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: 10371601
• 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/10371601
• 关键词: Acute Myelocytic Leukemia; Address; Affect; Alleles; Allogenic; Award; Bioinformatics; Biological Markers; Biology; Bone Marrow; Bone marrow failure; CBL gene; CRISPR/Cas technology; Cell Line; Cells; Chronic Myelomonocytic Leukemia; Clinical; Clinical Investigator Award; Clinical Trials; Clinical Trials Design; Comprehensive Cancer Center; Correlative Study; Cytokine Receptors; Development; Disease; Disease remission; Drug Targeting; Drug resistance; Dysplasia; Elderly; Ensure; Environment; Exhibits; Exposure to; FLT3 gene; Future; Genetic; Goals; Hematologic Neoplasms; Hematologist; High-Throughput Nucleotide Sequencing; In Vitro; In complete remission; Individual; Institutes; International; Interruption; Investigation; JAK2 gene; KRAS2 gene; Laboratories; Lead; 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; Protein Kinase; 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; base; cancer drug resistance; cancer therapy; career; career development; clinical investigation; clinical trial implementation; cohort; combinatorial; design; disorder risk; drug 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.

项目摘要/摘要 概述：该奖项的目标是为Ami Patel博士提供培训和修改研究经验 确保她过渡到具有生物学专业知识和治疗专业知识的独立调查员的成功 髓样恶性肿瘤。帕特尔博士的长期目标是创建和支持独立的基于实验室的 转化研究计划致力于研究髓样肿瘤中靶向耐药性的研究。 研究：慢性脊髓细胞性白血病（CMML）是与 惨淡的生存结果和低治疗潜力。治疗选择极为有限，耐受性不佳 并且无法解决许多与疾病有关的症状。目标剂代表一种有希望的疗法 CMML突变患者的机会，导致通过RAS/有丝分裂原的异常信号转导异常 活化激酶（MAPK）途径。拟议的研究旨在了解CMML的这一子集是否 患者可以受益于用RAS/MAPK信号传导的特定抑制剂Cobimetinib治疗。提案 包括一项临床试验，以测试cmmetinib在RAS/MAPK激活患者中的cmimetinib效率。 不幸的是，具有靶向抑制剂的临床经验支持耐药性的最终出现。 拟议的研究旨在理解，预防和克服预期的MEK抑制剂耐药性。 将使用整个外显子组和RNA分析在cobimetinib试验中接受治疗的患者的纵向样本 测序以鉴定耐药性的生物标志物。基于实验室的临床前研究将利用高级 细胞系，主要CMML细胞和患者的高通量测序和目标验证方法 CMML的衍生异种移植模型，以帮助识别可以交叉引用的电阻机制 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， 导致在RAS激活的CMML中发展新型组合治疗策略。 职业发展：帕特尔博士是一位出色的血液学家肿瘤学家 髓样恶性肿瘤的转化研究。但是，在启动独立研究计划之前， 帕特尔博士需要进一步培训高级测序和生物信息学分析，基因组编辑和 技术和临床试验实施和监督。结构化的保护时间，教学和 K08提供的指导将使Patel博士能够完成这项基本培训。帕特尔博士聚集了 一个经验丰富，潜水员和国际认可的指导团队致力于她未来的成功。 NCI指定的综合癌症中心和犹他大学的亨斯曼癌症研究所和 为帕特尔博士提供了丰富而支持的机构环境，以促进她的职业生涯。