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

项目概要/摘要 非甾体抗炎药（NSAID）具有癌症化学预防活性，但不是 由于环氧合酶（考克斯）引起的毒性，建议长期使用 抑制作用然而，舒林酸及其同类物吲哚美辛（indo）抑制生长并诱导 在体外抑制肿瘤细胞的凋亡，并通过以下方式潜在有效地治疗恶性疾病： 似乎与考克斯抑制无关的机制。广场实验室发现了一本小说 一系列具有有效肿瘤细胞生长抑制活性的非COX抑制性舒林酸衍生物 通过靶向cGMP磷酸二酯酶（PDE）同工酶、PDE 5和/或PDE 10以诱导cGMP 信号MCI-030是一种原型的非COX抑制性舒林酸衍生物，对COX-2具有选择性。 PDE 10抑制和强的体外和体内抗肿瘤活性。来自联合国的合作努力 Zhou和Piazza实验室发现，舒林酸MCI-030以及舒林酸同系物， 吲哚美辛（indo）能够在肿瘤细胞中诱导ER应激，并可使淋巴瘤增敏 细胞转化为经工程改造以表达靶向CD 19的嵌合抗原受体（CD 19 CAR）的T细胞。 这些发现确立了我们假设的前提，即设计和开发 具有有效的肿瘤细胞生长抑制和免疫刺激作用的新型舒林酸衍生物 通过靶向PDE 5和/或PDE 10的活性。我们研究的目的是确定 以及舒林酸及其非COX衍生物调节和 免疫原性肿瘤微环境。具体来说，我们将确定舒林酸和非- 考克斯抑制衍生物诱导癌症免疫原性细胞死亡，减轻Treg和MDSC- 介导的免疫抑制，并通过对涉及ER的肿瘤细胞的作用激活树突状细胞 应激诱导和致癌β-连环蛋白的抑制，我们假设这是由 PDE 5/10抑制（目的1）。我们将测试舒林酸和非COX抑制剂的有效性， 在增强癌症免疫治疗（包括PD 1）中抑制PDE 5和/或PDE 10的衍生物 阻断和过继性T细胞治疗在多个临床前模型（目的2）。所了解的情况 目标1和目标2中的三个目标将被纳入合成化学活动，以开发新的舒林酸 通过直接抑制肿瘤细胞生长和通过 间接激活抗肿瘤免疫，而没有与考克斯抑制相关的毒性（目的 3）。该项目的成功完成将为开发新型舒林酸铺平道路 在癌症免疫治疗的竞技场中作为癌症治疗的免疫调节剂的衍生物。

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.