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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：
8651433
负责人：
TOWIA A. LIBERMANN
金额：
$ 18.35万
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 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8651433
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）：尽管在透明细胞肾细胞癌（RCC）的早期治疗方面取得了重大进展，但转移性肾细胞癌的有效治疗策略很少，死亡率接近发病率。靶向治疗，特别是血管生成抑制剂如舒尼替尼，已经显示出对转移性RCC的疗效。然而，舒尼替尼治疗总是会导致耐药性，因此需要新的、更有效的治疗方法。我们利用了连接图（C-Map）数据库，这是一个用小分子谱处理的癌细胞系基因表达谱的概要，来验证我们的假设，即引发最反对舒尼替尼耐药性的基因特征的药物可能会克服、延迟或阻止对舒尼替尼的耐药性