Defining kinase interaction pathways to enhance anti-cancer efficacy and minimize associated morbidities of kinase inhibitor drugs.

定义激酶相互作用途径，以增强抗癌功​​效并最大限度地减少激酶抑制剂药物的相关发病率。

• 批准号: 10644554
• 负责人: Anna Pavlovna Hnatiuk Hnatiuk
• 金额: $ 12.25万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644554
• 关键词: ABL1 gene; Acceleration; Address; Adverse drug effect; Adverse effects; Advisory Committees; Affect; Antineoplastic Agents; Basic Science; Bioinformatics; Biological Assay; Blood Vessels; Bone Marrow Suppression; Cancer Patient; Cancer Survivor; Cancer Survivorship; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Lineage; Cell model; Cell physiology; Chemicals; Chronic Myeloid Leukemia; Clinical Sciences; Coagulation Process; Computer Analysis; Data; Development; Drug resistance; Endothelial Cells; Event; Exhibits; Genetic; Goals; Health; Heart; Human; In Vitro; Individual; Institution; Intervention; Knowledge; Leadership; MAPK11 gene; Maps; Mass Spectrum Analysis; Measures; Mediating; Mentors; Mitogen-Activated Protein Kinases; Molecular; Morbidity - disease rate; Mutation; Non-Small-Cell Lung Carcinoma; Oncology; Pathway interactions; Patient-Focused Outcomes; Peripheral; Pharmaceutical Preparations; Phase; Phenotype; Phosphorylation; Phosphotransferases; Physicians; Process; Productivity; Quality of life; RAF1 gene; RNA Interference; ROCK1 gene; Reporting; Research; Resistance; Role; Safety; Scientist; Signal Pathway; Signal Transduction; Technology; Testing; Therapeutic; Toxic effect; Training; Troponin; Tumor Suppression; Tyrosine Kinase Inhibitor; Universities; Vascular Endothelial Cell; Xenograft Model; analog; anti-cancer; anticancer activity; bcr-abl Fusion Proteins; candidate identification; career; cell type; drug development; drug efficacy; high throughput analysis; improved; in vivo; induced pluripotent stem cell derived cardiomyocytes; inhibitor therapy; innovation; kinase inhibitor; leukemia treatment; mutant; negative affect; neoplastic cell; new therapeutic target; novel; pharmacologic; preservation; prevent; protective effect; prototype; reconstruction; resistance mutation; response; side effect; skills; survivorship; tumor; tyrosine analog; vasculogenesis

PROJECT SUMMARY The decreased quality of life and increased morbidity due to oncological drugs such as Tyrosine Kinase Inhibitors (TKIs) is a serious and growing general health problem. In particular, cardiovascular (CV) morbidities are a major detrimental factor affecting the survivorship of cancer patients. The primary roadblock to addressing the toxicity of TKIs is that they inhibit multiple kinases besides those necessary to achieve the anti-cancer effect, but the kinases responsible for CV toxicity are poorly defined. This K99/R00 project supports a productive physician-scientist to identify kinase interaction networks relevant to the anti-cancer and CV toxic effects of TKIs. Preliminary data builds on the candidate’s research leading to the development of analogues of the TKI ponatinib that have greatly reduced toxicity, which can additionally be used as probes of signaling in CV and tumor cells. These studies identified candidate kinases that, when inhibited, are detrimental to cardiomyocyte and endothelial cells, as well as candidate kinases that, when inhibited, elicit potentially protective effects against CV morbidities. By using pharmacological and genetic probes, the broad objectives of the project are 1) determine the comprehensive kinase signaling networks responsible for anti-cancer activity in Chronic Myeloid Leukemia (CML) and the kinases that evoke the CV toxicity in each of the two major CV lineages (cardiomyocytes and vascular endothelial cell) and 2) verify and characterize kinases that, when inhibited, prevent this toxicity. The mentored (K99) phase of the project will focus on elucidating the kinase networks responsible for the anti-cancer effect in CML carrying the drug resistant mutation T315I (K99-Aim1) and for CV toxicity (K99-Aim 1). The independent (R00) phase of the project will examine candidate protective kinases networks (involving inhibition of ROCK1, RAF1 and MAPK11) using xenograft models of CML-T315I treated with ponatinib (R00-Aim1A) and non-small cells lung cancer treated with osimertinib (R00-Aim1B). The proposed research and training plan will prepare the applicant to successfully transition to a productive independent academic career defining mechanisms relevant to the safety and efficacy of oncology drugs. The mentoring plan describes roles of the primary mentor, an Advisory Committee consisting of highly regarded senior PIs at multiple institutions who are experts in clinical and basic science aspects of oncology, drug development and cardio-oncology, and collaborators who are leaders in kinase network mapping, and bioinformatics. The training plan will expand the applicant’s skills in cutting edge technologies such as kinase mapping approaches, mass spectrometry and computational analysis of the high-throughput data, and leadership skills. The training will be a critical factor for R00 independent phase and beyond. Training will take place at Stanford University enabling her to become an independent academic PI and leader in the development of safer and more effective oncology drugs to improve survivorship and life-quality of cancer patients.

项目摘要 酪氨酸激酶等肿瘤药物导致的生活质量下降和发病率增加 抑制剂（TKI）是一个严重的和日益增长的一般健康问题。尤其是心血管（CV）疾病 是影响癌症患者生存的主要不利因素。解决这一问题的主要障碍是 TKI的毒性在于它们抑制除实现抗癌作用所必需的激酶之外的多种激酶， 但导致CV毒性的激酶定义不明确。此K99/R 00项目支持高效的 医师-科学家，以确定与TKI的抗癌和CV毒性作用相关的激酶相互作用网络。 初步数据建立在候选人的研究基础上，导致TKI类似物的开发 泊那替尼具有大大降低的毒性，其可另外用作CV中的信号传导探针， 肿瘤细胞这些研究确定了候选激酶，当被抑制时，对心肌细胞是有害的。 和内皮细胞，以及候选激酶，当抑制时，引起潜在的保护作用， CV发病率。通过使用药理学和遗传探针，该项目的主要目标是：1） 确定负责慢性髓样白血病中抗癌活性的综合激酶信号网络 白血病（CML）和在两种主要CV谱系中引起CV毒性的激酶 （心肌细胞和血管内皮细胞）和2）验证和表征激酶，当被抑制时， 避免这种毒性。该项目的指导（K99）阶段将侧重于阐明激酶网络 负责携带耐药突变T315 I（K99-Aim 1）的CML的抗癌作用和CV 毒性（K99-目标1）。该项目的独立（R 00）阶段将检查候选保护性激酶 使用CML-T315 I的异种移植模型，使用经以下处理的CML-T315 I的异种移植模型， 泊那替尼（R 00-Aim 1A）和奥希替尼（R 00-Aim 1B）治疗的非小细胞肺癌。 拟议的研究和培训计划将准备申请人成功地过渡到一个富有成效的 独立的学术生涯定义与肿瘤药物的安全性和有效性相关的机制。的 指导计划描述了主要指导者的角色，一个由高度重视的 多个机构的高级PI，他们是肿瘤学、药物治疗和生物医学的临床和基础科学方面的专家。 开发和心脏肿瘤学，以及激酶网络图谱的领导者， 生物信息学培训计划将扩大申请人在尖端技术如激酶方面的技能 高通量数据的绘图方法、质谱分析和计算分析，以及 领导能力培训将是R 00独立阶段及以后的关键因素。培训将采取 在斯坦福大学的地方，使她成为一个独立的学术PI和领导者的发展 更安全、更有效的肿瘤药物，以提高癌症患者的生存率和生活质量。