Selection of Novel Therapies to Ablate Chemoresistant Myeloid Leukemia Stem Cell

消融化疗耐药性骨髓性白血病干细胞的新疗法的选择

• 批准号: 7981799
• 负责人: Monica L Guzman
• 金额: $ 253.5万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7981799
• 关键词: Ablation; Acute Myelocytic Leukemia; Allogenic; Blast Cell; Cell Line; Cells; Chemotherapy-Oncologic Procedure; Consolidation Therapy; Disease; Disease remission; Drug resistance; Gene Expression Profile; Goals; Myeloid Leukemia; Neoadjuvant Therapy; Outcome; Patients; Pharmaceutical Preparations; Population; Preclinical Drug Evaluation; Recurrent disease; Relapse; Resistance; Stem cell transplant; Stem cells; Therapeutic; abstracting; drug sensitivity; leukemic stem cell; novel; novel therapeutic intervention; novel therapeutics; outcome forecast

DESCRIPTION (Provided by the applicant) Abstract: The overall goal of this proposal is to optimize the selection and the identification of drugs that can ablate leukemia stem cells (LSCs) that are not effectively ablated during induction therapy. Acute myeloid leukemia (AML) treatment is to date unsatisfactory where most patients will die from their disease despite achieving initial complete remission (CR). Even under very aggressive multi-agent chemotherapy regimens and myeloablative allogeneic stem cell transplantation, relapse rates are high. The last 30 years have seen only marginal improvements in durable remission rates. Clearly, new therapeutic approaches are needed. Increasing evidence suggests that AML is originated and maintained by a population of cells known as LSCs, which are also resistant to standard chemotherapy regimens and are thereby available to provide a reservoir of cells that drive disease relapse. Indeed, studies have shown that a high percentage of phenotypically-defined LSCs correlates to especially poor prognosis. Therefore, we propose here that new therapies should center around new therapeutic endpoints such as the ablation of chemoresistant populations of LSCs. To achieve this goal, we hypothesize that LSCs are frequently present during remission at that they should be targeted during consolidation therapy. The aims of this proposal are to advance the targeting of LSCs and reduction of relapse by: (i) determining whether ex vivo treatments of LSCs more realistically reflect therapeutic outcome in patients compared to AML blast populations; (ii) defining the gene expression signatures of drug sensitivity and drug resistance of LSCs to identify better therapies; and (iii) identifying cell lines that best mimic the chemosensitivity of LSCs to have a readily available LSC surrogate in drug screens. Public Health Relevance: Acute myeloid leukemia (AML) is a fatal disease for most patients and novel treatment strategies are urgently needed. Most new agents are tested in patients with relapsed or refractory disease, but these patients generally have highly resistant disease that either will not respond to any treatment or proliferates so quickly that the drugs have no opportunity to work. This proposal describes a novel strategy to expand drug development and clinical trials in AML to specifically target the resistant residual leukemia cells of patients who seem to be in remission but are, in reality, destined to relapse.

