Signal transduction modulation as a therapy for malignant gliomas

恶性星形细胞瘤是最常见和致命的原发性脑肿瘤。他们的反应有限 对常规治疗的反应反映了对 DMA 损伤或丝裂原引起的细胞凋亡的抵抗 肿瘤抑制基因突变和生长因子异常激活导致的耗竭 发信号。然而，我们在上一个资助期间的研究表明，尽管存在限制 细胞凋亡触发，细胞凋亡的效应途径可能保持完整，并且可以通过抑制来激活 生长因子介导的信号传导或刺激死亡受体途径。这些研究还表明 尽管神经胶质瘤的一个子集对个体信号通路的调节有反应，但许多神经胶质瘤 显示出不完全的生长抑制，反映了平行途径的激活或内在抵抗 机制。这促使我们检查信号抑制组合策略的功效，使用 针对不同途径的药物。我们的初步研究表明了有趣的、协同的潜力 信号调节方法之间的相互作用，例如抑制 PKC 和 Raf 或 JAK/STAT， 以及通过 TRAIL 和常规疗法激活细胞凋亡信号传导。根据我们的发现，我们 假设阻断合理选择的生长信号组合的治疗方法 途径或增强细胞凋亡信号传导将为诱导神经胶质瘤细胞毒性提供新策略。 为了检验这一假设，我们将检查抑制药物对神经胶质瘤生长和活力的影响 平行途径的组合，例如 PKC、Ras/Raf 和 STAT，传递增殖信号 来自异常激活的上游受体。这些研究将纳入一组细胞系 定义的遗传改变来评估基因型特征是否影响功效，并建立生物学 响应的替代物。其次，我们将检查是否促进 caspase 的信号传导介质 表达可以增强 TRAIL 刺激死亡受体途径诱导的细胞凋亡，并且 评估预测功效的生物因素。这两项研究都将与项目 3 相结合，该项目将 提供用于递送 TRAIL、caspase 8 和显性失活 PKCe 的病毒载体，这可能会增强 TRAIL功效。第三，我们将确定信号调节是否可以增强放射治疗的疗效 以及所有神经胶质瘤或基因型定义的神经胶质瘤子集的常规化疗。第四，因为我们的 初步研究表明，通过信号转导调节诱导胶质瘤细胞凋亡可能 促进树突状细胞对肿瘤抗原的摄取，我们将建立在与项目的长期相互作用的基础上 2 确定信号转导调节策略是否可以增强其有效性 基于肽的疫苗接种。相关性：总而言之，这些研究将为 信号转导抑制和死亡受体激活作为治疗方法的转化 神经胶质瘤，并指出这些策略可用于增强其他疗法疗效的方法。

Malignant astrocytomas are the most common and deadly primary brain tumors. Their limited response to conventional therapy reflects resistance to undergoing apoptosis in response to DMA damage or mitogen depletion, resulting from tumor suppressor gene mutations and aberrant activation of growth factor signaling. However, our studies during the previous funding period indicated that despite the limitation in apoptotic triggering, effector pathways of apoptosis may remain intact and can be activated by inhibiting growth factor-mediated signaling or stimulating death receptor pathways. These studies also demonstrated that although a subset of gliomas were responsive to modulation of individual signaling pathways, many showed incomplete growth inhibition, reflecting activation of parallel pathways or intrinsic resistance mechanisms. This led us to examine the efficacy of combinatorial strategies for signaling inhibition, using agents targeting distinct pathways. Our initial studies suggested the potential for intriguing, synergistic interactions between signaling modulatory approaches, such as inhibition of PKC and Raf or JAK/STAT, and activation of apoptotic signaling by TRAIL, and with conventional therapies. Based on our findings, we hypothesize that therapeutic approaches that block rationally selected combinations of growth signaling pathways or that enhance apoptosis signaling will provide a novel strategy for inducing glioma cytotoxicity. To test this hypothesis, we will examine the effects on glioma growth and viability of inhibiting combinations of parallel pathways, such as PKC, Ras/Raf, and STAT, which transmit proliferative signals from aberrantly activated upstream receptors. These studies will incorporate a panel of cell lines with defined genetic alterations to assess whether genotypic features influence efficacy, and establish biological surrogates of response. Second, we will examine whether signaling mediators that promote caspase expression can enhance apoptosis induced by stimulation of death receptor pathways by TRAIL, and evaluate biological factors that predict efficacy. Both studies will be integrated with Project 3, which will provide viral vectors for delivery of TRAIL, caspase 8, and dominant negative PKCe, which may enhance TRAIL efficacy. Third, we will determine whether signaling modulation can enhance efficacy of radiotherapy and conventional chemotherapy in all, or a genotypically defined subset of, gliomas. Fourth, because our preliminary studies indicate that induction of glioma cell apoptosis by signal transduction modulation may promote uptake of tumor antigens by dendritic cells, we will build on longstanding interactions with Project 2 to determine whether signal transduction modulatory strategies can potentiate the effectiveness of peptide-based vaccination. Relevance: Taken together, these studies will provide a foundation for the translation of signal transduction inhibition and death receptor activation as therapeutic approaches for gliomas, and indicate ways in which these strategies can be used to enhance efficacy of other therapies.