CONTRIBUTION OF RESIDUAL DISEASE & STEM CELL DAMAGE TO CANCER THERAPY OUTCOME

残留疾病的影响

• 批准号: 6314042
• 负责人: JOHN G. GRIBBEN
• 金额: $ 22.61万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-10 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6314042
• 关键词: bone marrow transplantation; hematopoietic stem cells; human therapy evaluation; human tissue; leukemia; lymphoma; multiple myeloma; neoplasm /cancer chemotherapy; neoplasm /cancer diagnosis; neoplasm /cancer genetics; neoplasm /cancer immunotherapy; neoplasm /cancer relapse /recurrence; polymerase chain reaction

Whereas it might seem obvious that if cancer cells are detected in the body then additional therapy will be necessary for cure, this has not been definitively established for the minimal numbers of cancer cells that can now be detected using sensitive techniques such as polymerase chain reaction (PCR) amplification. PCR of tumor specific chromosomal translocations or gene rearrangements is capable of detecting one tumor cell in up to 106 normal cells and presents a considerable advance over previous techniques to detect minimal residual disease (MRD). The central thesis of this proposal is that eradication of residual cancer cells is necessary for cure. With the increasing use and success of dose intensified treatment strategies for the treatment of the hematologic malignancies, two critical questions have to be addressed. First, how is the outcome of treatment assessed and second, are the attendant toxicities tolerable and if not, are they preventable or reversible? Previous studies have demonstrated that eradication of PCR detectable lymphoma cells is associated with greatly improved outcome after high dose therapy for advanced stage lymphoma. However, this improved outcome resulting from elimination of lymphoma is not without cost as we and others have observed a greatly increased incidence in myelodysplasia after ABMT. The ability to predict outcome based on the detection of MRD would allow one to tailor treatment ot patients who require additional therapy and, just as importantly, to avoid potentially toxic therapy in patients who have no detectable MRD. Therefore the primary goal of this project is to determine the contribution of the eradication of minimal residual disease to cure and in addition, to determine how therapy to achieve this aim induces stem cell damage that will affect outcome following treatment of hematologic malignancies. To this end we propose Three specific aims. First, to develop and extend PCR based assays to detect, quantitate and determine the clinical significance of MRD in patients with lymphoma and myeloma and leukemia who receive conventional, high dose ablative and novel immunologic strategies Second, to assess the clinical significance of karyotypic abnormalities and clonal hematopoiesis in patients receiving conventional and high dose ablative therapy. Based on the premise that stem cell damage is therapy induced we plan Thirdly, to attempt to isolate stem cells from patients early in the course of their disease before significant stem cell damage has occurred. Since this will likely mean that the bone marrow or peripheral blood from these patients contains significant tumor involvement we aim to attempt to improve purging strategies to deplete this increased tumor burden and to assess the efficacy of these purging strategies using PCR. The success of this project is highly interdependent upon the identification of novel tumor specific translocations, the availability of tumor specimens from patients undergoing high dose ablative therapy and bone marrow samples before during and after novel treatment approaches.

尽管很明显，如果在人体内检测到癌细胞 然后需要额外的治疗才能治愈，这还没有 明确地建立了最小数量的癌细胞 现在使用聚合酶链式反应等敏感技术进行检测 反应(PCR)扩增。肿瘤特异性染色体的聚合酶链式反应 易位或基因重排能够检测到一个肿瘤 最多106个正常细胞中的细胞，比起 以前检测微小残留病(MRD)的技术。中环 这项建议的论点是根除残留的癌细胞是 对于治愈来说是必要的。随着剂量的使用和成功的增加 血液病的强化治疗策略 对于恶性肿瘤，有两个关键问题必须解决。首先，你好吗？ 第二，评估的治疗结果是伴随而来的毒性。 是可以容忍的，如果不是，它们是可以预防的还是可逆转的？以前的研究 已经证明根除可检测到聚合酶链式反应的淋巴瘤细胞 与大剂量治疗后预后显著改善有关 晚期淋巴瘤。然而，这一改善的结果是由于 正如我们和其他人所观察到的那样，消除淋巴瘤并不是没有代价的 ABMT后骨髓发育不良的发生率大大增加。有能力 基于MRD检测的预测结果将允许人们量身定做 需要额外治疗的患者的治疗，就像 重要的是，为了避免潜在的毒性治疗，没有 可检测到的MRD。因此，这个项目的主要目标是确定 根除微小残留病对治愈和治疗艾滋病的贡献 此外，为了确定实现这一目的的治疗是如何诱导干细胞 影响血液病治疗结果的损害 恶性肿瘤。为此，我们提出了三个具体目标。第一，要 发展和推广基于聚合酶链式反应的检测、定量和测定 淋巴瘤、骨髓瘤和骨髓瘤患者MRD检测的临床意义 接受常规、大剂量消融和新型免疫治疗的白血病患者 策略二，评估核型分析的临床意义 常规骨髓移植患者的异常和克隆性造血 大剂量消融治疗。基于干细胞损伤的前提 我们计划诱导治疗第三，尝试将干细胞从 病程早期的患者在重要的干细胞出现之前 已发生损坏。因为这很可能意味着骨髓或 这些患者的外周血中含有明显的肿瘤侵犯。 我们的目标是尝试改进净化策略，以耗尽这种增加的 并评估这些净化策略的有效性，使用 聚合酶链式反应。这个项目的成功高度依赖于 新的肿瘤特异性易位的鉴定，可用性 接受大剂量消融治疗的患者的肿瘤标本 新的治疗方法前、中、后的骨髓样本。