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: 10514613
• 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/10514613
• 关键词: Affect; Angiogenic Factor; Animal Model; Animals; Area; Award; Binding; Blood Vessels; Bypass; Cancer Patient; Categories; Cells; Chemical Exposure; Chemicals; Circulation; Classification; 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; Funding; Glutaminase; Glutamine; Goals; Healthcare; Hyperactivity; Immune; Immunotherapy; Incidence; Investigation; KRAS2 gene; Knock-out; Knockout Mice; Laboratories; Lipids; Lymphocyte; Lymphocytic Infiltrate; 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; Refractory; Regulation; Research; Resistance; Role; SDZ RAD; Scientist; Signal Pathway; Signal Transduction; Smoking; T-Cell Activation; T-Lymphocyte; Technology; Testing; Therapeutic; 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; kinase inhibitor; lipid biosynthesis; 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; translational potential; 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.

项目概要/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 在 RCS 奖励期间，我将继续：(1) 针对 mTOR 信号传导。 当前靶向治疗难以治愈的肺癌亚型中的通路。 此前，mTOR 是“旁路”激酶下游的常见信号传导节点， 针对 Rictor 的多种耐药情况，靶向 mTOR 是一种有前景的方法。 mTORC2 的一种独特成分，通常在大约 13% 的肺癌中被扩增。 虽然 mTOR 激酶抑制剂同时抑制 mTORC1 和 mTORC2，但选择性抑制 mTORC2 具有不干扰 mTORC1 依赖性负反馈环路和 mTORC1- 的优点 我们发现点突变可抑制突变型 Ras 肿瘤中的巨胞饮作用。 破坏 mLST8-mTOR 结合会特异性破坏 mTORC2 的稳定性，而不影响 mTORC1， 我们将继续获得对抑制剂设计的严格理解。 mTORC2 对目前靶向治疗难治性肺癌亚型的贡献 疗法，并进一步研究靶向 mLST8 是否可用于选择性抑制 mTORC2。 (2) 确定低剂量mTORC1抑制剂使肿瘤正常化的治疗潜力 我的实验室开创了 mTORC1 和招募抗肿瘤淋巴细胞的研究。 我们发现肿瘤血管中的mTORC2淋巴细胞浸润显着增加。 具有内皮特异性 Raptor 缺失（mTORC1 失活）的肿瘤。 高剂量的 Rapalogs 会抑制免疫功能，我们发现相对较低的免疫- 备用剂量的依维莫司 (RAD001)（一种 mTORC1 抑制剂）可使肿瘤血管正常化，并 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设定。 (3) EphA2 RTK在谷氨酰胺中的作用 我们偶然发现 ephrin-A1/EphA2。 信号轴调节癌细胞中的脂质积累使我们系统地研究了 ephrin-A1/EphA2 在肿瘤代谢中的作用揭示了显着的代谢特征。 谷氨酰胺分解的增加，这是一种产生脂肪生成中间体的关键代谢途径， 对 ephrin-A1 敲除或 EphA2 过表达肿瘤细胞的机制研究使我们发现。 发现 EphA2 RTK 通过上调谷氨酰胺促进谷氨酰胺代谢 通过激活转录来转运蛋白 ASCT2（由 SLC1A5 编码）和谷氨酰胺酶 GLS 然而，共激活剂 YAP 和 TAZ 敲除肿瘤细胞中的 GLS 会增加抗肿瘤免疫力。 我们将继续剖析肿瘤细胞特异性 GLS 缺失对细胞的影响和机制。 此外，我们将测试和比较谷氨酰胺通路抑制剂 (V-9302) 或 谷氨酰胺酶 (CB-839) 对比其抑制肿瘤细胞与抗肿瘤淋巴细胞的作用。 意义：这些项目的成功将为退伍军人带来巨大的转化潜力 通过确定难治性肺癌亚型的新治疗靶点 当前的靶向治疗，以及通过肿瘤血液正常化来增强免疫治疗 血管和抑制肿瘤代谢。