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Role of PI3Kgamma in Tumor Progression and Metastasis

PI3Kgamma 在肿瘤进展和转移中的作用

基本信息

批准号：
10801992
负责人：
Judith A VARNER
金额：
$ 53.59万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10801992
关键词：
Accounting Aftercare Animal Cancer Model Antibodies Antigen Presentation Biochemical Biological Cancer Patient Cell Proliferation Cell physiology Cells Cessation of life Clinic Clinical Clinical Trials Dendritic Cells Disease Disease model Disease-Free Survival Dissection Drug resistance Early Diagnosis Early treatment Gene Expression Profile Genetic Genetic Transcription Glioblastoma Goals Growth Head and Neck Cancer Human Immune Immune checkpoint inhibitor Immune response Immunooncology Immunosuppression Inflammation Inflammatory Invaded Lung Neoplasms Macrophage Malignant Neoplasms Malignant neoplasm of lung Mediating Modeling Molecular Mus Myeloid Cells Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Operative Surgical Procedures Outcome PIK3CG gene Pathway interactions Patients Phase I Clinical Trials Phenotype Phosphatidylinositol 4,5-Diphosphate Phosphotransferases Play Property Protein Isoforms Regulation Research Resected Resistance Role Signal Transduction Solid Neoplasm Survival Rate T memory cell T-Lymphocyte Testing Therapeutic Tumor Angiogenesis Tumor Immunity Tumor Promotion Tumor Tissue Tumor-associated macrophages adaptive immune response adaptive immunity antagonist anti-tumor immune response cell type checkpoint therapy chemotherapy granulocyte human model immune activation improved in vivo inhibitor inhibitor therapy innovation insight lung Carcinoma malignant breast neoplasm melanoma monocyte mouse model neoplastic cell neutrophil new therapeutic target novel therapeutic intervention novel therapeutics pharmacologic phase II trial prevent recruit resistance mechanism stemness synergism targeted treatment therapy resistant trafficking tumor tumor growth tumor microenvironment tumor progression

项目摘要

Lung cancer is one of the most lethal of solid tumors. The overall survival rate for patients with lung cancer remains low, at 21%. As 236,740 new cases of lung cancer and 130,180 deaths are expected in 2022, there remains a pressing need to advance research into new therapeutic approaches for the treatment of lung cancer. Solid tumors, such as lung tumors, are laden with abundant, tumor-promoting macrophages, monocytes and granulocytes. These innate immune cells promote tumor progression through profound inhibition of T cell recruitment and activation and through stimulation of tumor angiogenesis, stemness, drug resistance and metastasis. Strategies that reduce the accumulation of myeloid cells or alter their functional properties significantly slow or eliminate tumor progression in animal models of cancer and synergize with other therapeutic approaches to improve cancer outcomes. We previously discovered that a myeloid cell specific isoform of phosphatidylinositol-4,5-bisphosphate 3-kinase, PI3Kgamma (PI3Kg), controls both myeloid cell accumulation and immune suppressive polarization in tumors. Genetic or pharmacological inactivation of PI3Kg, but not other PI3K isoforms, reduces myeloid cell accumulation in tumors and alters the transcriptional profile of immune suppressive, pro-angiogenic tumor associated macrophages (TAMs) toward a pro-inflammatory, anti- tumor phenotype. We have found that PI3Kg inhibition synergizes with chemotherapy and with checkpoint inhibitors to activate memory T cells and reduce tumor growth in models of lung cancer, breast cancer, melanoma, head and neck cancer and glioblastoma. Based on our findings, the PI3Kg inhibitor, IPI-549 (eganelisib), was developed as an immune oncology therapeutic. We identified signatures of re-activated adaptive immune responses in tumor tissues from lung cancer patients who participated in IPI-549 Phase 1 clinical trials, indicating that PI3Kg blockade can re-awaken anti-tumor immunity in human tumors and thus may provide therapeutic benefit to lung cancer patients. However, we also identified pathways of resistance to therapy, indicating that further dissection of the roles that PI3Kg and its inhibitors play in lung tumors is warranted. The exact biochemical and cellular mechanisms by which PI3Kg inhibits anti-tumor immunity in murine and human lung cancer remain unclear. Deciphering these mechanisms will provide new therapeutic insights into the mechanisms of tumor immune suppression. Therefore, we propose studies to determine which molecular and cellular mechanisms are direct and indirect targets of PI3Kg mediated immune suppression, to identify and treat pathways of resistance to PI3Kg inhibitor therapy and to evaluate the impact of PI3Kg inhibition on immune responses in mouse and human models of NSCLC. The specific aims to accomplish these goals are: 1) To delineate molecular mechanisms by which PI3Kg regulates macrophage transcription; 2) To determine mechanisms by which PI3Kg controls lung tumor progression in vivo; 3) To discover and target mechanisms of resistance to PI3Kg inhibition in lung carcinoma.

