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

描述（由申请人提供）：本申请涉及PQ-22：“为什么许多癌细胞在突然失去癌基因编码的蛋白质时死亡？“Wnt经典信号在发育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治性手术，负责高发病率和几乎总是致命的。我们最近已经证明了Wnt通路激活的自分泌机制在高频率的人类胶质瘤细胞系和原发性胶质瘤。此外，与其他Wnt激活的肿瘤类型不同，其仅显示响应于Wnt下调的生长抑制，Wnt激活的神经胶质瘤如此依赖于Wnt信号传导，以至于它们响应于途径下调而经历大量细胞凋亡。我们已经发现了一种新的Wnt转录程序，其效应子可能负责这种成瘾以及Wnt成瘾性较低的肿瘤类型中的表达改变，这可能有助于解释它们响应Wnt下调的化学敏感性。我们计划利用这些发现来1）进一步阐明负责人胶质瘤的Wnt成瘾的转录程序和信号通路，2）在已经提供有希望的命中的功能筛选中利用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，和3）利用Wnt阳性神经胶质瘤中可能存在于其它Wnt激活的肿瘤类型中的Wnt成瘾性转录程序的那些方面来研究如何更好地靶向这些肿瘤。因此，该项目提供了一个独特的机会来开发机制的见解，可以改善Wnt阳性人类恶性胶质瘤和其他肿瘤类型的治疗。 公共卫生相关性：该项目的研究旨在阐明我们在人类恶性胶质瘤中发现的极端形式的Wnt成瘾的机制，并确定Wnt转录程序和相关途径。我们还将利用Wnt成瘾的神经胶质瘤细胞进一步表征对这些成瘾肿瘤细胞具有特异性的有希望的Wnt小分子抑制剂，并将探索由Wnt下调其他Wnt激活的肿瘤类型诱导的化学增敏的基础。我们的努力旨在了解可能导致Wnt激活肿瘤的新型治疗干预的机制。

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. PUBLIC HEALTH RELEVANCE: Investigations within this project are directed toward elucidating mechanisms responsible for an extreme form of Wnt addiction discovered by us in human malignant gliomas and to identify the Wnt transcriptional program and pathways responsible. We will also utilize Wnt addicted glioma cells to further characterize promising Wnt small molecule inhibitors with specificity for these addicted tumor cells and will explore the basi of chemorsensitization induced by Wnt downregulation of other Wnt activated tumor types. Our efforts are aimed at mechanistic understanding that could lead to novel therapeutic interventions for Wnt activated tumors.