PI3K Pathway Inhibition for Philadelphia-Like Acute Lymphoblastic Leukemia

费城样急性淋巴细胞白血病的 PI3K 通路抑制

基本信息

批准号：
9114524
负责人：
SARAH KATHLEEN TASIAN
金额：
$ 16.97万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-16 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9114524
关键词：
ABL1 gene Acute Lymphocytic Leukemia Adult Adult Acute Lymphocytic Leukemia Advisory Committees Aftercare Animals Apoptosis Biological Assay Biological Markers Biometry Blinded Cell Death Cells Chemosensitization Child Childhood Acute Lymphocytic Leukemia Clinic Clinical Clinical Research Clinical Trials Design Cytokine Receptors Cytometry Cytotoxic Chemotherapy Data Development Developmental Therapeutics Program Dexamethasone Diagnostic Discrimination Environment FRAP1 gene Flow Cytometry Foundations Gene Expression Profile Generations Goals Health Hematologic Neoplasms Human Immunoblotting International JAK1 gene JAK2 gene K-Series Research Career Programs Laboratories Laboratory Research Laboratory Study Lead MAP Kinase Gene Measurement Measures Mentors Mentorship Mutation Oncogenic Oncologist Outcome PDGFRB gene Pathway interactions Patients Pediatric Hematologist Pediatric Hospitals Pediatric Oncologist Pennsylvania Pharmacology Phase Phenotype Philadelphia Philadelphia Chromosome Phosphoproteins Phosphotransferases Physicians Prednisone Protein Isoforms Proteins Receptor Signaling Refractory Relapse Reporting Research Residual state Resistance Resources Safety Sampling Scientist Signal Pathway Signal Transduction Signal Transduction Inhibitor Signal Transduction Pathway Signaling Protein Sirolimus Solid Testing Therapeutic Toxic effect Training Translating Translational Research Treatment Failure Universities Up-Regulation Vincristine Xenograft Model analog asparaginase base biobank burden of illness career chemotherapy clinical efficacy combinatorial design experience genetic analysis genomic profiles high risk improved improved outcome in vivo inhibitor/antagonist leukemia mTOR Inhibitor new therapeutic target next generation sequencing novel patient oriented pre-clinical preclinical efficacy predicting response programs relapse patients relapse risk resistance mechanism senior faculty skills small molecule tumor

项目摘要

DESCRIPTION (provided by applicant): My long-term career goals are to develop better therapies, improve cure rates, and minimize toxicities for children with high-risk leukemias. My clinical experiences as a pediatric oncologist inspire the bench-based laboratory studies that will help me to achieve these goals. This mentored career development award (CDA) proposal is designed to facilitate my development as an independent translational physician-scientist via acquisition of critical laboratory skills in human leukemia xenograft models and preclinical signal transduction inhibitor testing, as well as to pursue additional didactic training in oncogenic signl transduction, cell death, pharmacology, and early phase clinical trial design and biostatistics. I will conduct the proposed studies under the outstanding mentorship of Dr. Stephan Grupp and Dr. Martin Carroll, both international leaders in translational leukemia research and experienced CDA mentors, and my multi-disciplinary Advisory Committee comprised of senior faculty with scientific and clinical expertise in hematologic malignancies. The resource-rich environment of the Children's Hospital of Philadelphia and the University of Pennsylvania provides an ideal setting in which to conduct these patient-oriented laboratory studies. We have focused upon the Philadelphia chromosome-like (Ph-like) subset of acute lymphoblastic leukemia (ALL), which comprises ≥15% of childhood and adult ALL and is associated with extremely high relapse rates and dismal long-term survival. We and others have observed constitutive activation of oncogenic cytokine receptor signaling in earlier studies of Ph- like ALL, particularly of the JAK/STAT and PI3K/Akt/mTOR pathways. While preclinical and early clinical studies of JAK inhibition in ALL are underway, therapeutic disruption of aberrant PI3K pathway signaling has not been specifically investigated in Ph-like ALL. We hypothesize that we can efficiently individualize high-risk ALL therapy by reliably identifying the Ph-like ALL phenotype by phosphoflow cytometry and can use these data for rational selection of signal transduction inhibitors for effective combinatorial therapy. During the next five years, I propose (1) to define the Ph-like ALL "phosphosignature" and to predict responses to signal transduction inhibitors, (2) to discover the most potent PI3K pathway signal transduction inhibitor in Ph-like ALL and to identify compensatory upregulation of signaling proteins as a potential mechanism of treatment failure, and (3) to determine the chemosensitization potential of PI3K pathway signal transduction inhibitor treatment in Ph-like ALL. Successful development of these laboratory and clinical research strategies will ultimately allow me to lead a translational research program in developmental therapeutics for children with clinically high-risk leukemias.

描述（由适用提供）：我的长期职业目标是开发更好的疗法，提高治愈率并最大程度地减少对高风险白血病儿童的毒性。我作为儿科肿瘤学家的临床经验激发了基于基础的实验室研究帮助我实现这些目标。这个修订的职业发展奖（CDA）提案旨在通过获得人类白血病异种移植模型和临床前信号的关键实验室技能来促进我作为独立翻译的物理科学家的发展转导抑制剂测试，以及在致癌签名转导，细胞死亡，药理学和早期临床试验设计和生物统计学中购买其他教学训练。我将根据斯蒂芬·格鲁普（Stephan Grupp）博士的杰出思想和马丁·卡罗尔（Martin Carroll）博士的杰出思想进行拟议的研究，这是转化性白血病研究的国际领导者和经验丰富的CDA导师，以及我的多学科咨询委员会委员会完成了高级教职员工，具有血液疾病的科学和临床专业知识。费城儿童医院和宾夕法尼亚大学的资源丰富的环境为进行这些面向患者的实验室研究提供了理想的环境。我们专注于急性淋巴细胞白血病（ALL）的费城染色体样（类似pH）子集，其中占童年和成人的≥15％，并且与非常高的继电器率和衰退的长期生存有关。我们和其他人已经观察到在类似pH的所有研究中，尤其是JAK/STAT和PI3K/AKT/MTOR途径的pH样研究中，致癌细胞因子受体信号传导的组成型激活。尽管正在进行所有对JAK抑制的临床前和早期临床研究，但在类似于pH的所有方面尚未对异常PI3K途径信号传导的治疗破坏进行专门研究。我们假设我们可以通过可靠地通过磷脂细胞仪可靠地识别所有类似pH的表型来有效地使所有疗法个性化，并可以使用这些数据来合理地选择信号转导抑制剂以进行有效的组合治疗。在接下来的五年中，我建议（1）定义 the Ph-like ALL "phosphosignature" and to predict responses to signal transduction inhibitors, (2) to discover the most potential PI3K pathway signal transduction inhibitor in Ph-like ALL and to identify compensatory upregulation of signaling proteins as a potential mechanism of treatment failure, and (3) to determine the chemosensitization potential of PI3K pathway signal transduction inhibitor treatment in Ph-like ALL.这些实验室和临床研究策略的成功开发最终将使我能够领导一项翻译研究计划，以开发临床高风险性白血病儿童的治疗剂。