to low oxygen conditions inherent in the tumor microenvironment and 5) activation of survival and inflammatory signaling. These findings suggests that reactivation of these primordial genes may impact a broad spectrum of signaling mechanisms and cell biological behaviors that promote tumor growth and survival. Thus, CT-antigens present previously unrecognized tumor-specific vulnerabilities that may be exploited for therapeutic intervention. Citation Format: Angelique Whitehurst. Framing therapeutic opportunities in tumor-activated gametogenic programs. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr IA20.