Novel targeted therapies for chronic myelomonocytic leukemia

慢性粒单核细胞白血病的新型靶向治疗

基本信息

批准号：
10696221
负责人：
Roger Vincent Belizaire
金额：
$ 26.92万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-02 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10696221
关键词：
Adaptor Signaling Protein Advisory Committees Alleles Binding Biological Biology Bone Marrow CBL Protein CBL gene CRISPR screen CRISPR/Cas technology Cell Line Cell Proliferation Cell Survival Cells Chronic Myelomonocytic Leukemia Clinical Collaborations Combined Modality Therapy Communities Dana-Farber Cancer Institute Dasatinib Data Development Development Plans Disease Disease Resistance Drug resistance Educational process of instructing Environment FDA approved FRAP1 gene Genetic Hematologic Neoplasms Hematopoietic Hematopoietic Neoplasms In Vitro Individual Knock-out LYN gene Laboratories Malignant Neoplasms Measures Mediating Mentors Mentorship Mus Mutate Mutation Myelogenous Neoplasms Oncogenic PI3K/AKT Pathologist Pathology Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Phosphotransferases Physicians Principal Investigator Prognosis Proliferating Regimen Research Research Personnel Research Proposals Resistance Role SYK gene Sampling Scientist Selection for Treatments Series Signal Transduction Therapeutic Time Training Translational Research Treatment Efficacy Tyrosine Kinase Inhibitor Work Writing acquired drug resistance career career development clinical practice clinical translation design drug resistance development effective therapy efficacy testing experimental study genome-wide improved in vivo inhibitor innovation loss of function mouse model mutant myeloid leukemia cell new therapeutic target novel therapeutics overexpression patient derived xenograft model pharmacologic prevent resistance mechanism src-Family Kinases transfusion medicine translational potential ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY Chronic myelomonocytic leukemia (CMML) is an aggressive hematologic malignancy with extremely poor survival and no effective pharmacologic therapies. The CBL gene, which encodes an E3 ubiquitin ligase and signaling adaptor protein, is frequently mutated in CMML patients. We identified hyperactivation of the SRC family kinase LYN as a key oncogenic driver in CBL-mutant cells. Consistent with this finding, we have also demonstrated the in vitro and in vivo anti-proliferative effects of LYN inhibition by dasatinib in CBL-mutant cell lines and patient-derived CMML samples, providing rationale to explore the therapeutic potential of dasatinib in patients with CBL-mutant CMML. The development of drug resistance represents a possible challenge to the efficacy of dasatinib in CMML patients. Thus, an understanding of dasatinib-resistance mechanisms is essential for the design of durable therapeutic approaches in CBL-mutant CMML. Moreover, discovery of other targetable pathways in CBL-mutant disease will guide the selection of combination therapies that prevent the emergence of drug resistance. Indeed, we have observed that an inhibitor of SYK, fostamatinib, also has anti-proliferative activity against CBL-mutant cell lines, presenting an opportunity to test the efficacy of combined LYN/SYK inhibition. In Aim 1 of this proposal, I will assess dasatinib resistance and intracellular signaling in CBL-mutant cells expressing a series of LYN and SYK alleles, including wild-type, kinase-dead, and drug-binding mutants. I will also define genetic mechanisms of dasatinib resistance via a genome-wide CRISPR-Cas9 knockout screen in dasatinib- or vehicle-treated cells. In Aim 2, I will assess the biological effects of combined treatment with dasatinib and a panel of FDA-approved inhibitors of SYK in vitro and test the efficacy of dasatinib plus fostamatinib in patient-derived xenograft murine models of CBL-mutant CMML. Altogether, the experiments proposed here will build significantly on our previous work and lead to further progress in the discovery of effective treatments for CMML patients. The applicant, Dr. Roger Belizaire, is a clinical pathologist and laboratory-based investigator in the Department of Oncologic Pathology at the Dana-Farber Cancer Institute (DFCI). He spends 80% of his time in translational research and 20% in clinical practice as a transfusion medicine physician. He has proposed a five-year career development plan to enable the development of his independent laboratory at the DFCI. Dr. Belizaire has assembled an Advisory Committee of world-renowned experts to provide scientific and career mentorship. He has established collaborations with experts in myeloid neoplasia, oncogenic signaling, and targeted cancer therapeutics to provide experimental guidance and specific training in the field. Dr. Belizaire will conduct this research under the mentorship of Dr. Benjamin Ebert at the DFCI and leverage the exceptional research and teaching environment at the DFCI. The DFCI, which comprises an outstanding research community with an extensive track-record of successfully mentoring physician-scientists, is an ideal environment for completion of these experimental and career development aims.

项目概要慢性粒单核细胞白血病（CMML）是一种侵袭性血液系统恶性肿瘤，其预后极差。生存且没有有效的药物治疗。 CBL 基因，编码 E3 泛素连接酶和信号接头蛋白在 CMML 患者中经常发生突变。我们发现 SRC 过度激活家族激酶 LYN 作为 CBL 突变细胞的关键致癌驱动因素。与这一发现相一致，我们还证明了达沙替尼在 CBL 突变细胞中抑制 LYN 的体外和体内抗增殖作用线和患者衍生的 CMML 样本，为探索达沙替尼的治疗潜力提供了理论依据 CBL 突变 CMML 患者。耐药性的发展对药物治疗来说是一个可能的挑战。达沙替尼对 CMML 患者的疗效。因此，了解达沙替尼耐药机制至关重要设计 CBL 突变 CMML 的持久治疗方法。此外，发现其他可靶向的 CBL 突变疾病的通路将指导联合疗法的选择，以防止出现的耐药性。事实上，我们观察到 SYK 抑制剂 fostamatinib 也具有抗增殖作用针对 CBL 突变细胞系的活性，提供了测试 LYN/SYK 组合功效的机会抑制。在本提案的目标 1 中，我将评估 CBL 突变体中的达沙替尼耐药性和细胞内信号传导表达一系列 LYN 和 SYK 等位基因的细胞，包括野生型、激酶死亡和药物结合突变体。我还将通过全基因组 CRISPR-Cas9 敲除筛选确定达沙替尼耐药性的遗传机制在达沙替尼或媒介物处理的细胞中。在目标 2 中，我将评估联合治疗的生物学效应达沙替尼和 FDA 批准的一组 SYK 抑制剂在体外进行测试，并测试达沙替尼加的疗效 Fostamatinib 用于 CBL 突变 CMML 患者来源的异种移植小鼠模型。总而言之，实验这里提出的建议将在很大程度上建立在我们之前的工作的基础上，并导致在发现方面取得进一步进展 CMML 患者的有效治疗方法。申请人 Roger Belizaire 博士是一名临床病理学家，丹娜—法伯癌症研究所肿瘤病理学系实验室研究员（DFCI）。他80%的时间用于转化研究，20%的时间用于输血医学的临床实践医生。他提出了一个五年职业发展计划，以使其能够独立发展 DFCI 实验室。贝利泽尔博士组建了一个由世界知名专家组成的咨询委员会，以提供科学和职业指导。他与骨髓瘤专家建立了合作，致癌信号传导和靶向癌症治疗，以提供实验指导和具体培训领域。 Belizaire 博士将在 DFCI 的 Benjamin Ebert 博士的指导下进行这项研究，利用 DFCI 卓越的研究和教学环境。 DFCI 包括杰出的研究社区，在成功指导医师科学家方面拥有广泛的记录，是完成这些实验和职业发展目标的理想环境。