描述（由申请人提供） 摘要：该提案的总体目标是优化选择和鉴定能够消融在诱导治疗期间未有效消融的白血病干细胞（LSC）的药物。迄今为止，急性髓系白血病（AML）的治疗效果并不令人满意，尽管实现了初步完全缓解（CR），但大多数患者仍会死于疾病。即使采用非常积极的多药化疗方案和清髓性同种异体干细胞移植，复发率也很高。过去 30 年，持久缓解率仅略有改善。显然，需要新的治疗方法。越来越多的证据表明，AML 是由一群称为 LSC 的细胞起源和维持的，这些细胞也对标准化疗方案具有抵抗力，因此可提供驱动疾病复发的细胞库。事实上，研究表明，高比例的表型定义的 LSC 与特别不良的预后相关。因此，我们在此建议新疗法应围绕新的治疗终点，例如消除 LSC 的化疗耐药群体。为了实现这一目标，我们假设 LSC 在缓解期间经常出现，因此在巩固治疗期间应以它们为目标。该提案的目的是通过以下方式推进 LSC 的靶向并减少复发：(i) 确定与 AML 母细胞群体相比，LSC 的离体治疗是否更真实地反映患者的治疗结果； (ii) 定义 LSC 的药物敏感性和耐药性的基因表达特征，以确定更好的治疗方法； (iii) 鉴定最能模拟 LSC 化学敏感性的细胞系，以便在药物筛选中拥有现成的 LSC 替代品。 公共卫生相关性：急性髓系白血病 (AML) 对大多数患者来说是一种致命性疾病，迫切需要新的治疗策略。大多数新药都在患有复发或难治性疾病的患者中进行测试，但这些患者通常患有高度耐药的疾病，要么对任何治疗都没有反应，要么扩散得如此之快，以至于药物没有机会发挥作用。该提案描述了一种扩大 AML 药物开发和临床试验的新策略，专门针对看似处于缓解状态但实际上注定会复发的患者的耐药残留白血病细胞。

项目成果

Acute myelogenous leukemia stem cells: from Bench to Bedside.

急性髓性白血病干细胞：从实验室到临床。

• DOI: 10.1016/j.canlet.2012.05.034
• 发表时间: 2013-09-10
• 期刊: Cancer letters
• 影响因子: 9.7
• 作者: Rico, J. Felipe;Hassane, Duane C.;Guzman, Monica L.
• 通讯作者: Guzman, Monica L.

Is minimal residual disease monitoring clinically relevant in adults with acute myelogenous leukemia?

微小残留病监测对于成人急性髓性白血病有临床意义吗？

• 发表时间: 2013-06
• 影响因子: 2.9
• 作者: Carlson, Karen;Guzman, Monica L
• 通讯作者: Guzman, Monica L

Dehydroleucodine, a Sesquiterpene Lactone from Gynoxys verrucosa, Demonstrates Cytotoxic Activity against Human Leukemia Cells.

Dehydroleucodine 是一种来自 Gynoxys verrucosa 的倍半萜内酯，具有针对人类白血病细胞的细胞毒性活性。

• 发表时间: 2016-04-22
• 影响因子: 5.1
• 作者: Ordóñez, Paola E;Sharma, Krishan K;Bystrom, Laura M;Alas, Maria A;Enriquez, Raul G;Malagón, Omar;Jones, Darin E;Guzman, Monica L;Compadre, Cesar M
• 通讯作者: Compadre, Cesar M

Phase I trial of plerixafor combined with decitabine in newly diagnosed older patients with acute myeloid leukemia.

普乐沙福联合地西他滨治疗新诊断老年急性髓系白血病患者的 I 期试验。

• 发表时间: 2018
• 影响因子: 10.1
• 作者: Roboz, Gail J;Ritchie, Ellen K;Dault, Yulia;Lam, Linda;Marshall, Danielle C;Cruz, Nicole M;Hsu, Hsiao;Hassane, Duane C;Christos, Paul J;Ippoliti, Cindy;Scandura, Joseph M;Guzman, Monica L
• 通讯作者: Guzman, Monica L

Selective activity of the histone deacetylase inhibitor AR-42 against leukemia stem cells: a novel potential strategy in acute myelogenous leukemia.

组蛋白脱乙酰酶抑制剂 AR-42 对白血病干细胞的选择性活性：急性髓性白血病的一种新的潜在策略。

• 发表时间: 2014-08
• 影响因子: 5.7
• 作者: Guzman, Monica L;Yang, Neng;Sharma, Krishan K;Balys, Marlene;Corbett, Cheryl A;Jordan, Craig T;Becker, Michael W;Steidl, Ulrich;Abdel;Levine, Ross L;Marcucci, Guido;Roboz, Gail J;Hassane, Duane C
• 通讯作者: Hassane, Duane C