Ketorolac and Related NSAIDs for Targeting Rho-family GTPases in Ovarian Cancer

酮咯酸和相关 NSAID 靶向治疗卵巢癌中的 Rho 家族 GTP 酶

基本信息

批准号：
9205393
负责人：
Angela Wandinger-Ness
金额：
$ 30.3万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9205393
关键词：
Actins Acute Pain Adhesions Animal Model Animal Testing Animals Behavior Binding Biological Assay Bioreactors Breast Cancer Patient Cancer Patient Cancer Relapse Cancer cell line Cell Adhesion Cell Proliferation Cells Clinical Trials Data Data Element Decision Making Development Disease Drug Formulations Drug Kinetics Epithelial Evaluation FDA approved Family Genes Guanine Nucleotides Guanosine Triphosphate Phosphohydrolases Hour Human Individual Inflammation Informatics Injection of therapeutic agent Intraperitoneal Injections Investigational Drugs Ketorolac Malignant Neoplasms Malignant neoplasm of ovary Measurement Mining Modeling Monitor Mus Neoplasm Metastasis Non-Steroidal Anti-Inflammatory Agents Nude Mice Ontology Outcome Outcome Measure Outcome Study Ovarian Pain Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phase Phase II Clinical Trials Placebos Population Preclinical Drug Evaluation Prostaglandin-Endoperoxide Synthase Publishing Readiness Recurrence Relapse Retrospective Studies Series Shelter facility Testing Therapeutic Time Toxic effect Tumor Burden Validation Work Xenograft Model Xenograft procedure base cancer stem cell cancer therapy cancer type carboxylate cheminformatics chemotherapy clinically relevant comparative enantiomer human disease implantation improved inhibitor/antagonist interest migration mouse model neoplastic cell novel novel therapeutics ovarian neoplasm overexpression pre-clinical prospective research study rho rho GTP-Binding Proteins species difference stem cell niche therapeutic target tool tumor tumor growth tumor xenograft virtual

项目摘要

PROJECT SUMMARY Cheminformatics identification of R-ketorolac as a novel pharmacologic entity with Rho-family GTPase inhibitory activity for ovarian cancer motivates a two-tiered validation strategy. Preclinical and ex vivo testing will evaluate repurposed new use of the FDA approved, clinically used [R,S]-ketorolac for ovarian cancer and R-ketorolac for an Investigational New Drug filing. Rho family GTPases (Rac, Rho and Cdc42) collectively control cell proliferation, adhesion and migration and are of interest as functional therapeutic targets in numerous epithelial cancers. A virtual drug screen of -carboxylate containing drugs first predicted the R- enantiomer of the approved drug [R,S]-ketorolac as a high value, clinically relevant GTPase inhibitor. Prior to our work, the S-enantiomer was considered the sole active component in the racemic drug formulations, with selective activity against cyclooxygenases (COX) for mitigating inflammation and acute pain. GTPase activity measurements demonstrate that R-ketorolac is an allosteric inhibitor of guanine nucleotide binding, while the S-enantiomer of ketorolac shows little to no activity against GTPases. In cell-based assays, R-ketorolac blocks Rac1 and Cdc42 activation, actin remodeling and downstream cell adhesion, migration and invasion of human ovarian cancer cell lines. Human efficacy is supported by both our retrospective study demonstrating significant survival benefit and our prospective Phase 0 trial. [R,S]-ketorolac administration, has favorable pharmacokinetic distribution, reduces GTPase activities, and inhibits behaviors associated with invasion and metastasis in patient tumor cells. Based on our comprehensive published data, we hypothesize that repurposing [R,S]-ketorolac and development of R-ketorolac as an Investigational New Drug will minimize ovarian cancer relapse by inhibiting Rac1 and Cdc42 dependent tumor metastasis, and reducing protection in specialized niches to increase vulnerability to chemotherapy. A series of three aims will validate 1) the benefit of ketorolac in reducing tumor relapse using an animal xenograft model of tumor recurrence, 2) the impact of ketorolac on minimizing tumor cell-niche interactions through ex vivo organotypic and bioreactor cultures, and 3) ketorolac/ovarian cancer as a predicted therapeutic/ indication pair. These studies will inform `Go vs. No Go' decision-making for Phase 2a clinical trial implementation of [R,S] ketorolac and R-ketorolac alone in ovarian cancer patients. An additional outcome of the studies will be to enhance readiness to submit an FDA Investigational New Drug filing for R-ketorolac as a new therapy for ovarian cancer to overcome the toxicities and limitations associated with racemic drug.

项目摘要 R-Ketorolac的化学信息学鉴定是一种新型药物实体，该实体具有Rho-family GTPase 卵巢癌的抑制活性激发了两层验证策略。临床前和体内测试将评估重新利用的FDA批准的，临床使用的[R，S] - 酮科的卵巢癌和 R-Ketorolac用于调查新药归档。 Rho Family GTPases（RAC，RHO和CDC42）统称控制细胞的扩散，广告和迁移，并作为功能性治疗靶点感兴趣许多上皮癌。含有药物的-羧酸酯的虚拟药物筛选首先预测了R- 批准的药物[R，S] -Ketorolac的对映异构体是高价值，临床相关的GTPase抑制剂。之前我们的工作，S-Enantiomer被认为是外围药物配方中的唯一活性成分，并具有针对环氧酶（COX）的选择性活性，以减轻注射和急性疼痛。 GTPase活性测量表明，R-Ketorolac是一种鸟嘌呤核苷结合的变构抑制剂，而是酮洛拉克的S-替代体对GTPase的活性几乎没有活性。在基于细胞的测定中，R-Ketorolac块 Rac1和Cdc42激活，肌动蛋白重塑和下游细胞粘附，迁移和侵袭人卵巢癌细胞系。我们的回顾性研究证明了人类效率显着的生存益处和我们的前瞻性0阶段试验。 [r，s] - 酮科管理，有利药代动力学分布，减少GTPase活性，并抑制与入侵和患者肿瘤细胞中的转移。根据我们全面发布的数据，我们假设重新利用[R，S] -Ketorolac和R-Ketorolac作为研究的新药的开发将最小化通过抑制RAC1和CDC42依赖性肿瘤转移来缓解卵巢癌，并减少保护专门的利基市场可以增加化学疗法的脆弱性。一系列三个目标将验证1）使用肿瘤复发的动物特征模型减少酮洛拉克拉克的肿瘤缓解，2） Ketorolac通过体内有机和生物反应器培养物最大程度地减少肿瘤细胞细胞的相互作用，以及 3）酮洛拉克/卵巢癌作为预测的治疗/适应性对。这些研究将告知“去vs. no go' 仅在卵巢中[R，S] Ketorolac和R-Ketorolac的2A期临床试验实施决策癌症患者。研究的另一个结果将是提高提交FDA的准备 R-Ketorolac的调查新药物提交作为卵巢癌的新疗法，以克服毒性和与外消毒药物有关的局限性。