肺癌是最致命的实体肿瘤之一。肺癌患者的总生存率仍然很低，只有21%。由于预计2022年将有236，740例肺癌新发病例和130，180例死亡，仍然迫切需要推进对用于治疗肺癌的新治疗方法的研究。实体瘤，如肺肿瘤，充满了丰富的促肿瘤巨噬细胞、单核细胞和巨噬细胞。粒细胞。这些先天性免疫细胞通过对T细胞的深度抑制来促进肿瘤的进展。募集和激活，并通过刺激肿瘤血管生成、干性、耐药性和转移减少骨髓细胞积聚或改变其功能特性的策略在癌症动物模型中显著减缓或消除肿瘤进展并与其它治疗剂协同作用改善癌症预后的方法。我们以前发现，一种髓样细胞特异性的同种型磷脂酰肌醇-4，5-二磷酸3-激酶，PI 3 K γ（PI 3 Kg），控制骨髓细胞肿瘤中的积聚和免疫抑制极化。PI 3 Kg的遗传或药理学失活，而不是其他PI 3 K亚型，减少肿瘤中骨髓细胞的积累，并改变PI 3 K的转录谱。免疫抑制性、促血管生成肿瘤相关巨噬细胞（TAMs）向促炎性、抗- 肿瘤表型我们发现PI 3 Kg抑制与化疗和检查点协同作用，抑制剂，以激活记忆T细胞并减少肺癌，乳腺癌，黑色素瘤、头颈癌和胶质母细胞瘤。根据我们的发现，PI 3 Kg抑制剂IPI-549 （eganelisib）被开发为免疫肿瘤学治疗剂。我们识别出了来自参加IPI-549第1阶段研究的肺癌患者的肿瘤组织的适应性免疫应答临床试验，表明PI 3 Kg阻断可以重新唤醒人类肿瘤中的抗肿瘤免疫，因此可能为肺癌患者提供治疗益处。然而，我们也确定了耐药途径，治疗，表明PI 3 Kg及其抑制剂在肺肿瘤中发挥的作用的进一步解剖是必要的。 PI 3 Kg抑制小鼠抗肿瘤免疫的确切生化和细胞机制，人类肺癌仍不清楚。破译这些机制将提供新的治疗见解，肿瘤免疫抑制的机制。因此，我们建议进行研究，以确定和细胞机制是PI 3 Kg介导的免疫抑制的直接和间接靶点，以鉴定和治疗对PI 3 Kg抑制剂疗法的抗性的途径，并评估PI 3 Kg抑制对免疫应答的影响。在小鼠和人NSCLC模型中的反应。实现这些目标的具体目标是：1）描述PI 3 Kg调节巨噬细胞转录的分子机制; 2）确定 PI 3 Kg在体内控制肺肿瘤进展的机制; 3）发现和靶向PI 3 Kg的机制，肺癌中PI 3 Kg抑制的抗性。