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

项目总结 R-酮咯酸Rho家族GTP酶新药理实体的化学信息学鉴定 卵巢癌的抑制活性激发了一个两级验证策略。临床前和体外试验 将评估FDA批准的、临床使用的酮咯酸用于卵巢癌和卵巢癌的新用途 R-酮咯酸申请新药调查。Rho家族GTP酶(Rac、Rho和CDC42)统称为 控制细胞的增殖、黏附和迁移，作为功能性治疗靶点具有重要意义 大量的上皮性癌症。含有药物的-羧酸盐的虚拟药物筛选首次预测了R- 批准的药物[R，S]-酮咯酸的对映体作为一种高价值、临床相关的GTP酶抑制剂。在.之前 我们的工作是，S对映体被认为是外消旋药物配方中唯一有效的成分， 针对环氧合酶(COX)的选择性活性，用于减轻炎症和急性疼痛。GTP酶活性 测定结果表明，R-酮咯酸是鸟嘌呤核苷酸结合的变构抑制剂，而 酮咯酸对映体S对GTP酶几乎没有活性。在基于细胞的分析中，R-酮咯酸阻断 Rac1和CDc42激活、肌动蛋白重塑与下游细胞黏附、迁移和侵袭 卵巢癌细胞株。我们的回溯性研究表明，人类的功效得到了支持 显著的生存益处和我们的预期0期试验。[R，S]-酮咯酸给药，有良好的 药代动力学分布，降低GTPase活性，并抑制与侵袭和 患者肿瘤细胞的转移。根据我们全面公布的数据，我们假设 [R，S]-酮咯酸的再利用和R-酮咯酸作为研究新药的开发将最小化 通过抑制rac1和CDc42依赖的肿瘤转移和减少对卵巢癌的保护来实现卵巢癌的复发 专门的利基市场，以增加对化疗的脆弱性。一系列的三个目标将验证1)好处 在异种移植肿瘤复发动物模型中酮咯酸在降低肿瘤复发中的作用，2)影响 酮咯酸通过体外器官表型和生物反应器培养最大限度地减少肿瘤细胞与壁龛的相互作用，以及 3)酮咯酸/卵巢癌作为可预测的治疗/适应症组合。这些研究将告诉我们“开始与不开始”。 卵巢内单独应用[R，S]酮咯酸和R-酮咯酸2a期临床试验的决策 癌症患者。这些研究的另一个结果将是增强提交FDA的准备 R-酮咯酸作为克服毒副作用的卵巢癌新疗法的研究新药申请 以及与外消旋药物相关的限制。

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.