Lineage-specific signaling and targeting of PI3K gamma in myeloid malignancies

髓系恶性肿瘤中 PI3K γ 的谱系特异性信号传导和靶向

• 批准号: 10345435
• 负责人: Kris Wood
• 金额: $ 42.27万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10345435
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Adult; Agammaglobulinaemia tyrosine kinase; Androgens; Animal Disease Models; Animal Model; Anthracycline; Antiandrogen Therapy; Antineoplastic Agents; Area; B-Lymphocytes; BCL2 gene; Bone Marrow; Breast; CRISPR screen; Cell Culture Techniques; Cell Death; Cell Line; Cell Lineage; Cell Survival; Cells; Chemoresistance; Chronic; Chronic Lymphocytic Leukemia; Chronic Myeloid Leukemia; Credentialing; Dependence; Development; Diagnosis; Disease; Disease model; Drug Targeting; Dysmyelopoietic Syndromes; Estrogen Antagonists; Event; Exhibits; Flow Cytometry; Foundations; Genetic; Genetically Engineered Mouse; Genomics; Gold; Hematologic Neoplasms; Hematology; Hematopoietic; Hematopoietic System; Holoenzymes; Human; Human Cell Line; MS4A1 gene; Malignant Neoplasms; Molecular; Monoclonal Antibody Therapy; Multienzyme Complexes; Mus; Myelogenous; Myeloid Cells; Myeloid Leukemia; Myeloproliferative disease; Neural Crest; Normal Cell; Normal tissue morphology; Outcome; Pathogenesis; Patient-Focused Outcomes; Patients; Pharmacology; Play; Primary Myelofibrosis; Prostate; Protein Isoforms; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; Resolution; Role; Safety; Signal Transduction; Survival Rate; System; Technology; Therapeutic; Translating; Treatment Efficacy; Tumor-Derived; Validation; Xenograft procedure; acute myeloid leukemia cell; antitumor effect; cancer therapy; cell type; chemotherapy; clinical development; cytotoxic; disorder control; high risk; humanized mouse; improved; improved outcome; inhibitor; inhibitor therapy; interest; leukemia; mortality; neoplastic; neoplastic cell; novel; older patient; patient derived xenograft model; phosphatidylinositol 3-kinase gamma; screening; selective expression; side effect; standard of care; survival outcome; systemic toxicity; targeted treatment; translational potential; tumor

Project Summary/Abstract Myeloid malignancies are a group of often lethal cancers that derive from cells of the myeloid lineage of the hematopoietic system and include acute myeloid leukemia (AML) and diverse myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), the latter of which include chronic myelogenous leukemia (CML) and primary myelofibrosis. AML, the most common acute leukemia in adults, is responsible for significant cancer-related mortality, with a five-year survival rate of 28.9%. Although recent advances in genomics and other areas have significantly improved our understanding of the molecular events that underlie AML pathogenesis, these advances have yet to translate to significant improvements in the overall outcomes of patients with the disease, which have remained relatively unchanged over the last 40 years. In notable contrast to the scenario for AML, outcomes in patients diagnosed with a different leukemia, chronic lymphocytic leukemia (CLL), have been transformed in recent decades by drugs that target proteins such as Bruton’s tyrosine kinase (BTK), PI3Kd, and CD20, whose expression and function are unique to the B cell lineage from which these cancers arise. These agents, which exhibit narrow side effect profiles, can thus be used chronically, alone or in combination with one another or additional agents to yield very long term disease control. Similar advances in the targeting of proteins with lineage-specific expression profiles and dependencies have led to substantial improvements in the treatment of patients with breast, prostate, and neural crest-derived tumors. Recently, we discovered that the PI3Kg holoenzyme, comprised of the catalytic p110g and regulatory p101 subunits, is a profound regulator of AKT signaling, survival, and chemosensitivity in AML whose expression is restricted to hematopoietic cells, and particularly those of the myeloid lineage. Thus, targeting this critical signaling node leads to marked antitumor effects in AML cell lines, patient-derived cultures, and PDX models without the systemic toxicities historically associated with pan- or a/b isoform-specific PI3K inhibition. In this proposal, we describe studies to comprehensively characterize the expression and function of PI3Kg across all major AML subtypes as well the normal cell types of the hematopoietic system. Further, we propose to define the fundamental mechanisms governing PI3Kg expression in AML, then evaluate the therapeutic efficacy and safety of targeting this signaling axis in gold standard xenograft, humanized mouse, and genetically engineered mouse models of AML. Together, these studies will define a novel, lineage-restricted signaling axis regulating survival in myeloid malignancies whose selective targeting may add substantially to the therapeutic armamentarium in AML.

项目摘要/摘要 髓样恶性肿瘤是一组经常致命的癌症，它们源自髓样谱系的细胞 造血系统，包括急性髓性白血病（AML）和多元化的骨髓增生综合症 （MDS）和骨髓增生性肿瘤（MPN），后者包括慢性骨髓性白血病 （CML）和原发性骨髓纤维化。 AML是成人最常见的急性白血病，负责 与癌症相关的显着死亡率，五年生存率为28.9％。虽然最近的进步 基因组学和其他领域已显着改善了我们对基于的分子事件的理解 AML发病机理，这些进步尚未转化为整体结果的显着改善 在过去的40年中，这种疾病的患者相对不变。 与AML的情况形成鲜明对比的是，诊断出患有不同白血病，慢性的患者的结果 最近几十年，靶向蛋白（例如 Bruton的酪氨酸激酶（BTK），PI3KD和CD20，其表达和功能是B细胞独有的 这些癌症出现的谱系。这些药物暴露了狭窄的副作用曲线，因此可以是 长期，单独或彼此结合或其他药物以产生非常长期疾病 控制。具有谱系特异性表达曲线的蛋白质靶向靶向的类似进展 依赖性已导致乳房，前列腺和 神经rest衍生的肿瘤。 最近，我们发现PI3KG全酶由催化P110G和调节P101组成 亚基是AML中Akt信号传导，生存和化学敏度的深刻调节剂，其表达是 仅限于造血细胞，尤其是髓样谱系的细胞。那是针对这个关键的 信号传导节点在AML细胞系，患者衍生培养物和PDX模型中导致明显的抗肿瘤作用 在历史上没有与泛或A/B同工型特异性PI3K抑制相关的全身毒性。在这个 提案，我们描述了研究以全面表征PI3KG的研究和功能 主要的AML亚型以及造血系统的正常细胞类型。此外，我们建议定义 管理AML中PI3KG表达的基本机制，然后评估治疗效率和 在黄金标准异种移植，人源化小鼠和遗传上靶向此信号轴的安全性 AML的工程鼠标模型。这些研究将共同​​定义一个新颖的谱系限制信号轴 调节其选择性靶向的髓样恶性菌中的生存可能会大大增加治疗性 AML的Armamentarium。