Mechanisms of resistance to MEK Inhibition in RAS-pathway activated chronic myelomonocytic leukemia

RAS 通路激活的慢性粒单核细胞白血病对 MEK 抑制的抵抗机制

• 批准号: 10652270
• 负责人: Ami B Patel
• 金额: $ 28.99万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652270
• 关键词: Acute Myelocytic Leukemia; Address; Affect; Alleles; Allogenic; Award; Bioinformatics; Biology; Bone Marrow; Bone marrow failure; CBL gene; CRISPR/Cas technology; Career Mobility; Cell Line; Cells; Chronic Myelomonocytic Leukemia; Clinical; Clinical Investigator Award; Clinical Trials; Clinical Trials Design; Comprehensive Cancer Center; Correlative Study; Cytokine Receptors; Dedications; Development; Disease; Disease remission; Drug Targeting; Drug resistance; Dysplasia; Elderly; Eligibility Determination; Ensure; Environment; Exhibits; Exposure to; FLT3 gene; Future; Genetic; Goals; Hematologic Neoplasms; Hematologist; High-Throughput Nucleotide Sequencing; In Vitro; In complete remission; Individual; Institution; International; Interruption; Investigation; JAK2 gene; KRAS2 gene; Laboratories; Leukemic Cell; Malignant Neoplasms; Mentors; Methodology; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Mitogens; Molecular Target; Mus; Mutate; Mutation; Myelogenous; Myeloproliferative disease; NF1 gene; Oncologist; Oral; PTPN11 gene; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase I/II Trial; Phase II Clinical Trials; Phosphotransferases; Physicians; Pre-Clinical Model; Proliferating; Protein Tyrosine Kinase; Ras Inhibitor; Receptor Signaling; Refractory; Relapse; Research; Research Personnel; Research Proposals; Resistance; Sampling; Scientist; Signal Transduction; Site; Somatic Mutation; Source; Stem cell transplant; Structure; Symptoms; Techniques; Testing; Therapeutic; Time; Training; Translational Research; Transplantation; Universities; Utah; Validation; acute myeloid leukemia cell; biomarker identification; cancer drug resistance; cancer therapy; career; career development; clinical investigation; clinical trial implementation; cohort; combinatorial; design; disorder risk; drug resistance development; effective therapy; efficacy testing; exome sequencing; experience; genome editing; high risk; improved; in vivo; inhibitor; kinase inhibitor; molecular targeted therapies; mortality; mutant; novel; open label; patient derived xenograft model; phase 2 study; preclinical study; prevent; programs; rational design; resistance mechanism; response; skills; small hairpin RNA; standard care; success; survival outcome; targeted agent; transcriptome sequencing; translational research program; treatment response; treatment strategy

PROJECT SUMMARY/ABSTRACT Overview: The goal of this award is to provide Dr. Ami Patel with the training and mentored research experience to ensure success in her transition to an independent investigator with expertise in the biology and treatment of myeloid malignancies. Dr. Patel’s long term goal is to create and support an independent laboratory-based translational research program dedicated to the investigation of targeted drug resistance in myeloid neoplasms. Research: Chronic myelomonocytic leukemia (CMML) is an aggressive hematologic malignancy associated with dismal survival outcomes and low curative potential. Treatment options are extremely limited, poorly tolerated and fail to address many disease-related symptoms. Targeted agents represent a promising therapeutic opportunity for CMML patients with mutations that lead to aberrant signal transduction through the RAS/mitogen activated kinase (MAPK) pathway. The proposed research aims to understand whether this subset of CMML patients could benefit from treatment with cobimetinib, a specific inhibitor of RAS/MAPK signaling. The proposal includes a clinical trial to test the efficacy of cobimetinib in CMML patients with RAS/MAPK activation. Unfortunately, clinical experience with targeted inhibitors support the eventual emergence of drug resistance. The proposed research aims to understand, prevent and overcome anticipated MEK inhibitor resistance. Longitudinal samples from patients treated on the cobimetinib trial will be analyzed using whole exome and RNA sequencing to identify biomarkers of drug resistance. Laboratory-based preclinical studies will utilize advanced high throughput sequencing and target validation methodologies in cell lines, primary CMML cells and patient derived xenograft models of CMML to help identify mechanisms of resistance that can be cross-referenced with clinical trial findings. Pathways implicated in MEK inhibitor resistance may be candidates for targeted inhibition, leading to the development of novel combinatorial treatment strategies in RAS-activated CMML. Career Development: Dr. Patel is an accomplished hematologist-oncologist with a strong background in translational research in myeloid malignancies. However, prior to starting an independent research program, Dr. Patel requires further training in advanced sequencing and bioinformatics analysis, genome editing and techniques and clinical trial implementation and oversight. The structured protected time,didactics and mentoring provided by the K08 will allow Dr. Patel to complete this essential training. Dr. Patel has assembled a highly experienced, diverse and internationally-recognized mentoring team committed to her future success. The Huntsman Cancer Institute, an NCI-designated Comprehensive Cancer Center, and the University of Utah provide a rich and supportive institutional environment for Dr. Patel to advance her career.

项目总结/摘要 概述：该奖项的目标是为Ami Patel博士提供培训和指导研究经验 以确保她成功过渡到一个独立的研究人员与专业知识的生物学和治疗， 骨髓恶性肿瘤帕特尔博士的长期目标是建立和支持一个独立的实验室， 致力于研究髓系肿瘤靶向耐药性的转化研究计划。 研究：慢性粒单核细胞白血病（CMML）是一种侵袭性血液恶性肿瘤， 生存率低，治愈率低。治疗选择极其有限，耐受性差 并且不能解决许多与疾病相关的症状。靶向药物代表了一种有前途的治疗方法 突变导致RAS/丝裂原信号转导异常的CMML患者的机会 活化激酶（MAPK）通路。拟议的研究旨在了解CMML的这个子集是否 患者可以从cobimetinib治疗中获益，cobimetinib是RAS/MAPK信号传导的特异性抑制剂。该提案 包括一项临床试验，以测试cobimetinib在RAS/MAPK激活的CMML患者中的疗效。 不幸的是，靶向抑制剂的临床经验支持耐药性的最终出现。 拟议的研究旨在了解，预防和克服预期的MEK抑制剂耐药性。 将使用全外显子组和RNA分析cobimetinib试验中治疗患者的纵向样本 测序以鉴定耐药性的生物标志物。基于药理学的临床前研究将利用先进的 细胞系、原代CMML细胞和患者中的高通量测序和靶向验证方法 衍生的CMML异种移植模型，以帮助确定耐药机制， 临床试验结果。与MEK抑制剂抗性有关的途径可能是靶向抑制的候选者， 从而导致RAS激活的CMML中新的组合治疗策略的发展。 职业发展：Patel博士是一位有成就的血液肿瘤学家，具有强大的背景， 骨髓恶性肿瘤的转化研究。然而，在开始独立研究计划之前， 博士帕特尔需要进一步培训先进的测序和生物信息学分析，基因组编辑， 技术和临床试验的实施和监督。结构化的保护时间，教学法和 K 08提供的指导将使Patel博士能够完成这项基本培训。帕特尔博士已经召集了 一个经验丰富，多元化和国际公认的指导团队致力于她未来的成功。 亨斯迈癌症研究所，一个国家癌症研究所指定的综合癌症中心，和犹他州大学 为Patel博士提供丰富和支持性的机构环境，以促进她的职业生涯。