A chemical biology approach towards understanding the anti-cancer innate immunity

了解抗癌先天免疫的化学生物学方法

• 批准号: 8804339
• 负责人: Lingyin Li
• 金额: $ 4.73万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-19 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8804339
• 关键词: Accounting; Adjuvant; Affect; Agonist; Antineoplastic Agents; Binding; Biochemical; Biochemistry; Biological Assay; Biological Factors; Biology; Biomedical Research; Blood; Blood Cells; Cancer Vaccines; Candidate Disease Gene; Cell Line; Cell surface; Cells; Chemicals; Chemistry; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Cytoplasm; DNA; Data; Degradation Pathway; Development; Dimethylxanthenone Acetic Acid; Dinucleoside Phosphates; Doctor of Philosophy; Dose; Drug Formulations; Drug Kinetics; Drug Targeting; Engineering; Enzymes; Flow Cytometry; Genes; Genetic; Genetic Screening; Goals; Growth; Haploidy; Health; Human; Hydrolase; Imiquimod; Immune; Immune response; Immune system; Immunity; Immunology; Insertional Mutagenesis; Interferon Activation; Interferons; Kinetics; Lead; Learning; Ligands; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measures; Mediating; Membrane; Membrane Transport Proteins; Modeling; Molecular Target; Mus; Natural Immunity; Organic Chemistry; Paracrine Communication; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Philosophy; Phosphotransferases; Plasma; Postdoctoral Fellow; Quality of life; Reaction; Receptor Signaling; Route; Signal Transduction; Skin Cancer; Solid Neoplasm; Specificity; Structure; Surface; TNFRSF5 gene; Testing; Therapeutic; Therapeutic Intervention; Training; Universities; Wisconsin; Work; analog; base; cancer cell; cancer pharmacology; cancer therapy; chemical genetics; cyclic compound; design; drug candidate; drug development; drug testing; experience; extracellular; genetic approach; improved; insight; interest; leukemia; man; medical schools; mouse model; next generation sequencing; novel; phosphoric diester hydrolase; professor; receptor; response; stem cell fate; synthetic drug; tool; transcription factor; tumor; uptake

DESCRIPTION (provided by applicant): Dr. Lingyin Li was trained in chemical biology and biochemistry. Her graduate training was with Professor Laura Kiessling at University of Wisconsin-Madison, where she used chemistry/engineering strategies to control stem cell fate and she received a Ph. D in organic chemistry. Hoping to learn what the most important problems are in biomedical research, she is seeking her postdoc training with Professor Timothy Mitchison at Harvard Medical School. With her experience there in cancer pharmacology, Dr. Li's long-term goal is to lead her academic team to make an impact on cancer treatment and significantly improve patients' quality of life. Using reverse pharmacology, Dr. Li recently identified the molecular target of a drug called DMXAA that cured solid tumors in mice via activating innate immunity, but failed in phase III human clinical trials. She discovered that DMXAA functions as an agonist ligand for mouse, but not human STING (Stimulator of the Interferon Genes), explaining its activity in mouse and lack of efficacy in man. STING is the receptor for the newly- discovered 2nd messenger 2'3'-cGAMP, which is synthesized by cGAS in response to DNA in the cytoplasm. 2'3'-cGAMP binds to STING, activates TBK-1 (a kinase) and IRF-3 (a transcription factor), and induces a panel of host response genes including interferon α/ß. This pathway opens multiple possible routes to therapeutic intervention. In this proposed project, Dr. Li will seek to uncover biochemical mechanisms in the cGAMP- STING pathway and in parallel develop therapeutic hypotheses and lead compounds. She proposes to use 2'3'-cGAMP analogs that she has synthesized to target human STING and her preliminary results showed extracellular activity of these analogs. She has also discovered the dominant hydrolase for 2'3'-cGAMP, which turned out to be an extracellular enzyme. These results hint extracellular biology of 2'3'-cGAMP, which is not being pursued by the immunology field, and might allow rapid drug development. In her aim 1, Dr. Li plans to further characterize her analogs and test them in mouse tumor models, which is her first bold move towards making an impact on cancer therapy. In aim 2, Dr. Li will study the degradation mechanisms of 2'3'-cGAMP and its internalization kinetics. The results will suggest whether there exists a cell surface signaling receptor for 2'3'-cGAMP or a membrane transporter that eventually leads to intracellular 2'3'-cGAMP signaling. In Aim 3, Dr. Li will use a genetics screen to identify signalig components for extracellular 2'3'-cGAMP (e.g. a membrane receptor or transporter) and this will lead to new biology and novel drug targets. Activating the innate immune system to stop nurturing cancer cells and instead attack them has already shown high potential as a therapeutic philosophy. Dr. Li's chemical genetics approach will provide more tools to awaken our anti- cancer immunity.

描述（由申请人提供）：李令银博士接受过化学生物学和生物化学方面的培训。她的研究生培训是在威斯康星大学麦迪逊分校的 Laura Kiessling 教授的指导下进行的，在那里她使用化学/工程策略来控制干细胞的命运，并获得了有机化学博士学位。为了了解生物医学研究中最重要的问题是什么，她正在哈佛医学院的蒂莫西·米奇森教授的指导下寻求博士后培训。凭借在癌症药理学方面的经验，李博士的长期目标是带领她的学术团队对癌症治疗产生影响并显着改善患者的生活质量。李博士最近利用反向药理学确定了一种名为DMXAA的药物的分子靶点，该药物通过激活先天免疫来治愈小鼠实体瘤，但在人体III期临床试验中失败。她发现 DMXAA 可以作为小鼠的激动剂配体，但不能作为人类 STING（干扰素基因刺激剂）的配体，这解释了它在小鼠中的活性以及在人类中缺乏功效的原因。 STING 是新发现的第二信使 2'3'-cGAMP 的受体，它是由 cGAS 响应细胞质中的 DNA 合成的。 2'3'-cGAMP 与 STING 结合，激活 TBK-1（一种激酶）和 IRF-3（一种转录因子），并诱导一组宿主反应基因，包括干扰素 α/ß。该途径开辟了多种可能的治疗干预途径。在这个拟议的项目中，李博士将寻求揭示 cGAMP-STING 通路中的生化机制，并同时开发治疗假设和先导化合物。她建议使用她合成的 2'3'-cGAMP 类似物来靶向人类 STING，她的初步结果显示了这些类似物的细胞外活性。她还发现了 2'3'-cGAMP 的主要水解酶，结果证明它是一种细胞外酶。这些结果暗示了 2'3'-cGAMP 的细胞外生物学，这并没有被免疫学领域所追求，并且可能允许快速药物开发。在她的目标 1 中，李博士计划进一步表征她的类似物，并在小鼠肿瘤模型中测试它们，这是她为影响癌症治疗而采取的第一个大胆举措。在目标2中，李博士将研究2'3'-cGAMP的降解机制及其内化动力学。结果将表明是否存在 2'3'-cGAMP 的细胞表面信号传导受体或最终导致细胞内 2'3'-cGAMP 信号传导的膜转运蛋白。在目标 3 中，李博士将使用遗传学筛选来识别细胞外 2'3'-cGAMP（例如膜受体或转运蛋白）的信号成分，这将带来新的生物学和新的药物靶标。激活先天免疫系统以停止培育癌细胞并攻击它们，作为一种治疗理念已经显示出巨大的潜力。李博士的化学遗传学方法将为唤醒我们的抗癌免疫力提供更多工具。