Targeting Cancer Stem Cells

靶向癌症干细胞

• 批准号: 10671621
• 负责人: RICHARD J JONES
• 金额: $ 16.56万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-21 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671621
• 关键词: Acute Myelocytic Leukemia; Address; Allogeneic Bone Marrow Transplantation; Allogenic; Antineoplastic Agents; Area; Autologous; Blood; Bone Marrow Transplantation; CD19 gene; Cancer Biology; Cells; Characteristics; Chemoprotection; Clinic; Clinical; Clinical Trials; Cyclophosphamide; Data; Disease; Disease remission; Exhibits; Explosion; FLT3 gene; Funding; Hematologic Neoplasms; IL3RA gene; Immune system; Immunologics; Leadership; Maintenance Therapy; Malignant Neoplasms; Microscopic; Multiple Myeloma; Patients; Pharmaceutical Preparations; Phenotype; Procedures; Quality of life; Relapse; Residual Neoplasm; Residual state; Resistance; Testing; Therapeutic; Therapeutic Studies; Toxic effect; Translating; Transplantation and Immune System; Tumor Burden; Tyrosine Kinase Inhibitor; Work; cancer cell; cancer immunotherapy; cancer stem cell; chemotherapy; disorder control; graft vs host disease; high risk; human disease; immune reconstitution; improved; improved outcome; leukemia; leukemic stem cell; mortality; mutant; post-transplant; pre-clinical; prevent; rare cancer; relapse risk; response; side effect; small molecule; stem cells; therapeutic target; tumor; tumor heterogeneity

Project 1 Project Summary Therapeutic advances over the past 3 decades now allow most hematologic malignancy patients to achieve major clinical responses. Although the responses can clearly decrease side effects and improve quality of life, most patients still eventually relapse and die of their disease. Our work suggest that the cancer stem cell (CSC) concept may explain why dramatic responses often fail to translate into cures. We found that relapse in many cancers appears to result from rare cells with stem cell characteristics; these so-called CSCs are often biologically distinct from their progeny that form the bulk of the tumor, notably exhibiting substantially different sensitivity to drugs. The rapid responses induced by chemotherapies in most hematologic malignancies are likely a consequence of their impressive activity toward the bulk of the tumor, against which the treatments were developed. The limited durability of many of these responses is consistent with our data showing that the CSCs are often relatively resistant to such therapies. Unfortunately, despite the explosion of work in the area of CSCs, there continues to be few clinical trials studying the therapeutic targeting of these cells and even fewer clinical trials offering "proof" of the CSC concept that targeting these cells will actually improve outcomes. Our studies have also shown that mismatched allogeneic blood or marrow transplantation (BMT) employing post- transplantation cyclophosphamide (PTCy) is now safe and effective, allowing nearly all patients in need of BMT to undergo this procedure. With issues of donor availability, GVHD, and non-relapse mortality (NRM) now taking on lesser importance in alloBMT, relapse has become by far the major concern. Emerging data suggest that a new, non-tolerant, and non-exhausted transplanted immune system has the ability to augment the activity of many anticancer agents, small molecule as well as immunologic. The MRD state post-alloBMT provides additional advantages for antitumor approaches, in that they will be utilized at lowest tumor burden as well as least tumor heterogeneity including being enriched for CSCs. Accordingly, the overall hypothesis of this Project is that targeting MRD in patients at high-risk for relapse after BMT with CSC-directed therapy, will improve disease control. The overall objective is to explore approaches that target leukemia and multiple myeloma (MM) CSCs and translate promising treatments into clinic in the setting of MRD after alloBMT. Since targets being studied are expressed primarily by AML (CD123) and myeloma (CD19) CSCs rather than the respective bulk tumor, if successful, these data should also provide strong evidence in support of the CSC concept.

项目1 项目摘要 过去30年的治疗进展使大多数恶性血液病患者能够实现 主要临床反应。虽然这些反应可以明显减少副作用并提高生活质量， 大多数患者最终仍会复发并死于疾病。我们的研究表明，癌症干细胞（CSC） 这一概念可以解释为什么戏剧性的反应往往不能转化为治愈。我们发现，在许多情况下， 癌症似乎是由具有干细胞特征的罕见细胞引起的;这些所谓的CSC通常是 在生物学上不同于形成肿瘤主体的它们的后代，特别是表现出实质上不同的肿瘤细胞。 对药物的敏感性在大多数恶性血液病中，化疗诱导的快速反应可能是 这是由于它们对肿瘤的大部分具有令人印象深刻的活性， 开发许多这些反应的有限持久性与我们的数据一致，表明CSC 通常对这种疗法有相对抵抗力。不幸的是，尽管社区服务公司领域的工作激增， 研究这些细胞的治疗靶向的临床试验仍然很少， 试验提供了CSC概念的“证据”，即靶向这些细胞实际上会改善结果。我们的研究 也表明，采用后处理的不匹配的同种异体血液或骨髓移植（BMT）， 环磷酰胺（PTCy）移植现在是安全有效的，几乎所有需要BMT的患者都可以接受 接受这个手术随着供体可用性、GVHD和非复发死亡率（NRM）的问题， 尽管在alloBMT中不太重要，但复发已成为目前的主要问题。新出现的数据表明， 新的、非耐受性的和未耗尽的移植免疫系统具有增强免疫系统活性的能力。 许多抗癌剂、小分子以及免疫剂。alloBMT后的MRD状态提供 抗肿瘤方法的其他优点在于，它们将以最低的肿瘤负荷使用， 最小的肿瘤异质性，包括富集CSC。因此，本项目的总体假设 针对骨髓移植后高复发风险患者的MRD， 疾病控制。总体目标是探索针对白血病和多发性骨髓瘤（MM）的方法 CSC和翻译有前途的治疗到临床上的MRD设置后alloBMT。因为目标是 主要由AML（CD 123）和骨髓瘤（CD 19）CSC表达，而不是各自的原液 如果成功的话，这些数据也应该为CSC的概念提供强有力的证据。