PI3K Pathway Inhibition for Philadelphia-Like Acute Lymphoblastic Leukemia

 描述(由申请人提供)：我的长期职业目标是开发更好的治疗方法，提高治愈率，并将高危白血病儿童的毒性降至最低。作为一名儿科肿瘤学家，我的临床经验启发了基于工作台的实验室研究，这将 帮助我实现这些目标。这个辅导式职业发展奖(CDA)建议旨在通过获取人类白血病异种移植模型和临床前信号方面的关键实验室技能，促进我作为一名独立翻译内科医生-科学家的发展。 转导抑制剂测试，以及在致癌信号转导、细胞死亡、药理学以及早期临床试验设计和生物统计学方面进行额外的教学培训。我将在斯蒂芬·格鲁普博士和马丁·卡罗尔博士的杰出指导下进行拟议的研究，他们都是转化性白血病研究的国际领导者和经验丰富的CDA导师，我的多学科咨询委员会由在血液恶性肿瘤方面具有科学和临床专业知识的高级教员组成。费城儿童医院和宾夕法尼亚大学资源丰富的环境为开展这些以患者为中心的实验室研究提供了理想的环境。我们重点研究了急性淋巴细胞白血病(ALL)的费城类染色体(Ph-like)亚群，它占儿童和成人ALL的15%，与极高的复发率和令人沮丧的长期生存有关。我们和其他人在早期对Ph样ALL的研究中观察到致癌细胞因子受体信号的结构性激活，特别是JAK/STAT和PI3K/Akt/mTOR通路。虽然JAK抑制在ALL中的临床前和早期临床研究正在进行中，但对Ph样ALL中异常的PI3K信号通路的治疗干扰还没有专门的研究。我们假设，通过流式细胞术可靠地识别Ph样ALL表型，我们可以有效地个体化高危ALL治疗，并可以利用这些数据合理选择有效的联合治疗的信号转导抑制剂。在未来五年内，我建议(1)界定 (2)发现Ph样ALL中最有效的PI3K信号转导抑制剂，并确定信号蛋白的代偿性上调是治疗失败的潜在机制，以及(3)确定PI3K信号转导抑制剂治疗Ph样ALL的化疗增敏潜力。这些实验室和临床研究策略的成功发展最终将使我能够领导一个针对临床高危白血病儿童的发展疗法的转化研究计划。

 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.