Heat Shock Directed Drug Discovery For The Treatment Of Gliomas

描述(申请人提供)：项目摘要：胶质瘤是最致命的一类原发中枢神经系统恶性肿瘤。许多治疗方法试图针对突变异常激活的信号通路的特定组成部分，然而越来越多的证据表明，肿瘤的生存也严重依赖于影响全球细胞过程的非突变、非癌基因系统；这种现象被称为非癌基因成瘾。调节蛋白质动态平衡的细胞成分是非癌基因成瘾的最重要的媒介之一，以HSP90和蛋白酶体抑制剂为靶点的这些功能可以产生强大的抗胶质瘤活性。此外，我们的团队还发现了另一个非癌基因成瘾的意想不到的介体--热休克因子1(HSF1)，它是调节热休克反应(HSR)的主要转录因子，它对与胶质瘤形成相关的信号通路起着强大的多方面调节作用。在这项提案中，我将检验这样一个假设，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种强有力的策略，以推动有效的抗胶质瘤疗法的发展。为了探索这一点，我们在两个高通量细胞为基础的100,000种化合物的表型筛选中使用了HSR作为生物传感器，并鉴定了100种诱导HSR的化合物和50种抑制HSR的化合物。为了验证我们的假设，我们提出了以下具体目标：目的1：确定HSR的药理调节对基于干细胞的胶质瘤模型的增殖和存活的影响；目标2：表征活性化合物的作用机制，以识别那些具有新靶点的化合物；目标3：评估活性化合物穿越血脑屏障的可能性；目标4：评估小分子蛋白质稳态调节剂在体内抑制胶质瘤生长的潜力。候选人是解剖学/神经病理学专业的医学博士和博士，寻求苏珊·林德奎斯特博士在胶质瘤化学生物学方面的指导。该提案概述了一项利用怀特黑德癌症研究所、布罗德癌症研究所和达纳·法伯癌症研究所的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类型之一，目前的治疗方法并不能明显改善患者的预后。通过表征胶质瘤中HSR的化学生物学，我们的目标是识别具有抗胶质瘤活性的铅分子。更重要的是，这些HSR调节药物中的一些可能应用于经典的蛋白质折叠中枢神经系统疾病，如神经退行性疾病和Pron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.