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.

项目概要/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 确保她成功过渡为具有生物学和治疗专业知识的独立研究者 Patel 博士的长期目标是创建并支持一个独立的实验室。 致力于调查骨髓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，与 生存结果惨淡，治疗潜力低，治疗选择极其有限，耐受性差。 并且无法解决许多疾病相关症状。靶向药物是一种有前途的治疗方法。 CMML 患者的突变导致 RAS/丝裂原信号转导异常 拟议的研究旨在了解 CMML 的这个子集是否存在。 患者可以受益于 cobimetinib（一种 RAS/MAPK 信号传导的特异性抑制剂）的治疗。 包括一项临床试验，旨在测试 cobimetinib 对 RAS/MAPK 激活的 CMML 患者的疗效。 不幸的是，靶向抑制剂的临床经验支持最终出现耐药性。 拟议的研究旨在了解、预防和预测 MEK 抑制剂耐药性。 将使用全外显子组和 RNA 分析接受 cobimetinib 试验治疗的患者的纵向样本 测序来识别耐药性生物标志物将利用先进的实验室临床前研究。 细胞系、原代 CMML 细胞和患者的高通量测序和靶标验证方法 衍生的 CMML 异种移植模型可帮助识别可交叉引用的耐药机制 临床试验结果涉及 MEK 抑制剂耐药性可能是靶向抑制的候选途径， 导致 RAS 激活的 CMML 新型组合治疗策略的开发。 职业发展：Patel 博士是一位卓有成就的血液肿瘤学家，在以下领域拥有深厚的背景： 然而，在开始独立研究计划之前， Patel 博士需要在高级测序和生物信息学分析、基因组编辑和 技术以及临床试验的实施和监督。 K08 提供的指导将使 Patel 博士能够完成 Patel 博士收集的这项重要培训。 一支经验丰富、多元化且国际认可的导师团队致力于帮助她未来取得成功。 亨茨曼癌症研究所 (NCI 指定的综合癌症中心) 和犹他大学 为帕特尔博士的职业发展提供丰富和支持性的制度环境。