Discovery and targeting of apoptosis resistance mechanisms in high-risk T-ALL

 描述(申请人提供)：尽管强化治疗方案的使用改善了“典型”T细胞急性淋巴细胞性白血病(T-ALL)患者的预后，但对于其白血病原始细胞在T细胞发育的最早阶段表现出分化停止的标志的患者，结果仍然令人沮丧。在这些病例中，导致化疗耐药性的机制尚不清楚。传统的联合化疗旨在诱导不同的促死亡信号，这些信号汇聚在线粒体的凋亡机制上，我们现在已经证明，治疗前对线粒体凋亡的抵抗是T-ALL治疗失败的一种细胞表型。然而，这种耐凋亡细胞表型背后的分子机制尚不清楚，这一认识差距是开发合理的治疗策略以逆转凋亡耐药并恢复高危T-ALL的化疗敏感性的主要障碍。我们现在已经证明，凋亡抵抗与EZH2的失活突变密切相关，EZH2是多梳抑制复合体2转录复合体的核心成分。此外，在T细胞发育的非常早期阶段分化停止的T-ALL病例对bcl2抑制选择性敏感，这种依赖反映了这些细胞的非恶性对应物的细胞环境。我们的首要前提是，通过确定导致常规化疗耐药的分子机制，并利用这一知识开发治疗干预措施，以恢复化疗敏感性，将实现T-ALL患者预后的最显著改善。我们建议通过以下具体目标的研究来实现这一点：1)确定EZH2失活诱导线粒体凋亡抵抗的机制，以及2)开发一种有效的治疗策略来逆转高危T-ALL的凋亡抵抗并恢复化疗敏感性。这项拟议的研究的意义在于，它有望为我们认为临床肿瘤学中尚未回答的主要问题提供答案：为什么不同肿瘤看似相同的患者对传统化疗的临床反应存在显著差异，一些患者实现了长期治愈，另一些患者甚至无法实现暂时缓解？这项提案的成功完成有望为这一问题提供答案，并导致对合理设计的治疗策略进行临床试验，以恢复这种特别侵袭性的白血病亚型的化疗敏感性。更广泛地说，这种方法将为合理开发创新的临床试验提供一个范例，以逆转化疗耐药并改善耐药肿瘤患者的临床结果。

 DESCRIPTION (provided by applicant): Although the use of intensified treatment regimens has improved outcomes for patients with "typical" T-cell acute lymphoblastic leukemia (T-ALL), outcomes remain dismal for patients whose leukemic blasts express markers of differentiation arrest at the earliest stages of T-cell development. The mechanisms responsible for chemotherapy resistance in these cases are unknown. Conventional combination chemotherapy is designed to induce diverse death-promoting signals that converge on the mitochondrial apoptotic machinery, and we have now shown that pre-treatment resistance to mitochondrial apoptosis is a cellular phenotype that predicts treatment failure in T-ALL. However, the molecular mechanisms underlying this apoptosis-resistant cellular phenotype are poorly defined, and this knowledge gap represents the primary obstacle to development of a rational therapeutic strategy to reverse apoptosis resistance and restore chemosensitivity in high-risk T-ALL. We have now shown that apoptosis resistance closely correlates with inactivating mutations of EZH2, a core component of the polycomb repressive complex 2 transcriptional complex. Moreover, T-ALL cases with differentiation arrest at very early stages of T-cell development are selectively sensitive to BCL2 inhibition, a dependence that reflects the cellular context of the non-malignant counterpart of these cells. Our overarching premise is that the most significant improvements in outcome for patients with T-ALL will be achieved by defining the molecular mechanisms responsible for resistance to conventional chemotherapy, and leveraging this knowledge to develop therapeutic interventions to restore chemosensitivity. We propose to achieve this through investigation of the following Specific Aims: 1) Define the mechanisms through which EZH2 inactivation induces resistance to mitochondrial apoptosis, and 2) Develop an effective therapeutic strategy to reverse apoptosis resistance and restore chemosensitivity in high-risk T-ALL. The significance of the proposed research is that it is expected to provide an answer to what is, in our opinion the major unanswered question in clinical oncology: why do different patients with seemingly identical tumors exhibit strikingly differences clinical responses to conventional chemotherapy, with some patients achieving long-term cures, and others suffering failure to achieve even a temporary remission? Successful completion of this proposal is expected to provide an answer to this question, and lead to a clinical trial of a rationally designed therapeutic strategy to restore chemosensitivity in this particularly aggressive subtype of leukemia. More broadly, this approach will provide a paradigm for the rational development of innovative clinical trials to reverse chemoresistance and improve clinical outcomes for patients with chemoresistant tumors.