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

• 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
• 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

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 非类固醇抗炎药(NSAIDs)具有癌症化学预防活性，但不具有 由于环氧合酶(COX)引起的毒性，建议长期使用 抑制力。然而，舒林酸及其同系物吲哚美辛(INDO)抑制生长并诱导 体外诱导肿瘤细胞凋亡，并可能通过以下途径治疗恶性疾病 似乎与COX抑制无关的机制。Piazza实验室发现了一部小说 具有强大肿瘤细胞生长抑制活性的系列非环氧合酶抑制舒林酸衍生物 通过靶向cGMP磷酸二酯酶(PDE)同工酶、PDE5和/或PDE10诱导cGMP 发信号。MCI-030是一种原型的非COX抑制舒林酸衍生物，具有选择性 PDE10具有较强的体外和体内抗肿瘤活性。来自 周和Piazza实验室发现舒林酸，MCI-030，以及舒林酸的同系物， 吲哚美辛(INDO)能在肿瘤细胞中诱导内质网应激，并能增敏淋巴瘤 T细胞转化为T细胞，表达CD19靶向嵌合抗原受体(CD19CAR)。 这些发现为我们的假设奠定了前提，即设计和开发是可行的 具有抑制肿瘤细胞生长和免疫刺激作用的新型舒林酸衍生物 以PDE5和/或PDE10为目标的活动。我们研究的目的是定义分子 以及舒林酸及其非COX衍生物引起血管紧张性心脏病的细胞机制 免疫原性肿瘤微环境。具体来说，我们将确定舒林酸和非舒林酸如何 COX抑制衍生物诱导肿瘤免疫原性细胞死亡，减轻Treg和MDSC- 介导免疫抑制，激活树突状细胞对ER相关肿瘤细胞的作用 应激诱导和抑制致癌的-连环蛋白，我们假设这是由 抑制PDE5/10(目标1)。我们将测试舒林酸和非COX抑制药的有效性 抑制PDE5和/或PDE10增强包括PD1在内的癌症免疫治疗的衍生物 在多种临床前模型中阻断和过继T细胞治疗(目标2)。获得的知识 将从目标1和目标2整合到合成化学活动中，以开发新的舒林酸 通过直接抑制肿瘤细胞生长和通过以下方式提高抗肿瘤活性的衍生物 间接激活抗肿瘤免疫，没有与COX抑制相关的毒性(目的 3)。该项目的顺利完成将为开发新型舒林酸铺平道路 在癌症免疫治疗领域，作为癌症治疗免疫调节剂的衍生物。