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 在过去的三十年中，治疗性进步现在使大多数血液恶性肿瘤患者达到 主要的临床反应。尽管反应可以清楚地降低副作用并改善生活质量，但 大多数患者仍然最终复发并死于疾病。我们的工作表明癌症干细胞（CSC） 概念可以解释为什么戏剧性反应通常无法转化为治疗方法。我们发现许多复发 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 在生物学上与肿瘤大部分的后代不同，尤其表现出很大不同 对药物的敏感性。大多数血液系统恶性肿瘤中化学疗法引起的快速反应可能是 他们对大部分肿瘤的令人印象深刻的活动的结果，治疗是 发达。许多此类响应的耐用性有限与我们的数据一致 通常对这种疗法相对抗药性。不幸的是，尽管CSC领域的工作爆炸了，但 继续研究这些细胞的治疗靶向，甚至更少的临床试验继续进行的临床试验。 提供CSC概念的“证明”的试验实际上将改善结果。我们的研究 还表明，使用后的同种异体血液或骨髓移植（BMT）不匹配 移植环磷酰胺（PTCY）现在是安全有效的，几乎所有需要BMT的患者 要接受此过程。现在涉及捐助者可用性，GVHD和非释放死亡率（NRM）的问题 在较小的AllobMT中，复发已成为迄今为止的主要问题。新兴数据表明 新的，不耐受性和无限度的移植免疫系统具有增强活性的能力 许多抗癌药，小分子以及免疫学。 MRD州后Allobmt提供 抗肿瘤方法的其他优势，因为它们将以最低的肿瘤负担以及 肿瘤异质性最少，包括富集CSC。因此，该项目的总体假设 是否针对高风险患者的MRD在使用CSC定向治疗后的BMT后复发，将改善 疾病控制。总体目的是探索靶向白血病和多发性骨髓瘤（MM）的方法 CSC并将有希望的治疗转化为AlloBMT后MRD的诊所。因为目标是 研究的主要用AML（CD123）和骨髓瘤（CD19）CSC表示，而不是相应的体积 肿瘤，如果成功，这些数据也应提供有力的证据，以支持CSC概念。