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

项目总结 由于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 抑制物(TKIs)是一个严重且日益严重的普遍健康问题。尤其是心血管(心血管)疾病 是影响癌症患者生存的主要有害因素。解决以下问题的主要障碍 TKI的毒性在于，除了达到抗癌效果所必需的那些外，它们还抑制多种激酶， 但是，与CV毒性有关的激酶还没有得到很好的解释。该K99/R00项目支持高效的 医生-科学家确定与TKI的抗癌和心血管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，导致开发出TKI的类似物 Ponatinib的毒性大大降低，它还可以用作CV和 肿瘤细胞。这些研究确定了候选激酶，当被抑制时，对心肌细胞有害 和内皮细胞，以及候选激酶，当被抑制时，引发潜在的保护作用 简历的病态。通过使用药理和遗传探针，该项目的广泛目标是1) 确定在慢性髓性白血病中参与抗癌活性的全面的激酶信号网络 白血病(CML)和引起两个主要CV谱系中的CV毒性的激酶 (心肌细胞和血管内皮细胞)和2)验证和表征当被抑制时， 防止这种毒性。该项目的指导(K99)阶段将集中于阐明激酶网络 携带耐药突变T315I(K99-Aim1)的CML的抗癌作用和CV 毒性(K99-Aim 1)。该项目的独立(R00)阶段将检查候选保护性激酶 抑制ROCK1、RAF1和MAPK11的CML-T315I异种移植瘤模型 Ponatinib(R00-Aim1A)和奥西美替尼(R00-Aim1B)治疗的非小细胞肺癌。 拟议的研究和培训计划将为申请者成功过渡到多产企业做好准备。 独立的学术生涯定义机制，与肿瘤药物的安全性和有效性相关。这个 指导计划描述了主要导师的角色，咨询委员会由高度尊重的 多个机构的高级私人助理，是肿瘤学、药物、临床和基础科学方面的专家 开发和心脏肿瘤学，以及在激酶网络图谱方面处于领先地位的合作者，以及 生物信息学。培训计划将扩大申请者在尖端技术方面的技能，如Kinase 高通量数据的作图方法、质谱学和计算分析，以及 领导才能。培训将是R00独立阶段及以后的关键因素。培训将需要 在斯坦福大学获得一席之地，使她成为一名独立的学术PI和开发领域的领导者 开发更安全、更有效的肿瘤药物，以提高癌症患者的生存和生活质量。

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.