Targeting BCL6 in tyrosine kinase-driven leukemia

描述（由申请人提供）：2010年，18，600名成人和儿童被诊断患有急性白血病（ALL和AML），预计死亡10，400人（55%）。在急性白血病中，具有致癌酪氨酸激酶的ALL和AML亚型具有特别高的复发频率和总体不良结局。例如，标准AML的中位无病生存期（DFS）为20个月，而FLT 3 ITD AML患者为4.6个月。同样，标准风险ALL的DFS为23.8个月，而携带BCR-ABL 1酪氨酸激酶的Ph+ ALL患者为8.7个月。虽然FLT 3 ITD AML和Ph+ ALL患者的初始TKI治疗最初是成功的，但TKI未能根除白血病起始细胞42，白血病总是复发。因此，TKD白血病代表了一个常见的未解决的临床问题。相比之下，强效TKI的出现使CML变成了一种长期疾病。2010年新诊断出4，870例患者，目前美国有24，800例CML患者，5年总生存率> 95%。然而，同样在CML中，TKI不能根除LIC，因此CML患者的TKI治疗通常是终身的，因为可测量量的LIC持续存在于骨髓中，并且一旦TKI治疗停止，CML再次出现。由于最近的研究表明白血病起始细胞（LIC）参与了疾病的初始耐药性和复发，因此目前的治疗方法需要关注LIC的根除。急性和慢性髓性白血病从表型不同的干细胞群体分层发展。然而，最近的研究表明，在B细胞中不存在分层明显的干细胞群， 谱系ALL 7.在缺乏干细胞分级的情况下，我们假设B细胞系ALL具有暂时获得干细胞能力的能力，即在异种移植物移植受者中引发白血病的能力。因此，我们将测试TKD-白血病细胞可以在“祖细胞样增殖”和“干细胞样静止”之间切换的假设。我们提出了四个目标：（1）验证BCL 6作为TKD白血病的治疗靶点，（2）定义BCL 6依赖性耐药的机制要素，（3）验证并优先考虑三种不同的BCL 6药理学抑制方法，（4）在复发性TKD白血病成人中开展BCL 6抑制的I期临床试验。

DESCRIPTION (provided by applicant): In 2010, 18,600 adults and children were diagnosed with acute leukemias (ALL and AML) with 10,400 expected deaths (55%). Among acute leukemias, ALL and AML subtypes with an oncogenic tyrosine kinase have a particularly high frequency of relapse and overall poor outcome. For instance, median disease-free survival (DFS) for standard AML is 20 months compared to 4.6 months for patients with FLT3ITD AML. Likewise, DFS for standard risk ALL is at 23.8 months compared to 8.7 months for patients with Ph+ ALL carrying the BCR-ABL1 tyrosine kinase. While initial TKI therapy for patients with FLT3ITD AML and Ph+ ALL is initially successful, TKI fail to eradicate leukemia-initiating cells42 and the leukemias invariably relapses. Therefore, TKD-leukemias represent a frequent unsolved clinical problem. By contrast, the advent of potent TKI has transformed CML into a long-term condition. With 4,870 patients newly diagnosed in 2010, currently 24,800 patients live with CML in the US with a 5-year overall survival of >95%. However, also in CML, TKI fail to eradicate LIC, thus TKI-treatment for CML patients is typically life-long since measurable amounts of LIC persist in the bone marrow and CML re-emerges once TKI-treatment ceases. Since recent work has implicated leukemia initiating cells (LIC) in both initial drug-resistance and relapse of the disease, current therapy approaches need to focus on LIC eradication. Acute and chronic myeloid leukemias develop hierarchically from a phenotypically distinct stem cell population. However, recent work suggests that no hierarchically distinct stem cell population exists in B cell lineage ALL7. In the absence of a stem cell hierarchy, we hypothesize that B cell linage ALL have the ability to temporarily acquire stem cell capabilities, i.e. the ability to initiate leukema in xenograft transplant recipients. We will thus test the hypothesis that TKD-leukemia cells can switch between 'Progenitor-like proliferation' and 'Stem cell-like quiescence'. We are proposing four Aims to (1) validate BCL6 as therapeutic target in TKD-leukemia, (2) define mechanistic elements of BCL6-dependent drug-resistance, (3) validate and prioritize three different approaches of pharmacological inhibition of BCL6 and (4) develop a Phase I clinical trial for BCL6 inhibition in adults with relapse TKD-leukemia.