AML Stem Cell Heterogeneity: Implications for Gemtuzumab Ozogomicin-based Therapy

描述(由申请者提供)：该候选人致力于急性髓系白血病(AML)领域的临床/转化性研究。他的长期目标是成为一名独立的研究员，能够将实验室研究带到床边，领导适当的临床试验，然后在实验室使用临床信息进一步揭示潜在的生物过程。在获奖期间，他将通过以科学素养和独立性为目标进行临床研究来发展自己的职业生涯。作为临床试验首席研究员的实践研究培训，他将通过正规课程学习获得临床研究理学硕士学位，进行与其临床试验相关的研究，并参与与研究和伦理相关的教育课程，同时保持最低限度但关键的患者护理责任。在职业发展的这一关键阶段，候选人将得到F·阿佩尔鲍姆博士和I·伯恩斯坦博士的指导，他们是急性髓细胞白血病临床试验和白血病干细胞(LSC)生物学的领先专家。在他的提案中，候选人寻求为AML开发新的疗法，特别是针对老年人。具体地说，他的目标是提高getuzumab ozogamicin(GO)的抗AML疗效，Go是一种抗CD33抗体和有毒的Calicheamicin-31衍生物之间的免疫结合物。由于GO作为单一药物的活性有限，因此需要新的药理学方法来提高其临床疗效。候选人的临床前研究证明了CD33表达和药物外排对GO疗效的定量重要性。他的研究进一步揭示了CD33和药物转运蛋白的逆成熟阶段依赖的表达，这一观察为使用细胞分化剂通过增加CD33的表达和药物摄取和/或减少药物外排来增强GO疗效提供了理论基础。事实上，他的体外研究表明，正在进行积极临床研究的诱导AML细胞分化的药物，如表观遗传疗法，可以调节这些特征，并降低GO毒性的凋亡阈值。为了验证他的假设，即这些药物可以改善GO的临床疗效，他提出了两项GO结合表观遗传疗法在老年AML患者中的临床试验。然后，他将确定与这些以GO为基础的治疗方案的反应相关的因素。这位候选人预测，包含GO的治疗后的有益结果仅限于AML的一部分，主要涉及更成熟的CD33+祖细胞。因此，他使用他的试验样本来表征白血病前体细胞和干细胞的CD33表达，并确定这些细胞的成熟期与GO易感性之间的关系。他还测试了表观遗传疗法对急性髓细胞白血病细胞特性的调节是否与体内GO敏感性的增加有关。他提议的研究结果可能为进一步在随机试验中进行测试提供了理论基础。此外，他的研究将确定对基于GO的治疗有不同反应概率的患者，从而通过将治疗限制在有最大反应可能性的患者的能力来优化这种定向抗AML药物的使用。与公共卫生相关：一种治疗急性髓系白血病(AML)的新方法，这是一种主要见于老年人的血癌，使用一种名为GO(getuzumab ozogamicin或Mylotarg的缩写)的抗体，该抗体识别白血病细胞并引导细胞向这些细胞杀伤，而大多数正常细胞不受影响。由于GO单独使用的有效性有限，该应用程序寻求与其他白血病药物联合研究GO，最终目标是开发出治疗老年患者AML的新的、更有效的治疗方法。还将进行研究，以找出哪些患者从这些疗法中受益最大，并看看这些药物组合如何准确地与GO一起作用于杀死白血病细胞。

DESCRIPTION (provided by applicant): This candidate is committed to a career in clinical/translational research in the field of acute myeloid leukemia (AML). His long-term goal is to become an independent investigator capable of bringing bench research to the bedside, leading appropriate clinical trials, and then using the clinical information back in the laboratory to further unravel underlying biologic processes. Over the award period, he will develop his career by performing clinical research with the objective of science accomplishment and independence. He will complement his practical research training as Principal Investigator of clinical trials with formal coursework leading to a Master in Science degree in Clinical Research, conduct of correlative studies associated with his clinical trials, and participation in research- and ethics-related educational sessions while maintaining minimal but critical patient care responsibilities. During this critical stage of career development, the candidate will receive mentorship from Drs. F. Appelbaum and I. Bernstein, leading experts in clinical AML trials and leukemia stem cell (LSC) biology. In his proposal, the candidate seeks to develop novel therapies for AML, in particular for older adults. Specifically, he aims to improve the anti-AML efficacy of gemtuzumab ozogamicin (GO), an immunoconjugate between an anti-CD33 antibody and a toxic calicheamicin-31 derivative. Since GO has limited activity as single agent, novel pharmacological approaches are needed to improve its clinical efficacy. The candidate's preclinical studies demonstrated the quantitative importance of CD33 expression and drug efflux for GO efficacy. His studies further revealed an inverse maturation stage-dependent expression of CD33 and drug transporter proteins, an observation that provided the rationale for the use of cellular differentiation agents to enhance GO efficacy by increasing CD33 expression and drug uptake and/or reducing drug efflux. Indeed, his in vitro studies indicated that drugs that are under active clinical investigation to induce AML cell differentiation such as epigenetic therapeutics modulate these characteristics and lower the apoptotic threshold for GO toxicity. To test his hypothesis that these agents improve clinical GO efficacy, he proposes two clinical trials of GO in combination with epigenetic therapeutics in older adults with AML. He will then determine the factors associated with response to these GO-based regimens. The candidate predicts that beneficial outcome after GO-containing therapy is restricted to a subset of AML that predominantly involves more mature CD33+ progenitors. He therefore uses specimens from his trials to characterize leukemic progenitor and stem cells with regard to CD33 expression and to determine the association between maturation stage of these cells and susceptibility to GO. He also tests whether modulation of cellular characteristics of AML cells by epigenetic therapeutics associates with increased sensitivity to GO in vivo. Findings from his proposed studies may provide the rationale for further testing in randomized trials. Furthermore, his studies will identify patients with varying probabilities of response to GO-based therapy and thereby lead to optimized use of this targeted anti- AML agent through the ability of restricting treatment to patients with the greatest likelihood of response. PUBLIC HEALTH RELEVANCE: A novel approach to treat acute myeloid leukemia (AML), a blood cancer mainly seen in older people, uses an antibody called GO (a short term for gemtuzumab ozogamicin or Mylotarg") that recognizes leukemia cells and directs cell kill towards these cells while leaving most normal cells unaffected. As GO's effectiveness is limited when used alone, this application seeks to study GO in combination with other leukemia drugs with the ultimate goal of developing novel, more effective treatments for AML in older patients. Research will also be performed to find out which patients benefit most from these therapies and to see how these drug combinations precisely work together with GO to kill leukemia cells.