Heat Shock Directed Drug Discovery For The Treatment Of Gliomas

项目概述：胶质瘤是原发性中枢神经系统恶性肿瘤中最致命的一类。许多治疗方法寻求靶向被突变异常激活的信号通路的特定组分，然而越来越多的证据表明，肿瘤存活也严重依赖于影响全局细胞过程的非突变、非癌基因系统；这种现象被称为非致癌基因成瘾。调节蛋白质稳态的细胞成分是非癌基因成瘾最重要的介质之一，用HSP90和蛋白酶体抑制剂靶向这些功能可产生强大的抗胶质瘤活性。此外，我们的研究小组还发现了另一种意想不到的非癌基因成瘾介质，即热休克因子1 (HSF1)，它是调节热休克反应（HSR）的主要转录因子，在与胶质瘤形成相关的信号通路中起着强大的多方面调节作用。在这一提议中，我将测试一个假设，即通过高通量技术调节蛋白质稳态将为识别先导化合物提供一个强有力的策略，从而推动有效的抗胶质瘤疗法的发展。为了探索这一点，我们在两次高通量细胞表型筛选中使用HSR作为生物传感器，筛选了10万种化合物，并鉴定了100种诱导HSR的化合物和50种抑制HSR的化合物。我们提出了以下具体目标来验证我们的假设：目标1：确定HSR的药理调节对“干细胞”神经胶质瘤模型增殖和存活的影响；目的2：表征活性化合物的作用机制，识别具有新靶点的活性化合物；目的3：评估活性化合物穿过血脑屏障的潜力；目的4：评估小分子蛋白稳态调节剂在体内抑制胶质瘤生长的潜力。该候选人是医学博士，解剖学/神经病理学博士，向Susan Lindquist博士寻求神经胶质瘤化学生物学方面的指导。提案中概述了一项利用Whitehead， Broad和Dana Farber癌症研究所广泛资源的研究计划，以及实现学术独立的职业发展计划。相关性：高级别胶质瘤是最具侵袭性的癌症之一，目前的治疗并没有显著改善患者的预后。通过表征胶质瘤中HSR的化学生物学特性，我们旨在鉴定具有抗胶质瘤活性的铅分子。另外，一些HSR调节药物可能应用于典型的蛋白质折叠中枢神经系统疾病，如神经退行性疾病和朊病毒疾病。

DESCRIPTION (provided by applicant): Project Summary: Gliomas constitute the most lethal class of primary CNS malignancies. Many therapeutic approaches seek to target specific components of signaling pathways that are aberrantly activated by mutation, yet mounting evidence demonstrates that tumor survival is also critically dependent on non-mutated, non-oncogene systems that impact global cellular processes; a phenomenon termed non-oncogene addiction. The cellular components that regulate protein homeostasis are among the most prominent mediators of non-oncogene addiction and targeting these functions with HSP90 and proteasome inhibitors results in robust anti-glioma activity. Moreover, our group has revealed another unexpected mediator of non-oncogene addiction, Heat Shock Factor 1 (HSF1), the main transcription factor regulating the heat shock response (HSR), which acts a powerful multifaceted regulator of signaling pathways relevant to gliomagenesis. In this proposal, I will test the hypothesis that modulating protein homeostasis by high-throughput techniques will provide a powerful strategy for identifying lead compounds to drive the development of effective anti-glioma therapeutics. To explore this, we have used the HSR as a biosensor in two high-throughput cell-based phenotypic screens of 100,000 compounds and have identified 100 compounds that induce and 50 that inhibit the HSR. The following specific aims are proposed to test our hypothesis: Aim 1: to determine the effects of pharmacological modulation of the HSR on proliferation and survival in 'stem cell' based models of glioma; Aim 2: to characterize the mechanism of action of active compounds to identify those with novel targets; Aim 3: to assess the potential of active compounds to cross the blood brain barrier; Aim 4: to assess the potential of small molecule modulators of protein homeostasis to inhibit glioma growth in vivo. The candidate is an M.D., Ph.D. trained in Anatomic/Neuropathology who seeks mentorship in the chemical biology of gliomas from Dr. Susan Lindquist. Outlined in the proposal is a research plan using the extensive resources of the Whitehead, Broad and Dana Farber Cancer Institutes and a career development plan for achieving academic independence. Relevance: High-grade gliomas are among the most aggressive forms of cancer and current treatments do not markedly improve patient prognosis. By characterizing the chemical biology of the HSR in gliomas we aim to identify lead molecules with anti-glioma activity. Of additional relevance, some of these HSR modulating drugs may have application in classic protein folding CNS disorders such as neurodegenerative and prion diseases.