(PQ5) Investigation of intertumoral and intratumoral heterogeneity of mitochondrial apoptotic sensitivity

(PQ5)线粒体凋亡敏感性的瘤间和瘤内异质性研究

基本信息

批准号：
9101582
负责人：
ANTHONY G LETAI
金额：
$ 39.05万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9101582
关键词：
Antineoplastic Agents Apoptosis Apoptotic BH3 peptide Biological Assay Cancer Patient Cell Death Cells Cessation of life Chemicals Clinic Clinical Colon Carcinoma DNA Drug Combinations Goals Heterogeneity Histology Hour Human In Vitro Individual Inter-tumoral heterogeneity Investigation Liquid substance Malignant Neoplasms Measurement Measures Microtubules Mitochondria Molecular Mus Nature Non-Malignant Patients Pharmaceutical Preparations Primary Neoplasm Property Proteins Regimen Sampling Signal Transduction Solid Neoplasm Specimen Technology Testing Therapeutic Therapeutic Index Translations Xenograft procedure base cancer cell cancer therapy chemotherapy colon cancer patients cytotoxic cytotoxicity design improved in vivo killings neoplastic cell novel novel strategies precision medicine public health relevance research study response screening small molecule libraries targeted agent targeted treatment tumor tumor heterogeneity

项目摘要

DESCRIPTION (provided by applicant): Inter- and intra-tumoral mitochondrial heterogeneity in response to chemical perturbation in cancer Response to therapy is heterogeneous between tumors of different histology, between different tumors of the same histology, and even among different tumor cells within the same tumor. Much of the cytotoxic response to therapy in cancer is governed by the mitochondrial pathway of apoptosis. Therefore, we hypothesize that heterogeneity in response at all three of these levels is governed by functional and molecular heterogeneity of mitochondria. BH3 profiling provides a functional measure of how close a cell is to the threshold of apoptosis by measuring mitochondrial sensitivity to BH3 peptides, a property we also refer to as apoptotic "priming". We have previously shown, in both hematologic and solid tumors, that pretreatment baseline priming of patient tumors predicts clinical response to conventional chemotherapy. Our approach to understanding response to targeted therapies is distinct. In contrast to the ubiquitous nature of the DNA and microtubules that are the targets of conventional chemotherapy, targeted therapies attack vulnerabilities that are selectively present in certain cancer cells. To identify where these vulnerabilities exist, we briefly (less than 24 hours) expose cancer cells to drugs and measure whether the drugs increase apoptotic priming. We have shown that this approach, which we call dynamic BH3 profiling (DBP), can predict death of tumor cells from targeted agents in vitro and in vivo for both hematologic and solid tumors. There are two important advantages of DBP over conventional measures of cytotoxicity. First, DBP can be applied much more efficiently to primary patient samples. Experiments measuring cytotoxicity in cancer cells often require days of culture. Because the long-term culture of primary patient samples is so unreliable, cytotoxic measurements in primary tumors are unreliable. DBP requires no more than a day of ex vivo culture since we measure well before frank cell death occurs, and we have demonstrated its predictive power in primary liquid and solid tumors. Second, there are many useful anti-cancer agents that do not cause frank cell death, but which nonetheless provoke apoptotic signaling that facilitates killing in combination regimens. Classical cytotoxic measurements do not identify these, but DBP does. We propose to study intra- and inter-tumoral heterogeneity based on differential response to compounds that sensitize mitochondria for apoptosis. We will focus on colon cancer tumors, as we have access to primary and PDX specimens of these tumors. Our main goals are to develop a therapeutic toolbox of potentially useful drugs, determine how best to combine these in a personalized way, and also to understand the molecular basis of the heterogeneity of mitochondrial function that underlies differences in response to these drugs.

描述（由申请人提供）：肿瘤内和肿瘤内线粒体对化学扰动的异质性不同组织学的肿瘤之间、相同组织学的不同肿瘤之间、甚至同一组织内的不同肿瘤细胞之间对治疗的反应是异质的癌症治疗的大部分细胞毒性反应是由线粒体凋亡途径控制的，因此，我们研究所有这三个水平的反应异质性是由线粒体的功能和分子异质性控制的。 BH3 分析通过测量线粒体对 BH3 肽的敏感性（我们也将其称为细胞凋亡“启动”）提供了一种功能性测量，用于测量细胞与细胞凋亡阈值的接近程度，我们之前已在血液肿瘤和实体瘤中证明了这一点。患者肿瘤的治疗前基线启动可预测对常规化疗的临床反应，这与作为常规治疗靶点的 DNA 和微管的普遍性不同。化疗、靶向疗法选择性地攻击某些癌细胞中存在的弱点，为了确定这些弱点存在的位置，我们将癌细胞短暂地（不到 24 小时）暴露于药物并测量药物是否会增加细胞凋亡启动。我们称之为动态 BH3 分析 (DBP)，可以预测血液肿瘤和实体传统肿瘤的体外和体内靶向药物导致的肿瘤细胞死亡。与 BH3 分析相比，DBP 有两个重要优势。首先，DBP 可以更有效地应用于原发性患者样本，测量癌细胞细胞毒性的实验通常需要数天的培养时间，因为原发性患者样本的长期培养非常不可靠，因此原发性肿瘤的细胞毒性测量也不可靠。 DBP 需要不超过一天的离体培养，因为我们在 Frank 细胞死亡发生之前就进行了测量，并且我们已经证明了它对原发性液体和实体瘤的预测能力。其次，有许多有用的抗癌药物不会引起 Frank 细胞死亡。细胞经典的细胞毒性测量无法识别这些细胞死亡，但它仍然会激发细胞凋亡信号，从而促进杀伤，但我们建议根据对线粒体细胞凋亡敏感的化合物的差异反应来研究肿瘤内和肿瘤间的异质性。我们将重点关注结肠癌肿瘤，因为我们可以获得这些肿瘤的原发性和 PDX 标本。我们的主要目标是开发潜在有用药物的治疗工具箱，确定如何以个性化方式最好地结合这些药物，并了解如何更好地结合这些药物。线粒体功能异质性的分子基础是对这些药物反应差异的基础。