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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.

项目总结/文摘