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.

项目摘要慢性脊髓细胞白血病（CMML）是一种侵略性的血液恶性肿瘤，极度差生存和没有有效的药理疗法。 CBL基因编码E3泛素连接酶和信号适配器蛋白在CMML患者中经常突变。我们确定了SRC的过度激活家族激酶Lyn是CBL突变细胞中的关键致癌驱动器。与这个发现一致，我们也有证明了dasatinib在CBL突变细胞中lyn抑制Lyn的体外和体内抗增殖作用线条和患者衍生的CMML样品，提供了探索达沙替尼治疗潜力的基本原理 CBL突变CMML的患者。耐药性的发展代表了对达沙替尼在CMML患者中的功效。因此，对达沙替尼抵抗机制的理解是必不可少的为了设计CBL突变的CMML的耐用治疗方法。此外，发现其他目标 CBL突变疾病的途径将指导选择防止出现的组合疗法耐药性。确实，我们观察到Syk的抑制剂Fostamatinib也具有抗增殖性针对CBL突变细胞系的活性，提供了测试合并LYN/SYK功效的机会抑制。在该提案的目标1中，我将评估CBL突变物中的dasatinib抗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敲除屏幕来定义dasatinib抗性的遗传机制在dasatinib或媒介物处理的细胞中。在AIM 2中，我将评估合并治疗与 dasatinib和一组FDA批准的Syk的抑制剂在体外并测试dasatinib plus的功效 fostamatinib在患者衍生的异种移植物CMML的异种移植鼠模型中。总共是实验在这里提出的建议将在我们以前的工作上有很大的发展，并在发现中进一步进步 CMML患者的有效治疗方法。申请人Roger Belizaire博士是临床病理学家，达纳 - 法伯癌症研究所肿瘤病理学系基于实验室的研究者（DFCI）。他将80％的时间用于转化研究，并在临床实践中作为输血医学进行20％医师。他提出了一项五年的职业发展计划，以使他的独立 DFCI的实验室。 Belizaire博士已组建了一个世界知名专家的咨询委员会咨询委员会提供科学和职业指导。他已经与髓样肿瘤专家建立了合作，致癌信号传导，并针对癌症治疗剂，以提供实验指导和特定的培训领域。 Belizaire博士将在DFCI的Benjamin Ebert博士的指导下进行这项研究，并利用DFCI的杰出研究和教学环境。 DFCI，包括杰出的研究社区，拥有广泛的成功指导医师科学家的田径记录，是完成这些实验和职业发展目标的理想环境。