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Exploiting the immunomodulatory effects of sulindac and novel non-COX inhibitory derivatives for cancer treatment

利用舒林酸和新型非 COX 抑制衍生物的免疫调节作用来治疗癌症

基本信息

批准号：
10360574
负责人：
Gary A Piazza
金额：
$ 42.31万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10360574
关键词：
Adverse effects Antineoplastic Agents Apoptosis Binding Biological CAR T cell therapy CD19 gene Chemicals Chemopreventive Agent Cialis Colonic Neoplasms Colorectal Cancer Complex Coxibs Cyclic GMP Cyclooxygenase Inhibitors Data Dendritic Cells Development Disease Fever Genetic Transcription Growth Ibuprofen Immune Immunomodulators Immunosuppression In Vitro Incidence Individual Indomethacin Inflammation Isoenzymes Knowledge Laboratories Lead Lymphoma cell Malignant - descriptor Malignant Neoplasms Mediating Modeling Modification Molecular Mus Non-Steroidal Anti-Inflammatory Agents Oncogenic Oral Administration Organ PD-1 blockade Pharmacotherapy Pre-Clinical Model Property Prostaglandin-Endoperoxide Synthase Prostaglandins Regulatory T-Lymphocyte Reporting Research Rodent Model Series Signal Transduction Small Interfering RNA Sulfones Sulindac Synthesis Chemistry T cell therapy T-Lymphocyte Testing Toxic effect Tumor Immunity anti-tumor immune response anticancer activity base beta catenin cancer cell cancer chemoprevention cancer immunotherapy cancer therapy celecoxib cell growth chemical synthesis chimeric antigen receptor cyclooxygenase 1 cyclooxygenase 2 design drug candidate drug development effectiveness testing endoplasmic reticulum stress engineered T cells epidemiology study immune activation immunogenic immunogenic cell death immunoregulation improved in vivo inhibitor knock-down migration mouse model neoplastic cell novel overexpression pain relief phosphoric diester hydrolase programs screening stem cell function tumor tumor microenvironment tumorigenesis

项目摘要

Project summary/abstract Nonsteroidal anti-inflammatory drugs (NSAIDs) have cancer chemopreventive activity, but are not recommended for long-term use because of toxicities resulting from cyclooxygenase (COX) inhibition. However, sulindac and its congener, indomethacin (indo) inhibit the growth and induce apoptosis of tumor cells in vitro and are potentially effective for treating malignant disease by mechanisms that appear to be unrelated to COX inhibition. The Piazza lab has identified a novel series of non-COX-inhibitory sulindac derivatives with potent tumor cell growth inhibitory activity by targeting cGMP phosphodiesterase (PDE) isozymes, PDE5 and/or PDE10 to induce cGMP signaling. MCI-030 is a prototypic non-COX-inhibitory sulindac derivative with selectivity for PDE10 inhibition and strong in vitro and in vivo anti-tumor activity. Collaborative efforts from the Zhou and Piazza laboratories discovered that sulindac, MCI-030, as well as a sulindac congener, indomethacin (indo) are capable of inducing ER stress in tumor cells and can sensitize lymphoma cells to T cells engineered to express CD19-targeting chimeric antigen receptors (CD19CAR). These findings establish the premise of our hypothesis that it is feasible to design and develop novel sulindac derivatives with potent tumor cell growth inhibitory and immunostimulatory activities by targeting PDE5 and/or PDE10. The objective of our study is to define the molecular and cellular mechanisms by which sulindac and its non-COX derivatives condition an immunogenic tumor microenvironment. Specifically, we will determine how sulindac and non- COX inhibitory derivatives induce cancer immunogenic cell death, mitigate Treg and MDSC- mediated immunosuppression, and activate dendritic cells via effects on tumor cells involving ER stress induction, and suppression of oncogenic -catenin, which we hypothesize are triggered by PDE5/10 inhibition (aim 1). We will test the effectiveness of sulindac and non-COX inhibitory derivatives that inhibit PDE5 and/or PDE10 in potentiating cancer immunotherapies including PD1 blockade and adoptive T cell therapy in multiple preclinical models (aim 2). Knowledge obtained from Aim 1 and 2 will be integrated into a synthetic chemistry campaign to develop new sulindac derivatives with improved antitumor activity by directly suppressing tumor cell growth and by indirectly activating antitumor immunity, without the toxicities associated with COX inhibition (aim 3). Successful completion of the project will pave the way for developing novel sulindac derivatives as immunomodulators for cancer treatment in the arena of cancer immunotherapies.

项目总结/文摘