Targeting Ral GTPases in Bladder Cancer

靶向 Ral GTP 酶治疗膀胱癌

• 批准号: 8230255
• 负责人: DAVID ROSS
• 金额: $ 20.32万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230255
• 关键词: Affinity; Allosteric Site; Animal Model; Binding; Binding Sites; Biological Assay; Biological Markers; Bladder; Cancer cell line; Cells; Chemicals; Clinical; Complement; Computer Simulation; Databases; Development; Disease; Docking; Drug Kinetics; Embryo; Enzyme-Linked Immunosorbent Assay; Evaluation; Fibroblasts; Funding; Gene Expression Profile; Generations; Goals; Growth; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Human; Immunohistochemistry; In Vitro; Inhibitory Concentration 50; Instruction; Libraries; Lung; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Measures; Mediating; Metastatic Neoplasm to the Lung; Modeling; Molecular; Molecular Conformation; Molecular Target; Mus; NMR Spectroscopy; Neoplasm Metastasis; Nuclear Magnetic Resonance; Nucleotides; Pathway interactions; Patients; Pharmaceutical Chemistry; Phase I Clinical Trials; Positioning Attribute; Process; Progression-Free Survivals; Property; Proteins; Radical Cystectomy; Research; Screening procedure; Series; Signal Pathway; Site; Solid; Structure; Therapeutic; Transitional Cell Carcinoma; Translating; Translations; Treatment Efficacy; Urogenital Cancer; Visceral; Work; Xenograft Model; anti-cancer therapeutic; base; cancer cell; cancer type; clinically significant; combinatorial; design; effective therapy; efficacy evaluation; gemcitabine; high risk; human tissue; improved; in vivo; inhibitor/antagonist; interest; member; metastatic process; monolayer; novel; paralogous gene; preclinical evaluation; programs; response; small molecule; success; therapeutic target; three-dimensional modeling; tumor

The last major advance in the treatment of metastatic bladder cancer (BC) took place in 1997 with the advent of gemcitabine. Despite this advance, visceral metastases are usually fatal. The overall goal of the proposed studies is to develop small molecule inhibitors that block a critical node in the metastatic process. We found that Rai GTPases serve as the molecular switches of a therapeutically tractable signaling pathway that allows UC cells to grow in the lung, the most common visceral metastatic site. The clinical significance of this pathway and validity of Rai as a therapeutic target is supported by finding that high Rai expression in tumors places patients at higher risk for metastasis and the requirement of Rai expression for lung metastasis to occur in animal models of UC. Our Guiding Hypothesis for this application is that small molecules targeting Rai provide effective therapy for metastatic UC. With support from the MD Anderson Bladder SPORE Developmental Research Program (DRP), we evaluated >500K compounds for their ability to bind RalA or RalB in computational and combinatorial screens and selected 99 "hits". These were evaluated in a series of secondary assays allowing us to select Rai Binding Compound (RUC)8 and 10 to be pursued in this application. RUC8 and 10 were selected because they: 1) inhibit RalA to RalBPI binding in human UC cells and RalA induced spreading in murine embryo fibroblasts; 2) inhibit in vitro monolayer growth (IC50 0.5-1.9 pM) of human UC cells; 3) bind RalB directly by nuclear magnetic resonance (NMR) spectroscopy; and 4) have good pharmacokinetic (PK) properties in mice (Cmax 1.3-23 pM, T1/2 3.7-4.6 hrs). To develop this novel class of agents we propose the following Specific Aims: Aim 1: Characterize higher potency 2"^* generation compounds based on RUC8 and 10 using medicinal chemistry, computational fragment-based design, and similarity search of chemical databases. In the unlikely situation that higher potency compounds are not found in Aim 1, we will pursue Aim 2 and 3 using RUC8 and 10, given their adequate IC50 and in vivo PK. Aim 2: Evaluate 2"" generation compounds for their in vivo therapeutic efficacy in novel human UC models of visceral metastasis. Aim 3: Develop predictive biomarkers of response to antlRal therapeutics in human tissues that will position us for Phase 1 trials by end of this project. Documented interest by Astra Zeneca in our work improves overall chances for success in translating our novel Rai inhibitors into the clinical setting as anticancer therapeutics.

转移性膀胱癌 (BC) 治疗的最后一次重大进展发生在 1997 年， 吉西他滨的问世。尽管取得了这一进展，但内脏转移通常是致命的。该项目的总体目标是 拟议的研究是开发小分子抑制剂，阻断转移过程中的关键节点。 我们发现 Rai GTPases 作为治疗上易于处理的信号通路的分子开关 这使得UC细胞能够在肺部（最常见的内脏转移部位）中生长。临床意义 通过发现 Rai 在 肿瘤使患者面临更高的转移风险，并且肺部需要 Rai 表达 UC动物模型中发生转移。我们对此应用的指导假设是小 靶向 Rai 的分子为转移性 UC 提供有效的治疗。在 MD 安德森的支持下 膀胱孢子发育研究计划 (DRP)，我们评估了 > 500K 化合物的能力 在计算和组合筛选中结合 RalA 或 RalB 并选择 99 个“命中”。这些是 在一系列二次测定中进行评估，使我们能够选择 Rai 结合化合物 (RUC)8 和 10 本申请中所追求的。选择 RUC8 和 10 是因为它们：1) 抑制 RalA 与 RalBPI 的结合 人UC细胞和RalA诱导小鼠胚胎成纤维细胞扩散； 2) 体外抑制单层细胞 人UC细胞的生长（IC50 0.5-1.9 pM）； 3)通过核磁共振(NMR)直接结合RalB 光谱学； 4) 在小鼠中具有良好的药代动力学 (PK) 特性（Cmax 1.3-23 pM，T1/2 3.7-4.6 小时）。为了开发此类新型药物，我们提出以下具体目标： 目标 1：表征 基于 RUC8 和 10 使用药物化学、计算的更高效力 2"^* 代化合物 基于片段的设计和化学数据库的相似性搜索。在不太可能的情况下，更高 目标 1 中未发现有效化合物，我们将使用 RUC8 和 10 来实现目标 2 和 3，因为它们 足够的 IC50 和体内 PK。目标 2：评估第二代化合物的体内治疗作用 在新型人类UC内脏转移模型中的疗效。目标 3：开发预测生物标志物 对人体组织中的抗肿瘤疗法的反应将使我们能够在今年年底前进行第一阶段试验 项目。阿斯利康 (Astra Zeneca) 对我们工作的兴趣可提高整体成功机会 将我们的新型 Rai 抑制剂作为抗癌疗法应用于临床。