Project 2: Overcoming drug-induced resistance to intrinsic apoptosis in glioblastoma

项目概要/摘要-项目2 胶质母细胞瘤（GBM）是所有癌症中最致命的一种。这在很大程度上是由于目前无法 现有的疗法诱导显著的肿瘤细胞死亡。使用整合的分子（外显子组和RNAseq）和 大型GBM患者标本库的功能（通过BH 3分析）表征， 该项目的数据表明，所有GBM肿瘤都由两种分子内在凋亡块组成， 由MCL 1和BCL-xL组成-驱动基础GBM存活。值得注意的是，虽然DNA损伤治疗（IR/TMZ） 或分子靶向治疗（例如，EGFR TKI）可以基因型特异性方式消融MCL 1阻断， BCL-xL阻断持续存在，最终在这些常用的治疗方案下驱动对细胞凋亡的抵抗。 范例这些令人兴奋的新结果，加上之前SPORE资助的补充发现， 导致了一种假设，即选择性靶向BCL-xL与IR/TMZ或EGFR TKI联合使用， 克服内在的凋亡抗性并诱导显著的GBM肿瘤消退。这个SPORE项目 《复兴》将通过以下目标检验这一假设。目的1将研究是否一种新的BCL-xL 具有GBM特异性的拮抗剂（与Abbvie合作）与TMZ/IR联合使用时具有抗肿瘤作用 或新的临床脑渗透剂EGFR TKI在临床前GBM模型中的应用。目标2包括“机会之窗” 临床试验，以探索这些新的临床药物是否可以消融复发性肿瘤中的两个内在凋亡阻滞， GBM患者。最后，目标3提出确定针对内在免疫缺陷的潜在抗性机制。 不同临床前GBM样品中的凋亡机制。总之，本申请中提出的研究 通过特异性操纵恶性肿瘤中的内在凋亡途径， 神经胶质瘤，并有长期的潜力，以改变目前的方法在神经胶质瘤治疗。

PROJECT SUMMARY/ABSTRACT – Project 2 Glioblastoma (GBM) is one of the most lethal of all cancers. This is in large part due to the inability of currently available therapies to induce significant tumor cell death. Using integrated molecular (exome and RNAseq) and functional (via BH3 Profiling) characterization of a large library of GBM patient specimens, compelling preliminary data for this project identify that all GBM tumors are comprised of two molecular intrinsic apoptotic blocks – consisting of MCL1 and BCL-xL – that drive basal GBM survival. Notably, while DNA damaging therapy (IR/TMZ) or molecularly targeted therapy (e.g., EGFR TKI) can ablate the MCL1 block in a genotype specific manner, the BCL-xL block persists ultimately driving resistance to apoptosis under these commonly used therapeutic paradigms. These exciting new results, together with complementary findings from the previous SPORE funding, has led to the hypothesis that selective targeting of BCL-xL in combination with either IR/TMZ or EGFR TKI can overcome intrinsic apoptotic resistance and induce profound GBM tumor regressions. This SPORE Project renewal will test this hypothesis through the following aims. Aim 1 will investigate whether a novel BCL-xL antagonist (in collaboration with Abbvie) with GBM specificity has anti-tumor effects when combined with TMZ/IR or a new, clinical brain penetrant EGFR TKI in preclinical GBM models. Aim 2 includes a “window of opportunity” clinical trial to explore whether these novel clinical drugs can ablate the two intrinsic apoptotic blocks in recurrent GBM patients. Finally, Aim 3 proposes to identify potential mechanisms of resistance to targeting the intrinsic apoptotic machinery in diverse preclinical GBM samples. Together, the studies proposed in this application present a new therapeutic paradigm through specific manipulation of intrinsic apoptotic pathways in malignant glioma and have the long-term potential to shift current approaches in glioma therapy.