Implications of Metabolic Regulation of BCL-2 Dependence for Myeloma Therapy

BCL-2 依赖性代谢调节对骨髓瘤治疗的影响

• 批准号: 9303686
• 负责人: MALATHY (MALA) SHANMUGAM
• 金额: $ 40.72万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-11 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303686
• 关键词: Accounting; Acute Myelocytic Leukemia; Alpha Cell; Apoptosis; Apoptosis Regulation Gene; Apoptotic; BAX gene; BCL-2 Protein; BCL1 Oncogene; BCL2 gene; BCL2L11 gene; Binding; Binding Proteins; Cell Line; Cells; Cessation of life; Dependence; Development; Disease; Dynein ATPase; Enzymes; Exhibits; Family; Family member; Fostering; Gene Expression; Generations; Glucose; Glutamates; Glutamine; Goals; Health; Hematologic Neoplasms; Hypoxia; In Vitro; Inhibition of Apoptosis; Isotopes; Lymphoblastic Leukemia; Maintenance; Malignant Neoplasms; Mass Fragmentography; Messenger RNA; Metabolic; Metabolic Pathway; Metabolism; Methods; Mission; Molecular Profiling; Multiple Myeloma; Norleucine; Normal Cell; Nutrient; Outpatients; Oxaloacetates; PMAIP1 gene; Pathway interactions; Patients; Phosphorylation; Plasma Cells; Protein Family; Proteins; Public Health; Puma; Pyruvate; Refractory; Regulation; Relapse; Research; Resistance; Resistance development; Risk; Role; Route; Sampling; Signal Transduction; Solid Neoplasm; Supplementation; Testing; Therapeutic; Tracer; Transaminases; United States National Institutes of Health; Up-Regulation; Withdrawal; alpha ketoglutarate; base; comparative; cytochrome c; deprivation; dynein light chain; experimental study; glutamine analog; improved; innovation; insight; leukemia; mRNA Expression; metabolomics; mimetics; mitochondrial membrane; neoplastic cell; novel; nutrient deprivation; overexpression; pre-clinical; protein expression; protein function; resistance mechanism; small molecule; transamination; tumor

PROJECT SUMMARY Multiple myeloma (MM) is a plasma cell malignancy accounting for 13% of all hematological malignancies and 11,000 deaths annually in the US, with the majority succumbing to disease due to the development of resistance. Evasion of apoptosis is central to tumor development and resistance. A key component to the development of resistance across most cancers lies in the ineffective engagement of the BCL-2 family of apoptosis regulators. Induction of the intrinsic pathway of apoptosis is dictated by the release of pro-apoptotic BH3-only activator proteins (BIM, PUMA, BID) from anti-apoptotic BCL-2 family members (BCL-2, BCL-xL, MCL-1, BCL-w and A1) that in turn activate BAX and BAK leading to mitochondrial membrane permeabilization and release of cytochrome C. BH3 activator proteins are released either by reduction in expression of an anti- apoptotic BCL-2 protein to which they are bound or if a sensitizer (such as NOXA, BAD or a BH3 mimetic) releases the BH3 activator protein from binding the anti-apoptotic. When a cell has its anti-apoptotics largely bound by pro-apoptotics (bringing it closer to the apoptotic threshold) it is “primed for death”. Resistant MM, acute myelogenous and lymphocytic leukemia and various solid tumors are found to be less primed for death that contributes to resistance. Thus finding alternative strategies to effectively re-engage BCL-2 proteins to increase the primed state can potentially circumvent resistance. Glucose and glutamine are key nutrients promoting proliferation and importantly, evasion of apoptosis through discrete regulation of BCL-2 proteins such as PUMA, BIM, NOXA, BAX, BAD and MCL-1. We have determined that nutrient deprivation leads to BCL-2 family alterations that effectively lower the apoptotic threshold i.e. increase the “primed state”. Comparative metabolomics enabled identification of a subset of metabolites with potential roles in regulating BCL-2 protein expression and interactions. Inhibition of this subset of metabolic pathways sensitized a genetically diverse panel of MM cell lines and relapse/refractory patient samples to the BH3 mimetic class of small molecules. Furthermore, examination of gene expression profiles of MM patient's revealed upregulation of the enzymes involved in generation of these specific metabolites and segregated out patients with lower overall survival. One of the central questions we will investigate is how elevated expression of these enzymes correlates with actual metabolic flux to inform us of actionable targets. These observations form the basis of our rationale that delineating non-redundant rate-limiting metabolic enzymes regulating BCL-2 dependence will reveal strategies of potent metabolically-driven synthetic lethality with selectivity for tumor cells given the lower BCL-2 dependence of normal cells. Therefore, our long-term goals are to 1) understand how specific metabolic enzymes regulate the BCL-2 family of proteins and 2) demonstrate the feasibility and therapeutic promise of targeting metabolic pathways in MM to circumvent resistance.

项目摘要 多发性骨髓瘤（MM）是浆细胞恶性肿瘤，占所有血液恶性肿瘤的13％和 每年在美国每年11,000人死亡，大多数人因发展而屈服于疾病 反抗。逃避凋亡对于肿瘤发育和抗药性至关重要。一个关键组件 大多数癌症的抵抗力发展在于Bcl-2家族的无效参与 凋亡调节剂。凋亡的内在途径的诱导取决于促凋亡的释放决定 抗凋亡BCL-2家族成员（Bcl-2，BCl-XL， Mcl-1，Bcl-W和A1）又激活BAX和BAK导致线粒体膜通透性 并释放细胞色素C. BH3激活蛋白是通过降低抗抗表达而释放的 凋亡的Bcl-2蛋白与它们结合的蛋白质或传感器（例如NOXA，BAD或BH3 MIMETIC） 释放BH3激活蛋白结合抗凋亡。当一个细胞具有抗寄生虫时，很大程度上 受培养皿的束缚（使其更接近凋亡阈值），它是“为死亡准备的”。抗性毫米， 急性粒细胞和淋巴细胞性白血病和各种实体瘤的死亡较少 这有助于抵抗。找到有效重新引入Bcl-2蛋白的替代策略 增加底漆状态可以潜在地规避耐药性。葡萄糖和谷氨酰胺是关键营养素 通过离散调节Bcl-2蛋白来促进凋亡的增殖，凋亡的演变 例如PUMA，BIM，NOXA，BAX，BAD和MCL-1。我们已经确定营养剥夺导致 Bcl-2家族的改变有效地降低了凋亡阈值，即增加“底漆状态”。 比较代谢组学允许鉴定一部分代谢物，并具有潜在的调节作用 Bcl-2蛋白表达和相互作用。抑制这种代谢途径的子集感觉A MM细胞系的遗传多样化面板和释放/难治性患者样品to bh3模拟类别的类别 小分子。此外，检查MM患者的基因表达谱显示了更新 涉及这些特定代谢产物的酶，并隔离了较低的患者 总体生存。我们将研究的主要问题之一是这些酶的表达如何升高 与实际的代谢通量相关，以告知我们可行的目标。这些观察构成了 我们的理由是，划定调节Bcl-2依赖性的非冗余限速代谢酶 揭示了潜在的代谢驱动的合成杀伤力的策略，并选择肿瘤细胞的选择性较低 正常细胞的Bcl-2依赖性。因此，我们的长期目标是1）了解特定代谢如何 酶调节蛋白质的Bcl-2家族，2）证明了可行性和治疗性的希望 靶向MM中的代谢途径以规避抗性。