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)治疗的上一次重大进展发生在1997年，当时 吉西他滨的问世。尽管有这样的进展，内脏转移通常是致命的。该计划的总体目标 拟议的研究是开发小分子抑制剂来阻断转移过程中的一个关键节点。 我们发现RAI GTP酶是治疗上易处理的信号通路的分子开关。 这使得UC细胞可以在肺内生长，肺是最常见的内脏转移部位。临床意义的探讨 Rai作为治疗靶点的有效性和这一途径的研究得到了支持，因为在 肿瘤使患者有更高的转移风险和对肺组织RAI表达的要求 在UC的动物模型中发生转移。我们对这一应用的指导性假设是 靶向RAI的分子为转移性UC提供了有效的治疗方法。在MD Anderson的支持下 膀胱孢子发育研究计划(DRP)，我们评估了&gt；500K化合物的能力 在计算和组合屏幕上绑定Rala或RalB，并选择99个“命中”。这些都是 在一系列二次化验中进行评估，使我们能够选择RAI结合化合物(RUC)8和10作为 在此应用程序中继续执行。选择RUC8和RUC10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 人UC细胞生长(IC_(50)0.5-1.9 PM)；3)核磁共振直接结合RalB 在小鼠体内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)。为了开发这类新的代理，我们提出了以下具体目标：目标1：表征 基于RUC8和10的更高效力的2“^*代化合物，使用药物化学，计算 基于片段的设计和化学数据库的相似性搜索。在这种不太可能的情况下 在目标1中没有发现有效化合物，我们将使用RUC8和10来实现目标2和目标3，因为它们 足够的IC50和体内PK。目的2：评价两种“”代化合物的体内治疗作用 新型人类UC内脏转移模型的疗效。目标3：开发可预测的生物标志物 在人体组织中对抗病毒治疗的反应，这将使我们在本期结束前进入第一阶段试验 项目。Astra Zeneca记录的对我们工作的兴趣提高了在 将我们的新型RAI抑制剂转化为临床抗癌治疗药物。