(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

• 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
• 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

 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）：癌症中化学扰动响应的肿瘤间和肿瘤内线粒体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、甚至同一肿瘤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，我们假设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”的特性）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。我们之前已经表明，在血液肿瘤和实体瘤中，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。我们了解靶向治疗反应的方法是独特的。与作为传统化疗靶标的 DNA 和微管的普遍性不同，靶向疗法攻击选择性存在于某些癌细胞中的脆弱性。为了确定这些漏洞存在的位置，我们将癌细胞短暂（不到 24 小时）暴露于药物中，并测量药物是否会增加细胞凋亡启动。我们已经证明，这种称为动态 BH3 分析 (DBP) 的方法可以在体外和体内预测血液肿瘤和实体瘤的肿瘤细胞因靶向药物而死亡。与传统的细胞毒性测量方法相比，DBP 有两个重要优点。首先，DBP 可以更有效地应用于主要患者样本。测量癌细胞细胞毒性的实验通常需要培养数天。由于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结果也不可靠。 DBP 需要不超过一天的离体培养，因为我们在细胞死亡发生之前就进行了测量，并且我们已经证明了它在原发性液体和实体瘤中的预测能力。其次，有许多有用的抗癌药物不会导致明显的细胞死亡，但它们仍然会激发细胞凋亡信号，从而促进联合治疗中的杀伤作用。经典的细胞毒性测量无法识别这些，但 DBP 可以。我们建议根据对使线粒体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标本和 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组合这些药物，并了解线粒体功能异质性的分子基础，这种异质性是对这些药物反应差异的基础。