Novel treatment strategies for enhancing sunitinib response in renal cell cancer

增强肾细胞癌舒尼替尼反应的新治疗策略

基本信息

批准号：
8524387
负责人：
TOWIA A. LIBERMANN
金额：
$ 22.71万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-15 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8524387
关键词：
Angiogenesis Inhibitors Angiogenic Factor Animal Cancer Model Animal Experiments Animals Apoptotic Binding Cancer cell line Caring Cell Line Cessation of life Clear Cell Clinical Clinical Trials Combined Modality Therapy Companions Computer Simulation Data Databases Death Rate Diagnostic Down-Regulation Drug effect disorder Endothelin-1 FDA approved Gene Expression Gene Expression Profile Genes Human Hypoxia IL8 gene In Vitro Incidence Interferons Intervention Malignant Epithelial Cell Malignant Neoplasms Maps Mediating Metastatic Renal Cell Cancer Molecular Molecular Profiling Neoplasm Metastasis Oncogenic Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Progression-Free Survivals Property Proteins Protocols documentation Relative (related person)Renal Cell Carcinoma Resistance Staging Systems Biology Testing Therapeutic Tumor Suppressor Proteins VEGFA gene Vascularization Xenograft Model Xenograft procedure angiogenesis base cancer therapy combinatorial drug candidate in vivo novel pre-clinical prevent public health relevance research clinical testing response small molecule standard of care terazosine treatment response treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): While there has been significant progress in management of early stages of clear cell renal cell carcinoma (RCC), metastatic RCC has few effective therapeutic strategies available and a death rate close to the incidence. Targeted therapies, particularly angiogenesis inhibitors such as sunitinib, have shown efficacy against metastatic RCC. Nonetheless, sunitinib treatment invariably leads to resistance, necessitating novel, more efficacious therapies. We have taken advantage of the Connectivity Map (C-Map) database, a compendium of gene expression profiles of cancer cell lines treated with a spectrum of small molecules, to test our hypothesis that drugs that elicit gene signatures most opposed to sunitinib resistance are likely to overcome, delay or prevent resistance to sunitinib in RCC. Transcriptome analysis of RCC xenografts treated with sunitinib enabled us to generate a sunitinib resistance gene signature that was applied to the C-Map database, resulting in identification of a ranking list of drugs anticipated to reverse most prominently the hypoxia-driven pro-angiogenic sunitinib resistance gene signature. We demonstrated that three of the highest ranking, FDA-approved candidate drugs, maprotiline, terazosin and clemastine, indeed reverse the sunitinib resistance gene signature in RCC cells, including various genes involved in angiogenesis. In order to move an actionable drug closer to a clinical trial we will, therefore, perform a preclinical assessment of the most promising drug, maprotiline, to prevent, delay or overcome sunitinib resistance in RCC xenografts, and determine predictors of therapeutic response as companion diagnostics and pharmacodynamics markers. Detailed mechanistic analysis of anti-RCC action for maprotiline will determine whether maprotiline-mediated suppression of pro-angiogenic factors is critical for reversing escape from sunitinib response, and whether maprotiline-mediated direct anti-oncogenic efficacy against RCC is a consequence of downregulation of miR- 21 and enhanced expression of pro-apoptotic genes. In Specific Aim 1 we will determine predictors of therapeutic response and the molecular mechanisms of anti-RCC action for maprotiline. In Specific Aim 2 preclinical in vivo assessment of maprotiline will determine whether maprotiline is able to prevent, delay or overcome sunitinib resistance. Our proof-of-concept data demonstrate that our strategy enables rapid discovery of new anti-cancer properties for drugs not typically used in cancer treatment. The demonstration of anti-tumor efficacy in small animal cancer models is a key bridge from in vitro studies to human clinical testing. In particular, if a drug is already approved for another indication, proceeding with clinical testing might require only a compelling in vitro storyline supported by a limited number o animal studies demonstrating in vivo anti-tumor efficacy. Since maprotiline is FDA-approved, clinical trials combining standard of care sunitinib with maprotiline could be rapidly initiated upn successful completion of the animal experiments.

描述（由申请人提供）：虽然在透明细胞肾细胞癌（RCC）早期阶段的治疗方面取得了显着进展，但转移性肾细胞癌几乎没有可用的有效治疗策略，并且死亡率接近发病率。靶向治疗，特别是舒尼替尼等血管生成抑制剂，已显示出对抗转移性肾细胞癌的功效。尽管如此，舒尼替尼治疗总是会导致耐药性，因此需要新的、更有效的疗法。我们利用连接图谱 (C-Map) 数据库（用一系列小分子处理的癌细胞系的基因表达谱概要）来检验我们的假设，即引发与舒尼替尼耐药性最相反的基因特征的药物很可能克服、延迟或预防对舒尼替尼的耐药性碾压混凝土。对用舒尼替尼治疗的肾细胞癌异种移植物进行转录组分析，使我们能够生成舒尼替尼耐药基因特征，并将其应用于 C-Map 数据库，从而确定了预计最显着逆转缺氧驱动的促血管生成舒尼替尼耐药的药物排名列表基因签名。我们证明，FDA 批准的三种排名最高的候选药物马普替林、特拉唑嗪和氯马斯汀确实可以逆转 RCC 细胞中的舒尼替尼耐药基因特征，包括参与血管生成的各种基因。因此，为了使可操作的药物更接近临床试验，我们将对最有前途的药物马普替林进行临床前评估，以预防、延迟或克服肾细胞癌异种移植物中的舒尼替尼耐药性，并确定治疗反应的预测因子作为伴随诊断和药效学标志物。马普替林抗 RCC 作用的详细机制分析将确定马普替林介导的促血管生成因子抑制是否对于逆转舒尼替尼反应的逃逸至关重要，以及马普替林介导的直接抗 RCC 功效是否是 miR 下调的结果- 21 并增强促凋亡基因的表达。在具体目标 1 中，我们将确定马普替林治疗反应的预测因子和抗 RCC 作用的分子机制。在具体目标 2 中，马普替林的临床前体内评估将确定马普替林是否能够预防、延迟或克服舒尼替尼耐药性。我们的概念验证数据表明，我们的策略能够快速发现通常不用于癌症治疗的药物的新抗癌特性。在小动物癌症模型中证明抗肿瘤功效是从体外研究到人体临床测试的关键桥梁。特别是，如果一种药物已经被批准用于另一种适应症，则进行临床测试可能只需要一个引人注目的体外故事情节，并由有限数量的动物研究证明体内抗肿瘤功效。由于马普替林已获得 FDA 批准，因此在成功完成动物实验后，可以迅速启动舒尼替尼标准护理与马普替林相结合的临床试验。