BLRD Merit Review Research Career Scientist (RCS) Award (IK6)

BLRD 优异评审研究职业科学家 (RCS) 奖 (IK6)

• 批准号: 10091653
• 负责人: Jin Chen
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2027-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10091653
• 关键词: Affect; Angiogenic Factor; Animal Model; Animals; Area; Award; Binding; Blood Circulation; Blood Vessels; Bypass; Cancer Patient; Categories; Cells; Chemical Exposure; Chemicals; Clinic; Clinical Trials; Data; Development; Disease; Dose; Drug resistance; EGFR gene; Endothelium; EphA2 Receptor; Ephrin-A1; Epidermal Growth Factor Receptor; Exposure to; FDA approved; FRAP1 gene; Feedback; Fibrinogen; Funding; Glutaminase; Glutamine; Goals; Healthcare; Hyperactivity; Immune; Immunotherapy; Incidence; Infiltration; Investigation; KRAS2 gene; Knock-out; Knockout Mice; Laboratories; Lead; Lipids; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of lung; Manuscripts; Mediating; Metabolic; Metabolic Pathway; Metabolism; Military Personnel; Mission; Molecular; Mutation; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Non-Small-Cell Lung Carcinoma; Nutrient; Oncogenic; Pathogenesis; Patient Care; Patients; Pharmaceutical Preparations; Phosphotransferases; Point Mutation; Population; Publishing; Quality of life; Raptors; Refractory; Regulation; Research; Resistance; Role; SDZ RAD; Scientist; Signal Pathway; Signal Transduction; Smoking; T-Cell Activation; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Transcription Coactivator; Transcriptional Activation; Translating; Tumor Angiogenesis; Tumor Immunity; Tumor-Infiltrating Lymphocytes; United States National Institutes of Health; Up-Regulation; Validation; Veterans; War; Work; angiogenesis; cancer cell; cancer subtypes; cancer therapy; career; checkpoint receptors; design; driver mutation; high standard; immune checkpoint blockade; immune function; improved; inhibitor/antagonist; kinase inhibitor; lipid biosynthesis; lymphoid neoplasm; mTOR Signaling Pathway; military veteran; molecular targeted therapies; mutant; neoplastic cell; neovascularization; new therapeutic target; novel; overexpression; pre-clinical; programs; recruit; screening; small molecule inhibitor; success; targeted treatment; therapeutic target; tumor; tumor growth; tumor metabolism; tumor progression; tumor-immune system interactions

Project Summary/Abstract The goals of my research programs are to elucidate molecular mechanisms of tumor angiogenesis, cancer metabolism, and anti-tumor immunity, and to translate our discoveries towards improved cancer therapy. During this RCS award period I will continue to: (1) Targeting mTOR signaling pathways in lung cancer subtypes that are refractory to current targeted therapies. We demonstrated previously that mTOR is a common signaling node downstream of “bypass” kinases, and targeting mTOR represents a promising approach in multiple settings of drug resistance. Rictor, a unique components of mTORC2, is commonly amplified in approximately 13% of lung cancer. While mTOR kinase inhibitors inhibit both mTORC1 and mTORC2, selective inhibition of mTORC2 has the advantage of not perturbing the mTORC1-dependent negative feedback loops and mTORC1- mediated inhibition of macropinocytosis in mutant Ras tumors. We found that point mutations disrupting mLST8-mTOR binding specifically destabilize mTORC2 without affecting mTORC1, pointing to a viable strategy for inhibitor design. We will continue to gain a rigorous understanding of the contribution of mTORC2 to subtypes of lung cancer that are currently refractory to targeted therapies, and to further investigate if targeting mLST8 can be used to selectively inhibit mTORC2. (2) Determine the therapeutic potential of low dose mTORC1 inhibitors in normalizing tumor blood vessels and recruiting anti-tumor lymphocytes. My lab pioneered studies of mTORC1 and mTORC2 in tumor blood vessels. We discovered that lymphocyte infiltration increased significantly in the tumors with endothelial-specific deletion of Raptor (mTORC1 inactivation). Although standard high doses of Rapalogs can inhibit immune function, we discovered that a low, relatively immune- sparing dose of everolimus (RAD001), an mTORC1 inhibitor, normalized tumor blood vessels and enhanced tumor infiltrating lymphocytes. Promising results of pre-clinical animal studies will set the stage for initiating a clinical trial to improve immunotherapy. (3) Role of EphA2 RTK in glutamine metabolism and anti-tumor immunity. Our serendipitous discovery that the ephrin-A1/EphA2 signaling axis regulates lipid accumulation in cancer cells has led us systematically to investigate the role of ephrin-A1/EphA2 in tumor metabolism. Global metabolic profiling revealed a significant increase in glutaminolysis, a critical metabolic pathway that generates intermediates for lipogenesis, in ephrin-A1 knockout or EphA2 overexpressing tumor cells. Investigation of mechanisms led us to discover that EphA2 RTK promotes glutamine metabolism by upregulation of the glutamine transporter ASCT2 (encoded by SLC1A5) and glutaminase GLS via activation of the transcription coactivators YAP and TAZ. Knockout of GLS in tumor cells, however, increases anti-tumor immunity. We will continue to dissect the effects and mechanisms by which tumor cell-specific loss of GLS on immune cells. Further, we will test and compare inhibitors of glutamine access (V-9302) or glutaminase (CB-839) on their effects in inhibiting tumor cells versus anti-tumor lymphocytes. Significance: Success of these projects will have significant translational potential for the veteran populations, by identifying new therapeutic targets for lung cancer subtypes that are refractory to current targeted therapies, and by enhancing immunotherapies via normalization of tumor blood vessels and inhibition of tumor metabolism.

