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

基本信息

批准号：
10595677
负责人：
Kris Wood
金额：
$ 40.23万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10595677
关键词：
Acute Myelocytic Leukemia Acute leukemia Adult Agammaglobulinaemia tyrosine kinase Animal Disease Models Animal Model Anthracycline Antiandrogen Therapy Antineoplastic Agents Area B-Lymphocytes BCL1 Oncogene 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 Hematologic Neoplasms Hematology Hematopoietic Hematopoietic System Holoenzymes Human Human Cell Line MS4A1 gene Malignant Neoplasms Malignant neoplasm of prostate Molecular Monoclonal Antibody Therapy Multienzyme Complexes Mus Myelodysplastic/Myeloproliferative Disease Myelogenous Myeloid Cells Myeloid Leukemia Myeloproliferative disease Neural Crest Neuroblastoma Normal Cell Normal tissue morphology Outcome PIK3CG gene Pathogenesis Patient-Focused Outcomes Patients Play Primary Myelofibrosis Proliferating Prostate Protein Isoforms Proteins Proteomics Proto-Oncogene Proteins c-akt Resolution Role Safety Signal Transduction Sorting Survival Rate System Technology Therapeutic Translating Treatment Efficacy 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 leukemia treatment malignant breast neoplasm mortality neoplastic neoplastic cell novel older patient patient derived xenograft model pharmacologic phosphatidylinositol 3-kinase gamma screening selective expression side effect standard of care survival outcome systemic toxicity targeted treatment translational potential tumor

项目摘要

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.

项目概要/摘要髓系恶性肿瘤是一组通常致命的癌症，源自骨髓系的髓系细胞。造血系统，包括急性髓系白血病 (AML) 和多种骨髓增生异常综合征（MDS）和骨髓增生性肿瘤（MPN），后者包括慢性粒细胞白血病 (CML) 和原发性骨髓纤维化是成人最常见的急性白血病。癌症相关死亡率很高，五年生存率为 28.9%。基因组学和其他领域显着提高了我们对潜在分子事件的理解 AML 发病机制，这些进展尚未转化为总体结果的显着改善患有这种疾病的患者数量在过去 40 年中相对保持不变。与 AML 的情况形成鲜明对比的是，诊断患有不同白血病、慢性白血病的患者的结果近几十年来，淋巴细胞白血病（CLL）已被靶向蛋白质的药物所改变，例如布鲁顿酪氨酸激酶 (BTK)、PI3Kd 和 CD20，其表达和功能是 B 细胞所独有的因此，这些具有狭窄副作用的药物可以被认为是这些癌症的起源。长期单独使用或与另一种药物或其他药物联合使用以产生非常长期的疾病具有谱系特异性表达谱的蛋白质靶向方面也取得了类似的进展。依赖性导致乳腺癌、前列腺癌和前列腺癌患者的治疗取得了显着改善。神经嵴衍生的肿瘤。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、生存和化疗敏感性的重要调节因子，其表达为仅限于造血细胞，特别是骨髓细胞系，因此，针对这一关键细胞。信号传导节点在 AML 细胞系、患者来源的培养物和 PDX 模型中产生显着的抗肿瘤作用没有历史上与泛或 a/b 亚型特异性 PI3K 抑制相关的系统毒性。提案中，我们描述了全面表征 PI3Kg 在所有细胞中的表达和功能的研究此外，我们建议定义主要的 AML 亚型以及造血系统的正常细胞类型。了解 AML 中 PI3Kg 表达的基本机制，然后评估治疗效果和在金标准异种移植、人源化小鼠和遗传中靶向该信号轴的安全性这些研究将共同定义一种新型的、谱系限制的信号轴。调节骨髓恶性肿瘤的生存，其选择性靶向可能会大大增加治疗效果 AML 的治疗方法。