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

基本信息

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
项目类别：
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

项目摘要

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）：在过去几年中，许多癌症类型的生存率已显着提高。然而，对化疗的耐药性仍然是诊所的主要问题。在鉴定分子改变和细胞中性机制方面取得了显着的进展，这些机制促进了癌细胞中对化疗的抗性。然而，这些细胞获得的机制持续存在为最小残留疾病（MRD），知之甚少。虽然众所周知，MRD的存在高度与治疗后的复发和预后不良相关，但化学疗法后MRD生存的机制仍不清楚。我有兴趣发现癌细胞在体内发展抗化疗的机制。为了研究此问题，我使用的是PH+ B型B细胞急性淋巴细胞白血病（pH+ ALL）的小鼠模型。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中时会产生限于造血组织的白血病表型。为了发现化学疗法反应的介体，我们使用1300个shrnas库进行了体内RNAi遗传筛选。该文库包括与细胞微环境过程和旁分泌信号传导有关的基因。为了验证屏幕的结果，我们选择了与未经处理的样品相比，在用前线化学疗法（环磷酰胺或阿霉素）处理后，发夹表示最显着降低的候选者。使用这种方法，我们已经确定了与细胞微环境过程和旁分泌信号有关的几种候选蛋白，该蛋白质源自前线化学疗法的作用，体内。为了发现这些蛋白质用于介导治疗反应的机制，我提出了以下特定目的：1。评估遗传筛查中在pH+的小鼠模型中，在遗传筛查中鉴定出的候选因子的作用。 2。确定这些候选蛋白介导的耐药性的基本机制。研究这些候选者的下游信号如何在DNA损伤中发出的信号网络上汇聚。我们认为，从该筛选中获得的结果将发现未表征的细胞固有和外在药物靶标，如果抑制，可以增强前线化学治疗剂的作用，例如环磷酰胺和多克萨尔巴蛋白。