Targeting Ral GTPases in Bladder Cancer

靶向 Ral GTP 酶治疗膀胱癌

基本信息

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
项目类别：
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

项目摘要

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.

1997年，转移性膀胱癌（BC）治疗转移性膀胱癌（BC）的最后一个重大进展与吉西他滨的出现。尽管有这一进步，但内脏转移通常是致命的。总体目标拟议的研究是开发小分子抑制剂，该抑制剂阻止转移过程中的临界节点。我们发现RAI GTPases充当可治疗障碍信号通路的分子开关这使UC细胞可以在肺部生长，这是最常见的内脏转移部位。临床意义通过发现高RAI在肿瘤使患者处于转移的风险较高，RAI表达的肺部转移发生在UC的动物模型中。我们对此应用的指导假设是很小的靶向RAI的分子为转移性UC提供有效的治疗。在MD Anderson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屏幕中结合Rala或Ralb，并选择99个“命中”。这些是在一系列辅助测定中评估，使我们能够选择RAI结合化合物（RUC）8和10为在本申请中追求。选择RUC8和10是因为它们：1）抑制Rala对Ralbpi的结合人UC细胞和Rala诱导的鼠类胚胎成纤维细胞传播； 2）抑制体外单层人类UC细胞的生长（IC50 0.5-1.9 pm）； 3）直接通过核磁共振（NMR）结合拉尔布光谱；和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 HRS）。为了开发这种新颖的代理类，我们提出以下特定目的：目标1：表征使用药物化学，计算基于碎片的设计以及化学数据库的相似性搜索。在不太可能的情况下在AIM 1中找不到效能化合物，我们将使用RUC8和10追求AIM 2和3 足够的IC50和体内PK。 AIM 2：评估2“”的生成化合物的体内治疗内脏转移的新型人类UC模型的功效。目标3：开发的预测生物标志物对人类组织中的Antlral Therapeutics的反应，该疗法将在此之前将我们定位为1阶段试验项目。 Astra Zeneca对我们的工作的兴趣提高了成功的总体机会将我们的新型RAI抑制剂转化为临床环境，作为抗癌治疗剂。