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

项目摘要 本提案的目的是评估使用HMGCR抑制剂（他汀类药物）增强 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的抑制剂，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， 在全球范围内广泛使用的药物。然而，他汀类药物也被认为具有抗癌作用， 潜力我们在人细胞系中观察到他汀类药物与ABT-199联合的有效协同作用 来源于弥漫性大B细胞淋巴瘤（DLBCL）。这种协同作用也见于鼠B淋巴瘤 来自基因工程小鼠模型的细胞。使用BH 3分析测定，我们观察到 辛伐他汀增加线粒体启动，与其与ABT-199协同作用的能力相关。 机制研究支持他汀类药物引发淋巴瘤细胞凋亡的假设， 通过HMG-CoA还原酶阻断甲羟戊酸生产下游的异戊二烯化途径。在这 我们将在这些发现的基础上提出他汀类药物/ABT-199联合治疗的可行性。 第一个目的是确定他汀类药物是否可以在肿瘤细胞中达到药理学暴露， 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， 最佳他汀类药物和具有药效活性的最小剂量。第二个目标是 评价他汀类/ABT-199组合在淋巴瘤模型中的功效和耐受性。使用 小鼠同基因B细胞淋巴瘤由BCL-2和MYC驱动，我们将评估差异， 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 行动上我们还将研究药物对体外原代人淋巴瘤细胞存活的影响。在 同时，我们将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。的 第三个目的是测试线粒体引发是否提供他汀类药物功效的预测性生物标志物。 使用动态BH 3分析，我们将确定他汀类药物是否增加了线粒体启动， 与对他汀类药物/ABT-199组合的反应相关。这些实验将共同建立 他汀类药物加ABT-199组合的疗效、肿瘤选择性和预测性生物标志物， 提供概念验证，以支持未来在侵袭性淋巴瘤中的临床试验。

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.