Targeting Cancer Stem Cells

靶向癌症干细胞

• 批准号: 10197001
• 负责人: RICHARD J JONES
• 金额: $ 22.81万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197001
• 关键词: Acute Myelocytic Leukemia; Address; Allogenic; Antineoplastic Agents; Area; Autologous; Biological; 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 项目概要 过去三十年的治疗进展现在使大多数血液恶性肿瘤患者能够实现 主要临床反应。尽管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。我们的工作表明癌症干细胞（CSC） 这个概念可以解释为什么戏剧性的反应往往无法转化为治愈方法。我们发现很多人都复发了 癌症似乎是由具有干细胞特征的稀有细胞引起的；这些所谓的 CSC 通常是 在生物学上与其形成肿瘤主体的后代不同，特别是表现出显着不同 对药物的敏感性。大多数血液系统恶性肿瘤的化疗可能会引起快速反应 这是它们对大部分肿瘤具有令人印象深刻的活性的结果，而治疗方法是针对这些肿瘤的 发达。其中许多响应的持久性有限，这与我们的数据一致，表明 CSC 通常对此类疗法具有相对抵抗力。不幸的是，尽管 CSC 领域的工作呈爆炸式增长， 研究这些细胞的治疗靶向的临床试验仍然很少，甚至更少 试验提供了 CSC 概念的“证据”，即针对这些细胞实际上会改善结果。我们的研究 还表明，不匹配的同种异体血液或骨髓移植（BMT）采用后 移植环磷酰胺 (PTCy) 现在安全有效，几乎所有需要 BMT 的患者都可以使用 来接受这个程序。随着捐赠者可用性、GVHD 和非复发死亡率 (NRM) 等问题的出现， 尽管在 alloBMT 中重要性较低，但迄今为止，复发已成为主要问题。新出现的数据表明 新的、非耐受的、未耗尽的移植免疫系统有能力增强 许多抗癌药物、小分子以及免疫药物。 alloBMT 后的 MRD 状态提供 抗肿瘤方法的额外优势在于它们将以最低的肿瘤负荷以及 最小的肿瘤异质性，包括富集 CSC。据此，本项目的总体假设 是针对 BMT 后复发高危患者的 MRD 进行 CSC 定向治疗，将改善 疾病控制。总体目标是探索针对白血病和多发性骨髓瘤 (MM) 的治疗方法 CSC 并将有前途的治疗方法转化为 alloBMT 后 MRD 环境中的临床。由于目标是 研究的主要由 AML (CD123) 和骨髓瘤 (CD19) CSC 表达，而不是各自的本体 如果成功的话，这些数据也应该为支持CSC概念提供强有力的证据。