Defining mechanisms and targets in Wnt addicted human malignancies (PQ22)

描述（由申请人提供）：本申请针对PQ-22：“为什么当突然失去致癌基因编码的蛋白质时，许多癌细胞会死亡？”Wnt典型信号在发育过程中具有高度保守的功能，其组成性激活在越来越多的肿瘤类型的发病机制中发挥作用。人类恶性胶质瘤是难以治愈的手术，负责高发病率和几乎总是致命的。我们最近在人类胶质瘤系和原发性胶质瘤中证明了Wnt通路被高频自分泌机制激活。此外，与其他Wnt激活的肿瘤类型不同，Wnt激活的胶质瘤在响应Wnt下调时仅表现出生长抑制，而Wnt激活的胶质瘤对Wnt信号非常依赖，以至于在响应通路下调时发生大量凋亡。我们发现了一种新的Wnt转录程序，其效应物可能是这种依赖性的原因，以及Wnt依赖性较低的肿瘤类型的表达改变，这可能有助于解释它们对Wnt下调的化学致敏反应。我们计划利用这些发现，1)进一步阐明人类胶质瘤Wnt成瘾的转录程序和信号通路，2)在功能筛选中利用Wnt成瘾的恶性胶质瘤细胞，鉴定和表征特异性和有效的Wnt靶向小分子抑制剂，这些抑制剂已经提供了有希望的成功。3)利用Wnt阳性胶质瘤中可能存在于其他Wnt激活肿瘤类型的Wnt成瘾转录程序的那些方面来研究如何更好地靶向此类肿瘤。因此，该项目提供了一个独特的机会来发展机制的见解，可以改善治疗Wnt阳性的人类恶性胶质瘤和其他肿瘤类型。

DESCRIPTION (provided by applicant): This application addresses PQ-22: "Why do many cancer cells die when suddenly deprived of a protein encoded by an oncogene?" Wnt canonical signaling has highly conserved functions in development, and its constitutively activation plays a role in the pathogenesis of an increasing number of tumor types. Human malignant gliomas are refractory to curative surgery, responsible for high morbidity and almost invariably lethal. We have recently demonstrated Wnt pathway activation by an autocrine mechanism at high frequency in human glioma lines and primary gliomas. Moreover, unlike other Wnt activated tumor types, which show only growth inhibition in response to Wnt downregulation, Wnt activated gliomas, are so addicted to Wnt signaling that they undergo massive apoptosis in response to pathway downregulation. We have discovered a novel Wnt transcriptional program, whose effectors are likely to be responsible for this addiction as well as expression alterations i less Wnt addicted tumor types that could help to explain their chemo-sensitization in response to Wnt downregulation. We plan to exploit these findings to 1) further elucidate the transcriptional program and signaling pathways responsible for Wnt addiction of human gliomas, 2) identify and characterize specific and potent Wnt targeted small molecule inhibitors utilizing Wnt addicted malignant glioma cells in a functional screen that has already provided promising hits, and 3) exploit those aspects of the Wnt addictive transcriptional program in Wnt positive gliomas that may be present in other Wnt activated tumor types to investigate how to better target such tumors. Thus, this project offers a unique opportunity to develop mechanistic insights that could improve therapies for Wnt positive human malignant gliomas and other tumor types as well.