Targeting the Metabolic Regulator SIRT5 in Acute Myeloid Leukemia

靶向急性髓系白血病的代谢调节因子 SIRT5

• 批准号: 10437469
• 负责人: Michael W. Deininger
• 金额: $ 37.13万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10437469
• 关键词: ABL1 gene; Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acyl Coenzyme A; Adult; Age; Antibodies; Antibody-drug conjugates; Antigen Targeting; Antigens; B-Lymphocytes; Biological Markers; CD19 gene; CRISPR/Cas technology; Cell Line; Cell Maturation; Cells; Chemotherapy-Oncologic Procedure; Child; Clinical Trials; Cognitive; Common Acute Lymphoblastic Leukemia; DNA sequencing; Data; Dependence; Disease-Free Survival; Drug resistance; Energy Metabolism; Exhibits; Genetic; Genetic Transcription; Genotype; Global Change; Glucocorticoids; Growth; Head; Hematologic Neoplasms; Hematopoietic Neoplasms; Immunity; Immunoglobulin Somatic Hypermutation; Immunoglobulins; Incidence; Individual; Link; Lymphoid; Lysine; Maintenance; Malignant - descriptor; Malignant Childhood Neoplasm; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Mutation; Necrosis; Neuropathy; Oncogenes; PAX5 gene; Pathway interactions; Patients; Prognosis; Quality of life; Refractory; Relapse; Reporting; Resistance; Resistance development; Role; Salvage Therapy; Sampling; Survivors; T-Cell Receptor; T-Lymphocyte; TLX1 gene; Testing; Therapeutic; Treatment-related toxicity; Work; Xenograft procedure; acute lymphoblastic leukemia cell; base; chemotherapy; chimeric antigen receptor T cells; effective therapy; functional disability; high risk; improved; improved outcome; in vivo; inhibitor; knock-down; leukemia; malignant phenotype; metabolic profile; metabolomics; mortality; mouse model; novel strategies; patient derived xenograft model; pediatric patients; precursor cell; programs; relapse patients; risk variant; small hairpin RNA; small molecule inhibitor; targeted cancer therapy; targeted treatment; therapy resistant; transcription factor; transcriptome sequencing

Supported by R01CA254354: Targeting the Metabolic Regulator SIRT5 in Acute Myeloid Leukemia (AML) we have reported that the lysine deacylase SIRT5 is a druggable metabolic target in AML (Yan et al. Blood Cancer Discov. 2021;2(3):266-287). Our new preliminary data suggest that the role of SIRT5 may extend to acute lymphoblastic leukemia (ALL), including relapsed/refractory (R/R) ALL. ALL is the most common cancer in children. After a peak at age 9, incidence initially declines, but then rises steadily after the age of 30. Most ALL cases originate from B-lymphoid precursor cells (B-ALL), but 15% are of T cell origin (T-ALL). Aggressive chemotherapy has greatly improved outcome in children, but often at the expense of long-term functional impairment. In contrast, long-term survival in adults is <50%, reflecting high-risk genotypes and higher treatment- related mortality. Chimeric antigen receptor (CAR) T cells targeting B cell antigens are effective in a subset of R/R B-ALL, but resistance often develops due to loss of the target antigen. Salvage therapies for RR T-ALL are ALL survival and reduce functional impairment in survivors. While ALL is genetically heterogeneous, most cases exhibit a differentiation block at the level of a B or T cell precursor. There is evidence that energy restriction creates a barrier to malignant transformation as B cell precursors undergo somatic hypermutation during antibody diversification. Mutational inactivation of B lineage transcription factors disables this metabolic brake and allows malignant transformation by oncogenes such as BCR-ABL1. Similar mechanisms may operate in T cell precursors during T cell receptor diversification. Our discovery that SIRT5 is a key regulator of AML metabolism and the reported interplay between metabolic reprogramming and malignant transformation in ALL, we asked whether SIRT5 dependence extends to ALL. We find that many ALL cell lines, including drug-resistant lines, are sensitive to SIRT5 knockdown (KD), prompting us to hypothesize that SIRT5 is required for maintaining ALL metabolism. Our Aims are: (1) Determine the effects of SIRT5 disruption on ALL cell lines and primary cells and correlate with global changes in energy metabolism. We will use shRNA, CRISPR/Cas9 and small molecule inhibitors to disrupt SIRT5 in ALL cells, correlate effects on growth and viability with changes in energy metabolism, and test whether disrupting SIRT5 is synergistic with other ALL therapeutics. (2) Identify SIRT5- regulated pathways and biomarkers of SIRT5 dependency in ALL. We will subject ALL cells to RNA and DNA sequencing and metabolomic profiling and identity features associated with SIRT5 dependency. (3) Determine whether SIRT5 disruption reduces leukemia burden and improves survival in mouse models of ALL. We will test the effect of SIRT5 disruption in genetic ALL models and patient-derived xenografts. Metabolic plasticity limits the efficacy of inhibiting individual metabolic pathways. To circumvent metabolic plasticity and avoid therapy escape, we will target SIRT5 as a master controller of ALL metabolism. If successful our studies will establish SIRT5 as a therapy target in RR ALL.

