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.

受R 01 CA 254354支持：在急性髓系白血病（AML）中靶向代谢调节因子SIRT 5 我们已经报道了赖氨酸脱酰酶SIRT 5是AML中的药物代谢靶标（Yan等，Blood 癌症发现。2021;2（3）：266-287）。我们的新的初步数据表明，SIRT 5的作用可能延伸到 急性淋巴细胞白血病（ALL），包括复发性/难治性（R/R）ALL。ALL是最常见的癌症 小儿在9岁达到高峰后，发病率开始下降，但在30岁后稳步上升。最 ALL病例起源于B淋巴前体细胞（B-ALL），但15%是T细胞起源（T-ALL）。侵略性 化疗大大改善了儿童的预后，但往往以牺牲长期功能为代价。 损伤相比之下，成人的长期生存率<50%，反映了高风险基因型和较高的治疗水平。 相关死亡率。靶向B细胞抗原的嵌合抗原受体（CAR）T细胞在以下亚群中是有效的： R/R B-ALL，但由于靶抗原的丢失，通常会产生耐药性。RR T-ALL的挽救治疗是 ALL存活率和减少幸存者的功能障碍。虽然ALL是遗传异质性的，但大多数病例 在B或T细胞前体水平上表现出分化阻滞。有证据表明，能量限制 当B细胞前体细胞在生长过程中经历体细胞超变时， 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 并允许通过致癌基因如BCR-ABL 1的恶性转化。类似的机制可能在T T细胞受体多样化过程中的细胞前体。我们发现SIRT 5是AML的关键调节因子 代谢和代谢重编程与ALL恶性转化之间的相互作用， 我们问SIRT 5依赖性是否扩展到ALL。我们发现许多ALL细胞系，包括耐药细胞， 细胞系对SIRT 5敲低（KD）敏感，这促使我们假设SIRT 5是维持SIRT 5表达所必需的。 所有代谢。我们的目标是：（1）确定SIRT 5破坏对所有细胞系和原代细胞的影响 细胞和相关的全球变化的能量代谢。我们将使用shRNA，CRISPR/Cas9和小 分子抑制剂破坏ALL细胞中的SIRT 5，将对生长和活力的影响与能量变化相关联， 研究人员还发现，干扰SIRT 5是否与其他ALL治疗剂协同作用。(2)识别SIRT 5- ALL中SIRT 5依赖性的调节途径和生物标志物。我们将所有细胞都置于RNA中， 与SIRT 5依赖性相关的DNA测序和代谢组学分析以及身份特征。（三） 确定SIRT 5破坏是否降低了小鼠模型中的白血病负担并提高了存活率 所有的。我们将测试SIRT 5破坏在遗传ALL模型和患者来源的异种移植物中的作用。 代谢可塑性限制了抑制个体代谢途径的功效。为了避免新陈代谢 我们将SIRT 5作为ALL代谢的主要控制者。如果成功 我们的研究将确立SIRT 5作为RR ALL的治疗靶点。