Novel treatment strategies for enhancing sunitinib response in renal cell cancer

描述（由申请人提供）：虽然在透明细胞肾细胞癌（RCC）早期阶段的管理方面取得了重大进展，但转移性RCC几乎没有有效的治疗策略，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，已显示出对转移性RCC的疗效。 尽管如此，舒尼替尼治疗总是导致耐药性，需要新的，更有效的治疗。 我们利用连接图（C-Map）数据库，一个用一系列小分子处理的癌细胞系的基因表达谱的概要，来测试我们的假设，即引发最反对舒尼替尼耐药的基因签名的药物可能克服，延迟或预防对舒尼替尼的耐药性。 RCC。 用舒尼替尼治疗的RCC异种移植物的转录组分析使我们能够产生应用于C-Map数据库的舒尼替尼抗性基因签名，从而鉴定出预期最显著地逆转缺氧驱动的促血管生成舒尼替尼抗性基因签名的药物的排名列表。 我们证明了FDA批准的候选药物马普替林、特拉唑嗪和氯马斯汀中排名最高的三种确实逆转了RCC细胞中舒尼替尼耐药基因的特征，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RCC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。 对马普替林抗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逆转舒尼替尼反应逃逸至关重要，以及马普替林介导的对RCC的直接抗癌疗效是否是miR- 21下调和促凋亡基因表达增强的结果。 在具体目标1中，我们将确定治疗反应的预测因子和马普替林抗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，进行临床试验可能只需要一个令人信服的体外故事情节，并得到有限数量的动物研究的支持，证明体内抗肿瘤疗效。 由于马普替林是FDA批准的，因此在成功完成动物实验后，可以快速启动舒尼替尼与马普替林联合标准治疗的临床试验。

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.