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

 描述（由申请人提供）：尽管强化治疗方案的使用改善了“典型”T细胞急性淋巴细胞白血病（T-ALL）患者的结局，但对于白血病原始细胞在T细胞发育的最早阶段表达分化停滞标志物的患者，结局仍然令人沮丧。在这些病例中，导致化疗耐药的机制尚不清楚。传统的联合化疗旨在诱导不同的死亡促进信号，这些信号聚集在线粒体凋亡机制上，我们现在已经表明，治疗前对线粒体凋亡的抵抗是预测T-ALL治疗失败的细胞表型。然而，这种细胞凋亡耐药细胞表型的分子机制定义不清，这种知识差距是开发合理的治疗策略以逆转凋亡耐药和恢复高危T-ALL化疗敏感性的主要障碍。我们现在已经表明，凋亡抗性与EZH 2的失活突变密切相关，EZH 2是多梳抑制复合物2转录复合物的核心成分。此外，在T细胞发育的非常早期阶段具有分化停滞的T-ALL病例对BCL 2抑制选择性敏感，这种依赖性反映了这些细胞的非恶性对应物的细胞背景。我们的首要前提是，T-ALL患者结局的最显著改善将通过定义对常规化疗耐药的分子机制来实现，并利用这些知识来开发治疗干预措施以恢复化疗敏感性。我们建议通过研究以下具体目标来实现这一目标：1）确定EZH 2失活诱导线粒体凋亡抗性的机制，2）开发有效的治疗策略来逆转凋亡抗性并恢复高危T-ALL的化疗敏感性。这项研究的重要性在于，它有望回答临床肿瘤学中的一个主要未回答的问题：为什么看似相同的肿瘤的不同患者对常规化疗表现出惊人的临床反应差异，一些患者实现了长期治愈，而另一些患者甚至无法实现暂时缓解？该提案的成功完成有望为这个问题提供答案，并导致合理设计的治疗策略的临床试验，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临床试验提供范例，以逆转化疗耐药性并改善化疗耐药肿瘤患者的临床结局。

 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.