Targeting BCL6 in tyrosine kinase-driven leukemia

靶向 BCL6 治疗酪氨酸激酶驱动的白血病

基本信息

批准号：
8507080
负责人：
Markus Müschen
金额：
$ 32.56万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-15 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8507080
关键词：
ABL1 gene Ablation Acute Acute Lymphocytic Leukemia Acute leukemia Address Adult B-Lymphocytes BCL6 gene BTB/POZ Domain Blast Phase Blood Bone Marrow Caring Cell Aging Cell Lineage Cells Cessation of life Child Chronic Myeloid Leukemia Clinical Clinical Trials Collaborations Data Development Diagnosis Disease-Free Survival Dose Dose-Limiting Drug resistance Drug resistance pathway Eastern Cooperative Oncology Group Elements Exhibits FLT3 gene Frequencies Genes Genetic Genetic Models Goals Grant Heterogeneity Human Individual Left Letters Life Malignant - descriptor Measurable Mediating Mediator of activation protein Modeling Molecular Chaperones Mus Mutation Myelogenous Nature Newly Diagnosed Oncogenic Outcome Pathway interactions Patients Peptides Pharmaceutical Preparations Phase Phase I Clinical Trials Phenotype Point Mutation Production Proliferating Protein Tyrosine Kinase Proto-Oncogenes Recurrent disease Refractory Relapse Relative (related person)Reporter Repression Resistance Risk Safety Sampling Schedule Stem cells Surface Antigens Surrogate Markers System Testing Therapeutic Toxic effect Transcription Repressor/Corepressor Translating Transplant Recipients Tyrosine Kinase Inhibitor Up-Regulation Work Xenograft procedure base chemotherapy design gene repression high risk in vivo inhibitor/antagonist large cell Diffuse non-Hodgkin&apos s lymphoma leukemia leukemic stem cell mutant novel novel therapeutics pre-clinical progenitor public health relevance research study self-renewal small molecule stem cell population therapeutic target tyrosine kinase ABL1

项目摘要

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.

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），预计死亡人数为 10,400 人（55%）。在急性白血病中，具有致癌酪氨酸激酶的 ALL 和 AML 亚型的复发频率特别高，且总体预后较差。例如，标准 AML 的中位无病生存期 (DFS) 为 20 个月，而 FLT3ITD AML 患者的中位无病生存期 (DFS) 为 4.6 个月。同样，标准风险 ALL 患者的 DFS 为 23.8 个月，而携带 BCR-ABL1 酪氨酸激酶的 Ph+ ALL 患者的 DFS 为 8.7 个月。虽然 FLT3ITD AML 和 Ph+ ALL 患者的初始 TKI 治疗最初是成功的，但 TKI 无法根除白血病起始细胞42，并且白血病总是会复发。因此，TKD-白血病是一个常见的未解决的临床问题。相比之下，强效 TKI 的出现已将 CML 转变为长期疾病。 2010 年，美国新诊断出 4,870 名 CML 患者，目前有 24,800 名 CML 患者，5 年总生存率 >95%。然而，在 CML 中，TKI 也无法根除 LIC，因此 CML 患者的 TKI 治疗通常是终生的，因为骨髓中持续存在可测量量的 LIC，一旦 TKI 治疗停止，CML 就会重新出现。由于最近的研究表明白血病起始细胞 (LIC) 与疾病的初始耐药性和复发有关，因此当前的治疗方法需要重点关注 LIC 的根除。急性和慢性粒细胞白血病由表型不同的干细胞群分层发展。然而，最近的研究表明，B 细胞中不存在等级不同的干细胞群血统 ALL7。在不存在干细胞层次结构的情况下，我们假设 B 细胞谱系 ALL 具有暂时获得干细胞能力的能力，即在异种移植受者中引发白血病的能力。因此，我们将检验 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。我们提出四个目标：(1) 验证 BCL6 作为 TKD 白血病的治疗靶点，(2) 定义 BCL6 依赖性耐药的机制要素，(3) 验证并优先考虑三种不同的 BCL6 药理学抑制方法，以及 (4 ) 开展一项针对患有复发性 TKD 白血病的成人患者进行 BCL6 抑制的 I 期临床试验。