Repurposing statins to enhance efficacy of BCL-2 antagonists in blood cancer

重新利用他汀类药物以增强 BCL-2 拮抗剂治疗血癌的疗效

• 批准号: 9178942
• 负责人: DAVID Alexander FRUMAN
• 金额: $ 17.85万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9178942
• 关键词: 17p; Address; Apoptosis; Apoptotic; B-Cell Lymphomas; B-Lymphocytes; BCL2 gene; Biological Assay; Blood Cells; Cell Line; Cells; Cessation of life; Cholesterol; Chronic Lymphocytic Leukemia; Clinical; Clinical Trials; Collaborations; Development; Dose; Enzymes; FDA approved; Familiarity; Family; Feedback; Follicular Lymphoma; Future; Genetically Engineered Mouse; Goals; Grant; Guanosine Triphosphate Phosphohydrolases; Hematopoietic Neoplasms; Human; Human Cell Line; Human Volunteers; Hydroxymethylglutaryl-CoA reductase; Immunocompetent; In Vitro; LDL Cholesterol Lipoproteins; Lymphocyte; Lymphoma; Malignant Neoplasms; Measures; Membrane; Mitochondria; Modeling; Monomeric GTP-Binding Proteins; Mus; Normal Cell; Oncogenic; Oncologist; Oxidoreductase; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Phase III Clinical Trials; Plasma; Pre-Clinical Model; Production; Property; Protein Isoprenylation; Proteins; Reaction; Refractory; Relapse; Safety; Signaling Protein; Simvastatin; Surrogate Markers; Testing; Toxic effect; Translations; Tumor Tissue; base; cell killing; cell transformation; chemotherapeutic agent; cholesterol control; clinically relevant; geranylgeranylation; glutaryl coA; improved; in vivo; inhibitor/antagonist; killings; large cell Diffuse non-Hodgkin' s lymphoma; leukemia; leukemia/lymphoma; mevalonate; mouse model; neoplastic cell; novel strategies; novel therapeutic intervention; outcome forecast; overexpression; pharmacodynamic biomarker; predictive marker; prenylation; research study; response; rho; small molecule inhibitor; tumor

Project Summary The goal of this proposal is to evaluate the feasibility of using HMGCR inhibitors (statins) to enhance efficacy of ABT-199 in preclinical models of B cell cancers. ABT-199 (venetoclax) is a small molecule inhibitor of BCL-2, a key pro-survival protein that is highly expressed in many leukemias and lymphomas. Statins are commonly used to control plasma cholesterol levels and are among the most widely prescribed medications worldwide. However, statins are also known to have anti-cancer potential. We have observed potent synergy of statins combined with ABT-199 in human cell lines derived from diffuse large B cell lymphoma (DLBCL). This synergy is also seen in murine B lymphoma cells derived from a genetically engineered mouse model. Using a BH3 profiling assay, we observed that simvastatin increases mitochondrial priming, correlating with its ability to synergize with ABT-199. Mechanistic studies support the hypothesis that statins prime lymphoma cells for apoptosis by blocking prenylation pathways downstream of mevalonate production by HMG-CoA-reductase. In this proposal we will build on these findings to address the feasibility of the statin/ABT-199 combination. The first Aim is to determine whether statins can achieve pharmacological exposure in tumor cells at a clinically relevant dose. We will compare three different statins in a mouse lymphoma model to identify the optimal statin and minimal dose with pharmacodynamic activity. The second Aim will be to evaluate the efficacy and toleratibility of the statin/ABT-199 combination in lymphoma models. Using a mouse syngeneic B cell lymphoma driven by BCL-2 and MYC, we will assess differences in lymphoma outgrowth and mouse survival, and correlate with a pharmacodynamic marker of statin action. We will also examine drug effects on survival of primary human lymphoma cells in vitro. In parallel we will measure the impact of drug treatments on normal lymphocytes using both the in vivo mouse model, and using peripheral blood mononuclear cells from healthy human volunteers. The third Aim is to test whether mitochondrial priming provides a predictive biomarker of statin efficacy. Using dynamic BH3 profiling, we will determine whether increased mitochondrial priming by statins correlates with response to the statin/ABT-199 combination. Together these experiments will establish efficacy, tumor selectivity, and a predictive biomarker for the combination of statins plus ABT-199, providing proof-of-concept to support future clinical trials in aggressive lymphomas.

项目概要 该提案的目标是评估使用 HMGCR 抑制剂（他汀类药物）增强的可行性 ABT-199 在 B 细胞癌临床前模型中的功效。 ABT-199（venetoclax）是一种小分子 BCL-2 抑制剂，BCL-2 是一种关键的促生存蛋白，在许多白血病中高度表达， 淋巴瘤。他汀类药物通常用于控制血浆胆固醇水平，是最常用的药物之一 世界范围内广泛使用的处方药。然而，他汀类药物也具有抗癌作用 潜在的。我们在人类细胞系中观察到他汀类药物与 ABT-199 联用的有效协同作用 源自弥漫性大 B 细胞淋巴瘤 (DLBCL)。这种协同作用也见于小鼠 B 淋巴瘤 来自基因工程小鼠模型的细胞。使用 BH3 分析测定，我们观察到 辛伐他汀可增加线粒体启动，这与其与 ABT-199 协同作用的能力相关。 机制研究支持这样的假设：他汀类药物通过以下方式促进淋巴瘤细胞凋亡： 阻断 HMG-CoA 还原酶产生甲羟戊酸下游的异戊二烯化途径。在这个 我们将在这些发现的基础上研究他汀类药物/ABT-199 组合的可行性。 第一个目的是确定他汀类药物是否可以在一定的条件下在肿瘤细胞中实现药理学暴露。 临床相关剂量。我们将在小鼠淋巴瘤模型中比较三种不同的他汀类药物，以确定 具有药效活性的最佳他汀类药物和最小剂量。第二个目标是 评估他汀类药物/ABT-199 组合在淋巴瘤模型中的疗效和耐受性。使用 对于由 BCL-2 和 MYC 驱动的小鼠同基因 B 细胞淋巴瘤，我们将评估 淋巴瘤生长和小鼠存活，并与他汀类药物的药效学标志物相关 行动。我们还将在体外检查药物对原代人类淋巴瘤细胞存活的影响。在 同时，我们将使用体内两种方法来测量药物治疗对正常淋巴细胞的影响 小鼠模型，并使用来自健康人类志愿者的外周血单核细胞。这 第三个目的是测试线粒体启动是否提供他汀类药物疗效的预测生物标志物。 使用动态 BH3 分析，我们将确定他汀类药物是否增加线粒体启动 与他汀类药物/ABT-199 组合的反应相关。这些实验将共同建立 他汀类药物与 ABT-199 组合的疗效、肿瘤选择性和预测生物标志物， 提供概念验证以支持未来侵袭性淋巴瘤的临床试验。