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：
10113565
负责人：
Gary A Piazza
金额：
$ 43.17万
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/10113565
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/antagonist 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.

项目摘要/摘要非甾体类抗炎药（NSAIDS）具有癌症化学预防活性，但不是由于环氧酶（COX）引起的毒性，建议长期使用抑制。然而，苏莱达克及其同类霉素（Indo）抑制了生长和影响肿瘤细胞在体外凋亡，可能有效地治疗恶性疾病似乎与Cox抑制无关的机制。广场实验室已经确定了一本小说具有有效肿瘤细胞生长活性的一系列非Cox抑制性硫酸衍生物通过靶向CGMP磷酸二酯酶（PDE）同工酶，PDE5和/或PDE10诱导CGMP 信号。 MCI-030是一种原型非Cox抑制性苏氏衍生物，具有选择性 PDE10抑制作用，体外和体内抗肿瘤活性。来自周和广场实验室发现Sulindac，MCI-030以及Sulindac同步者，吲哚美辛（印度）能够在肿瘤细胞中诱导ER应激，并且可以感觉到淋巴瘤细胞到设计以表达CD19靶向嵌合抗原受体（CD19CAR）的细胞。这些发现确定了我们假设的前提，即设计和发展是可行的具有有效肿瘤细胞生长抑制性和免疫刺激性的新型硫酸衍生物通过靶向PDE5和/或PDE10的活动。我们研究的目的是定义分子和细胞机制，硫酸及其非钙衍生物条件A 免疫原性肿瘤微环境。特别是，我们将确定Sulindac和sulindac和非 - COX抑制衍生物诱导癌症免疫原性死亡，减轻Treg和MDSC- 介导的免疫抑制，并通过对涉及ER的肿瘤细胞的影响激活树突状细胞压力诱导和抑制致癌-catenin，我们假设这是由 PDE5/10抑制（AIM 1）。我们将测试Sulindac和非Cox抑制的有效性抑制PDE5和/或PDE10的衍生物在增强癌症免疫疗法（包括PD1）中多种临床前模型中的胃和自适应T细胞疗法（AIM 2）。获得的知识从AIM 1和2中，将纳入一项合成化学运动，以开发新的苏莱达克通过直接抑制肿瘤细胞生长并通过间接激活抗肿瘤免疫力，而没有与Cox抑制相关的毒性（AIM 3）。该项目的成功完成将为开发新颖的苏琳克铺平道路衍生物作为癌症免疫疗法领域的癌症治疗的免疫调节剂。