由 R01CA254354 支持：针对急性髓系白血病 (AML) 的代谢调节因子 SIRT5 我们已经报道，赖氨酸脱酰酶 SIRT5 是 AML 中的一个可药物代谢靶标（Yan 等人，Blood） 癌症发现。 2021；2(3):266-287)。我们的新初步数据表明 SIRT5 的作用可能会扩展到 急性淋巴细胞白血病 (ALL)，包括复发/难治性 (R/R) ALL。 ALL 是最常见的癌症 在儿童中。在 9 岁达到峰值后，发病率最初下降，但在 30 岁后稳步上升。大多数 ALL 病例源自 B 淋巴细胞前体细胞 (B-ALL)，但 15% 源自 T 细胞 (T-ALL)。挑衅的 化疗极大地改善了儿童的预后，但往往以牺牲长期功能为代价 损害。相比之下，成人的长期生存率<50%，反映了高风险基因型和更高的治疗- 相关死亡率。靶向 B 细胞抗原的嵌合抗原受体 (CAR) T 细胞在以下子集中有效： R/R B-ALL，但由于靶抗原的丢失，常常会产生耐药性。 RR T-ALL 的挽救疗法是 ALL 存活并减少幸存者的功能损伤。虽然 ALL 具有遗传异质性，但大多数病例 在 B 或 T 细胞前体水平上表现出分化阻断。有证据表明能量限制 由于 B 细胞前体在恶性转化过程中经历体细胞超突变，因此形成了恶性转化的障碍 抗体多样化。 B 谱系转录因子的突变失活使这种代谢制动失效 并允许 BCR-ABL1 等癌基因发生恶性转化。类似的机制可能会在 T 中运行 T 细胞受体多样化过程中的细胞前体。我们发现 SIRT5 是 AML 的关键调节因子 代谢以及据报道的 ALL 中代谢重编程和恶性转化之间的相互作用， 我们询问 SIRT5 依赖性是否延伸至 ALL。我们发现许多 ALL 细胞系，包括耐药细胞系 线，对 SIRT5 敲低（KD）敏感，促使我们假设 SIRT5 是维持 所有新陈代谢。我们的目标是： (1) 确定 SIRT5 破坏对所有细胞系和原代细胞的影响 细胞并与能量代谢的整体变化相关。我们将使用 shRNA、CRISPR/Cas9 和小 分子抑制剂可破坏所有细胞中的 SIRT5，将对生长和活力的影响与能量变化相关联 代谢，并测试破坏 SIRT5 是否与其他 ALL 疗法具有协同作用。 (2)识别SIRT5- ALL 中 SIRT5 依赖性的调节途径和生物标志物。我们将对所有细胞进行 RNA 处理并 与 SIRT5 依赖性相关的 DNA 测序、代谢组学分析和身份特征。 (3) 确定 SIRT5 破坏是否会减轻小鼠模型的白血病负担并提高生存率 全部。我们将测试 SIRT5 破坏对遗传性 ALL 模型和患者来源的异种移植物的影响。 代谢可塑性限制了抑制个体代谢途径的功效。为了规避新陈代谢 可塑性并避免治疗逃逸，我们将把 SIRT5 作为所有代谢的主控制器。如果成功 我们的研究将确立 SIRT5 作为 RR ALL 的治疗靶点。