项目总结/摘要 我的研究项目的目标是阐明肿瘤血管生成的分子机制， 癌症代谢和抗肿瘤免疫，并将我们的发现转化为改善 癌症治疗。在RCS获奖期间，我将继续：（1）针对mTOR信号传导 目前靶向治疗难治的肺癌亚型中的通路。我们 先前证明mTOR是“旁路”激酶下游的常见信号传导节点， 靶向mTOR代表了在多种耐药性环境中有希望的方法。里克特， mTORC 2是mTORC 2的独特组分，通常在约13%的肺癌中扩增。 虽然mTOR激酶抑制剂抑制mTORC 1和mTORC 2，但选择性抑制mTORC 2 具有不干扰mTORC 1依赖性负反馈回路和mTORC 1-依赖性负反馈回路的优点。 在突变Ras肿瘤中介导的巨胞饮抑制。我们发现点突变 破坏mLST 8-mTOR结合特异性地使mTORC 2不稳定而不影响mTORC 1， 指出了抑制剂设计的可行策略。我们将继续严格了解 mTORC 2对目前靶向治疗难治的肺癌亚型的贡献 因此，本发明的目的在于进一步研究靶向mLST 8是否可用于选择性抑制mTORC 2。 (2)确定低剂量mTORC 1抑制剂在使肿瘤正常化中的治疗潜力 血管和募集抗肿瘤淋巴细胞。我的实验室开创了mTORC 1的研究， 肿瘤血管中的mTORC 2。我们发现，淋巴细胞浸润显著增加 Raptor内皮特异性缺失（mTORC 1失活）的肿瘤。虽然标准 高剂量的雷帕霉素类似物可以抑制免疫功能，我们发现，低，相对免疫- 保留剂量的依维莫司（RAD 001），一种mTORC 1抑制剂，使肿瘤血管正常化， 增强的肿瘤浸润淋巴细胞。临床前动物研究的有希望的结果将使 启动临床试验以改善免疫疗法的阶段。(3)EphA 2 RTK在谷氨酰胺中的作用 代谢和抗肿瘤免疫。我们偶然发现肝配蛋白A1/EphA 2 信号轴调节癌细胞中的脂质积累，这使我们系统地研究了 ephrin-A1/EphA 2在肿瘤代谢中的作用总体代谢分析显示， 增加多巴胺分解，这是一种产生脂肪生成中间体的关键代谢途径， 在ephrin-A1敲除或EphA 2过表达的肿瘤细胞中。对机制的研究使我们 发现EphA 2 RTK通过上调谷氨酰胺代谢促进谷氨酰胺代谢， 转运蛋白ASCT 2（由SLC 1A 5编码）和转氨酶GLS通过转录激活 共活化剂雅普和TAZ。然而，在肿瘤细胞中敲除GLS增加抗肿瘤免疫。 我们将继续研究肿瘤细胞特异性GLS缺失对肿瘤细胞增殖的影响和机制。 免疫细胞此外，我们将测试和比较谷氨酰胺通路抑制剂（V-9302）或 抗肿瘤活性的研究包括抗肿瘤酶（CB-839）对它们抑制肿瘤细胞相对于抗肿瘤淋巴细胞的作用的影响。 意义：这些项目的成功将为退伍军人带来巨大的转化潜力 人群，通过确定新的肺癌亚型的治疗靶点， 目前的靶向治疗，并通过肿瘤血液正常化增强免疫治疗， 血管和抑制肿瘤代谢。