Signal transduction modulation as a therapy for malignant gliomas

恶性星形细胞瘤是最常见和最致命的原发脑肿瘤。他们的反应有限 对常规治疗的反应反映了对DNA损伤或有丝分裂原所致的细胞凋亡的抵抗 肿瘤抑制基因突变和生长因子异常激活所致的耗竭 发信号。然而，我们在上一个资助期的研究表明，尽管在 凋亡的触发，凋亡效应通路可能保持不变，并可通过抑制激活 生长因子介导的信号或刺激死亡受体通路。这些研究也证明了 尽管胶质瘤的一部分对单个信号通路的调制有反应，但许多 表现出不完全的生长抑制，反映平行通路或内在抗性的激活 机械装置。这导致我们研究了信号抑制的组合策略的有效性，使用 以不同路径为目标的特工。我们的初步研究表明，有可能产生有趣的、协同的 信号调节途径之间的相互作用，如抑制PKC和Raf或JAK/STAT， 并通过TRAIL和传统疗法激活细胞凋亡信号。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 增强细胞凋亡信号的通路将为诱导胶质瘤细胞毒作用提供新的策略。 为了验证这一假设，我们将检验抑制对胶质瘤生长和生存能力的影响。 并行路径的组合，如PKC、RAS/Raf和STAT，它们传输增殖信号 来自异常激活的上游受体。这些研究将包括一组细胞系， 明确的遗传改变，以评估基因类型特征是否影响疗效，并建立生物学 代言人的回应。第二，我们将研究促进caspase的信号介体 TRAIL表达可增强TRAIL刺激死亡受体通路诱导的细胞凋亡 评估预测疗效的生物学因素。这两项研究将与项目3相结合，该项目将 为TRAIL、caspase 8和显性负性PKCE提供病毒载体，这可能会增强 试验药效。第三，我们将确定信号调制是否可以提高放射治疗的疗效 和常规化疗的所有，或基因定义的子集，胶质瘤。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 促进树突状细胞摄取肿瘤抗原，我们将建立在与Project的长期互动基础上 2确定信号转导调节策略是否能增强 基于多肽的疫苗接种。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翻译 并指出这些策略可用于提高其他疗法的疗效。

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.