Targeting Cancer Stem Cells

项目1 项目摘要 过去30年的治疗进展现在允许大多数血液系统恶性肿瘤患者达到 主要临床反应。虽然这些反应可以明显减少副作用，提高生活质量， 大多数患者最终仍会复发并死于他们的疾病。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的反应往往无法转化为治愈。我们发现在许多人中复发 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CSCs通常是 与构成肿瘤主体的后代在生物学上截然不同，特别是表现出显著不同的 对药物敏感。在大多数血液系统恶性肿瘤中，化疗引起的快速反应可能是 这是他们对大部分肿瘤表现出令人印象深刻的活性的结果，治疗是针对这些肿瘤的 发展起来的。其中许多反应的有限持久性与我们的数据一致，表明CSCs 通常对这种疗法具有相对的抵抗力。不幸的是，尽管CSC领域的工作呈爆炸式增长， 研究这些细胞靶向治疗的临床试验仍然很少，临床试验就更少了。 提供CSC概念的“证据”的试验表明，以这些细胞为靶点实际上会改善结果。我们的研究 还表明，不匹配的异基因血液或骨髓移植(BMT)使用后- 移植环磷酰胺(PTCy)现在是安全有效的，几乎可以让所有需要骨髓移植的患者 接受这一手术。在供者可获得性、GVHD和无复发死亡率(NRM)的问题上 在allBMT中不那么重要的是，到目前为止，复发已经成为主要的担忧。新出现的数据表明， 新的、不耐受和未耗尽的移植免疫系统具有增强 许多抗癌药物，小分子以及免疫学。AllBMT后的MRD状态提供 抗肿瘤方法的其他优点，因为它们将以最低的肿瘤负担以及 肿瘤异质性最低，包括对CSCs的富集性。因此，本项目的总体假设 在骨髓移植后复发的高危患者中使用CSC指导的治疗针对MRD是否会有所改善 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。 CSCs，并将有希望的治疗方法转化为临床应用于异基因骨髓移植后的MRD。由于目标是 所研究的主要由AML(CD123)和骨髓瘤(CD19)CSC表达，而不是各自的BULK 肿瘤，如果成功，这些数据也应该提供强有力的证据支持CSC的概念。

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.