Mechanisms of Chemo/Radioresistance in Human Gliomas

描述（由申请人提供）：恶性胶质瘤是人类最难以治愈的癌症之一，尽管有积极的手术、放射治疗、化疗和新的靶向分子治疗方法的出现。这种对当前治疗方法的无反应在很大程度上源于恶性胶质瘤细胞对广泛的细胞毒性药物的先天抵抗。在我们最初的资助阶段，我们确定了SF/HGF（一种在人类恶性胶质瘤中过度表达的多功能生长因子）保护胶质瘤细胞免受基因毒性药物的转录前和转录后机制。我们发现，体内靶向SF/HGF可诱导胶质瘤细胞死亡，使胶质瘤对放射治疗敏感，并显着延长表达SF/HGF的脑肿瘤动物的存活时间。这些令人兴奋的发现为新启动的和计划中的临床试验提供了生物学依据，这些试验检测多形性胶质母细胞瘤中SF/HGF:c-Met途径抑制剂。这一雄心勃勃的合作研究项目的持续目标是确定胶质瘤对细胞毒性抗性的生化和分子机制，并进一步开发新的和潜在的可翻译策略，以克服对诱导死亡药物的抗性。死亡受体激动剂（TRAIL， FASL）具有选择性杀伤肿瘤细胞的能力，是一种很有前途的抗肿瘤药物。我们已经确定了使胶质瘤细胞对死亡受体激动剂敏感的新策略（例如，大霉素诱导的核素毒性应激）。在目标1中，我们将确定基因毒性和核糖素毒性胁迫诱导DISC（死亡启动信号复合物）形成和caspase-8激活的机制。在目标#2中，我们将确定SF/HGF和其他受体酪氨酸激酶途径保护胶质瘤细胞免受死亡受体激动剂影响的机制。与激酶相比，我们对磷酸酶如何参与致癌信号级联知之甚少。我们发现两种含有sh2的肌醇-5磷酸酶（SHIP1和SHIP2）调节胶质瘤细胞对化疗药物的敏感性。在Aim #3中，我们将确定这些脂质磷酸酶调节胶质瘤细胞死亡的机制。在Aims #4中，我们将应用Aims #1-3的新型死亡调节策略来增强临床前体内胶质瘤模型对细胞毒性治疗（死亡受体激动剂、化疗和放射治疗）的抗肿瘤反应。这些实验的成功完成将揭示促进胶质瘤细胞死亡的新机制，并为其治疗适用性提供临床前证据。公共卫生相关性：多形性胶质母细胞瘤是成人中最常见、最具侵袭性的脑肿瘤，平均预期寿命约为14个月，不到30%的患者在诊断后存活2年。这些对积极治疗的令人沮丧的反应是由于胶质瘤细胞对目前的细胞毒性治疗的先天抵抗。该研究计划将确定分子/生化方法来克服胶质瘤细胞对细胞毒性药物的耐药性，并测试其在体内的治疗适用性。

DESCRIPTION (provided by applicant): Malignant glioma ranks among the least curable of human cancer despite aggressive surgery, radiation therapy, chemotherapy, and the emergence of new targeted molecular therapeutics. This unresponsiveness to current therapeutics stems to a great degree from the innate resistance of malignant glioma cells to a broad range of cytotoxic agents. During our initial funding period, we identified pre- and post-transcriptional mechanisms by which SF/HGF, a multifunctional growth factor overexpressed by human malignant gliomas, protects glioma cells against genotoxic agents. We showed that targeting SF/HGF in vivo induces glioma cell death, sensitizes glioma to radiation therapy, and markedly prolongs the survival of animals bearing SF/HGF- expressing brain tumors. These exciting discoveries contributed to the biological rationale for newly activated and planned clinical trials testing SF/HGF:c-Met pathway inhibitors in glioblastoma multiforme. The continued goals of this ambitious and collaborative research program are to identify biochemical and molecular mechanisms of glioma resistance to cytotoxicity and to further develop novel and potentially translatable strategies for overcoming resistance to death-inducing agents. Death receptor agonists (TRAIL, FASL) are promising anti-tumor agents by virtue of their ability to selectively kill tumor cells. We have identified novel strategies (e.g. anisomycin-induce ribotoxic stress) for sensitizing glioma cells to death receptor agonists. In Aim #1 we will determine the mechanisms by which genotoxic and ribotoxic stresses induce DISC (death- initiating signaling complex) formation and caspase-8 activation. In Aim #2 we will determine mechanisms by which SF/HGF and other receptor tyrosine kinase pathways protect glioma cells against death receptor agonists. In contrast to kinases, little is known of how phosphatases contribute to oncogenic signaling cascades. We found that two SH2-containing inositol-5-phosphatases (SHIP1 and SHIP2) regulate glioma cell sensitivity to chemotherapeutics. In Aim #3 we will determine the mechanisms by which these lipid phosphatases modulate glioma cell death. In Aim #4 we will apply the novel death modulating strategies of Aims #1-3 to enhance anti-tumor responses to cytotoxic therapeutics (death receptor agonists, chemotherapy, and radiation therapy) in pre-clinical in vivo glioma models. The successful completion of these experiments will reveal novel mechanisms for enhancing glioma cell death and provide pre-clinical evidence supporting their therapeutic applicability. PUBLIC HEALTH RELEVANCE: Glioblastoma multiforme, the most common and aggressive brain tumor in adults, has a median life expectancy of ~ 14 mo and fewer that 30% of patients are alive 2 years after diagnosis. These dismal responses to aggressive therapy are due to the innate resistance of glioma cells to current cytotoxic treatments. This research plan will identify molecular/biochemical approaches for overcoming glioma cell resistance to cytotoxic agents and test their therapeutic applicability in vivo.