Biology of major folate transporters and STING signaling in cancer

主要叶酸转运蛋白的生物学和癌症中的 STING 信号传导

• 批准号: 10597540
• 负责人: Zhanjun Hou
• 金额: $ 7.7万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-05 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597540
• 关键词: Adenosine Monophosphate; Agonist; Anions; Area; Bacteria; Biology; CD8B1 gene; Cell membrane; Cell model; Cells; Clinical; Clinical Data; Clinical Trials; Code; Complex; Coupled; Cyclic GMP; Cytosol; DNA; Dinucleoside Phosphates; Dose; Endoplasmic Reticulum; Ensure; Environment; Epigenetic Process; Folic Acid; Folic Acid Deficiency; Frequencies; Genetic Polymorphism; Genetic Transcription; Genomics; Goals; Human; Immune; Immune checkpoint inhibitor; Infection; Infiltration; Inflammatory Response; Interferon Type I; Interferons; Investigational Drugs; Lesion; Lymphoma; Malignant Neoplasms; Mammalian Cell; Methotrexate; Molecular; Mus; Pathway interactions; Patients; Pemetrexed; Periodicity; Phase I Clinical Trials; Physiological; Positioning Attribute; Post-Transcriptional Regulation; Protons; Publishing; Radiation therapy; Regulation; Reporting; Research; Role; SLC19A1 gene; Signal Transduction; Solid Neoplasm; Source; Specificity; Stimulator of Interferon Genes; Structure; Substrate Specificity; System; T-Lymphocyte; Tetrahydrofolates; Therapeutic; Therapeutic Effect; Tissues; Tumor Immunity; analog; cancer cell; cancer immunotherapy; checkpoint therapy; clinical efficacy; clinical translation; cytokine; ds-DNA; extracellular; folate-binding protein; human tissue; immunogenicity; improved; inhibitor therapy; innate immune sensing; insight; neoplastic cell; novel; overexpression; pharmacologic; pre-clinical; preclinical study; promoter; protein protein interaction; response; sensor; success; symporter; tool; tumor; tumor growth; uptake

ABSTRACT In mammalian cells, cyclic dinucleotides (CDNs) act as prominent danger signals that are sensed by the innate immune sensor, stimulator of interferon genes (STING). Activation of STING elicits a signaling cascade that culminates in the induction of type I interferons (IFNs) and various cytokines, thereby promoting a powerful inflammatory response. Mammalian cells are able to produce their own CDNs, catalyzed by the cyclic guanosine monophosphate–adenosine monophosphate (GMP-AMP) synthase (cGAS), which is activated by double-strand DNAs to synthesize the eukaryotic CDN, 2′3′-cGAMP. Beyond intracellular CDNs, STING-activating CDNs can originate from extracellular sources, such as therapeutic CDNs, cGAMP produced by tumor cells, and CDNs from extracellular bacteria. The role of the cGAS-STING pathway in anti-tumor immunity supports the use of STING agonists as cancer therapeutics. Inspired by the discovery that 2′3′-cGAMP activates human STING to initiate robust downstream IFN signaling, STING-activating agents (mostly 2′3′-cGAMP analogues) were synthesized. Direct pharmacologic activation of STING was shown to restrict tumor growth by a T cell-driven tumor regression mechanism and to enhance immunogenicity. Administration of cGAMP in tumor-bearing mice also potentiated the therapeutic effects of immune-checkpoint inhibitors and radiotherapy. Based on results with CDN analogs in mice, two phase I clinical trials were initiated for the intra-tumoral delivery of STING agonists (ADU-S100 and MK-1454) to solid tumors and lymphomas. Despite the impressive anti-tumor activity of STING agonists in mice, initial results from clinical trials of such agonists have indicated a lower efficacy in humans. The regulatory interplay among the import, export and degradation of CDNs remains an important and interesting area for future research. Exogenous 2′3′-cGAMP and synthetic CDNs, including the investigational new drug (IND) 2′3′-CDAS used in cancer immunotherapy, traverse the cell membrane through the reduced folate carrier (RFC; SLC19A1) to activate STING in target cells, and the proton-coupled folate transporter (PCFT; SLC46A1) enhances such response. RFC and PCFT are major facilitative transporters of folate in human tissues and tumors. PCFT is unique from RFC in that it has an acidic rather than neutral pH optimum. RFC and PCFT share substrates such as clinically used methotrexate and pemetrexed but also show their own unique substrate specificities. Our group has studied RFC and PCFT structure, function and regulation extensively. In this R03 application, we explore the unique biology of RFC, as well as PCFT, and STING agonists in cancer, with a goal of further understanding CDN uptake by these facilitative transporters and, by extension, improving therapeutic applications. We propose in Aim 1 to study mechanisms of CDN uptake by RFC and PCFT under physiological conditions. In Aim 2, we will study the molecular regulation of RFC in relation to CDN uptake, including transcriptional epigenetics, and the potential role of protein-protein interactions in regulating RFC. Our proposed studies are distinctive for their novelty and potential for clinical translation.

摘要