Framing Therapeutic Opportunities in Tumor-Activated Gametogenic Programs

 描述（由申请人提供）：肿瘤经常重新激活基因，否则这些基因的表达仅限于配子发生组织，包括卵巢、胎盘和睾丸。这些基因的致瘤表达，统称为癌睾丸抗原 (CTA)，已有超过 25 年的记录；然而，关于这些基因产物对肿瘤发生的贡献的功能知识仍然很少。为了研究 CTA 在致瘤表型中的作用，我们部署了一个多维定量发现平台来检查 120 种 CT 抗原对 11 种不同致瘤环境中肿瘤表型和信号级联的贡献。利用这个筛选平台，我们鉴定出了对许多癌症特征至关重要的 CT 抗原，包括：1) 阻止细胞死亡信号传导；2) 增强能量产生；3) 劫持促进自我更新和转移的发育程序；4) 适应肿瘤微环境固有的低氧条件；5) 对 DNA 损伤和非整倍性的耐受。因此，该提案的目的是详细阐述癌症睾丸抗原对肿瘤过程的贡献。对这些 CTA 在致瘤过程中的作用的深入研究将为肿瘤细胞调节环境提供概念性突破，并为可用于治疗干预的肿瘤细胞特异性靶标提供重要的新见解。

 DESCRIPTION (provided by applicant): Tumors frequently re-activate genes whose expression is otherwise restricted to gametogenic tissues including the ovary, placenta and testes. Tumorigenic expression of these genes, known collectively as cancer-testes antigens (CTAs), has been documented for over 25 years; however functional knowledge of the contribution of these gene products to tumorigenesis remains scant. To examine the roles of CTAs in tumorigenic phenotypes, we have deployed a multidimensional quantitative discovery platform to examine the contribution of 120 CT antigens to neoplastic phenotypes and signaling cascades in 11 diverse tumorigenic settings. Using this screening platform, we have identified CT-antigens that are essential to many of the hallmarks of cancer including: 1) thwarting cell death signaling 2) enhanced energy production 3) hijacking developmental programs that promote self-renewal and metastases 4) adaption to low oxygen conditions inherent in the tumor microenvironment and 5) tolerance of DNA damage and aneuploidy. Thus, the objective of this proposal is to elaborate the contribution of cancer-testes antigens to neoplastic processes. The in-depth examination of the role of these CTA's in tumorigenic processes will provide conceptual breakthroughs with respect to the tumor cell regulatory environment as well as important new insights into tumor cell specific targets that could be exploited for therapeutic intervention.