Targeting tumor-microenvironment interaction to overcome leukemia chemoresistance

靶向肿瘤-微环境相互作用以克服白血病化疗耐药性

• 批准号: 8783014
• 负责人: Yadira M Soto-Feliciano
• 金额: $ 4.27万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8783014
• 关键词: Acute Lymphocytic Leukemia; Aftercare; B-Cell Acute Lymphoblastic Leukemia; B-Cell Lymphomas; B-Lymphocytes; Cells; Clinic; Cyclophosphamide; DNA Damage; Diagnosis; Doxorubicin; Drug Targeting; Drug resistance; Exhibits; Genes; Genetic Screening; Human; Injection of therapeutic agent; Libraries; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Paracrine Communication; Patients; Pharmaceutical Preparations; Phenotype; Process; Proteins; Public Health; RNA Interference; Relapse; Research; Research Training; Residual Neoplasm; Resistance; Resistance development; Role; Sampling; Screening Result; Signal Transduction; Survival Rate; Therapeutic Agents; base; bcr-abl Fusion Proteins; cancer cell; cancer type; chemotherapy; design; functional genomics; hematopoietic tissue; improved; in vivo; interest; leukemia; loss of function; mouse model; neoplastic cell; novel; novel therapeutics; outcome forecast; public health relevance; research clinical testing; research study; response; tumor microenvironment

DESCRIPTION (provided by applicant): Survival rates for many cancer types have improved significantly in the last few years. However, resistance to chemotherapy remains a major issue in the clinic. There has been remarkable progress in identifying molecular alterations and cell-intrinsic mechanisms that promote resistance to chemotherapy in cancer cells. However little is known about the mechanisms acquired by these cells to persist as a minimal residual disease (MRD). While it is generally known that the presence of an MRD highly correlates with relapse after therapy and poor prognosis, the mechanisms underlying the survival of the MRD after chemotherapy remain unclear. I am interested in uncovering the mechanisms used by cancer cells to develop resistance to chemotherapy in vivo. To study this problem, I am using a mouse model of Ph+ pre-B cell acute lymphoblastic leukemia (Ph+ ALL). This model is based on mouse pre-B cells expressing human BCR-ABL that generate a leukemic phenotype restricted to hematopoietic tissues upon injection into recipient mice. To uncover mediators of chemotherapy response, we performed an in vivo RNAi genetic screen, using a library of 1300 shRNAs. This library included genes that have been implicated in cell microenvironment processes and paracrine signaling. In order to validate the results from the screen, we selected candidates that showed the most significant reduction in hairpin representation upon treatment with front-line chemotherapies (cyclophosphamide or doxorubicin) when compared to the untreated sample. Using this approach, we have identified several candidate proteins implicated in cell microenvironmental processes and paracrine signaling originating from the action of the front-line chemotherapeutics, in vivo. To uncover the mechanisms utilized by these proteins to mediate therapy response, I propose the following specific aims: 1. Assess the role of candidate factors identified in a genetic screen in therapy response in a mouse model of Ph+ ALL. 2. Identify the basic mechanisms of drug resistance mediated by these candidate proteins. Investigate how downstream signaling from these candidates converge on signaling networks emanating from DNA damage. We believe that the results obtained from this screen will uncover uncharacterized cell intrinsic and extrinsic drug targets that, when inhibited, can potentiate the effects of front-line chemotherapeutics, like cyclophosphamide and doxorubucin.

描述（由申请人提供）：过去几年，许多癌症类型的生存率显着提高。然而，化疗耐药仍然是临床上的一个主要问题。在识别促进癌细胞化疗耐药的分子改变和细胞内在机制方面取得了显着进展。然而，人们对这些细胞作为微小残留病（MRD）持续存在的机制知之甚少。虽然众所周知，MRD 的存在与治疗后复发和不良预后高度相关，但化疗后 MRD 存活的机制仍不清楚。我有兴趣揭示癌细胞在体内产生化疗耐药性的机制。为了研究这个问题，我使用 Ph+ 前 B 细胞急性淋巴细胞白血病 (Ph+ ALL) 小鼠模型。该模型基于表达人 BCR-ABL 的小鼠前 B 细胞，该细胞在注射到受体小鼠体内后会产生仅限于造血组织的白血病表型。为了揭示化疗反应的介质，我们使用 1300 个 shRNA 库进行了体内 RNAi 遗传筛选。该文库包含与细胞微环境过程和旁分泌信号传导有关的基因。为了验证筛选结果，我们选择了与未处理的样本相比，在使用一线化疗（环磷酰胺或多柔比星）治疗后发夹代表性减少最显着的候选者。使用这种方法，我们已经确定了几种与细胞微环境过程和源自体内一线化疗药物作用的旁分泌信号有关的候选蛋白质。为了揭示这些蛋白质介导治疗反应的机制，我提出以下具体目标： 1. 评估基因筛选中确定的候选因子在 Ph+ ALL 小鼠模型治疗反应中的作用。 2. 确定这些候选蛋白介导的耐药性的基本机制。 研究这些候选物的下游信号如何汇聚到 DNA 损伤产生的信号网络上。我们相信，从该筛选中获得的结果将揭示未表征的细胞内在和外在药物靶标，这些靶标在被抑制时可以增强一线化疗药物（如环磷酰胺和阿霉素）的效果。