Tissue-based predictive biomarkers for Cabozantinib therapy in metastatic renal cell carcinoma

项目摘要/摘要 转移性肾细胞癌的多系统治疗及其靶点 几种不同的分子通路，包括血管内皮生长因子(VEGF)信号转导，免疫 检查点、细胞因子信号转导和雷帕霉素(MTOR)途径的机制靶点。然而，少于 一半的患者对任何一种特定的治疗都会有反应，治疗的最佳顺序仍然是 不清楚。因此，在护理肾细胞癌患者中迫切需要的一个领域是发展健壮的 预测治疗反应的生物标志物。血管内皮生长因子受体小分子抑制物 在过去十年中一直是mRCC患者最首选的一线治疗方法，而卡波赞替尼是一种 VEGFR、MET和AXL的多激酶抑制剂最近被批准为一线治疗。 我们小组和其他人的初步研究表明，透明细胞肾癌(CcRCC)的特征是 血管生成相关基因的高水平表达和/或特定基因的体细胞突变 (即PBRM1)可能更依赖于VEGF信号，因此可能对VEGFR靶向做出更好的反应 治疗。此外，由于肿瘤相关的血管生成可能促进免疫抑制 微环境和卡波赞替尼已知具有免疫调节作用，我们预计 肿瘤微环境中特定免疫通路的激活可能与反应或 对这种毒剂的抵抗力。 在这项应用中，我们建议通过以下方法来评估候选预测生物标记物对卡波赞替尼的反应 利用经治疗的转移性肾细胞癌患者的治疗前肿瘤标本 随机III期流星临床试验，比较卡波赞替尼和mTOR抑制剂依维莫司。 具体地说，我们将检验血管生成相关基因的表达可以预测临床的假设。 对卡波赞替尼的反应(目标1)。我们还将评估肿瘤基因改变作为临床预测生物标记物 对卡波赞替尼的反应(目标2)。最后，我们将探索激活免疫通路的基因特征 可能与对卡波赞替尼的反应或耐药性有关(目标3)。 拟议的前瞻性-回溯性研究为临床的发展提供了一个独特的机会。 有用的生物标志物，可以显著改善mRCC患者的治疗。

PROJECT SUMMARY/ABSTRACT Multiple systemic therapies are effective in the treatment of metastatic renal cell carcinoma (mRCC) and target several distinct molecular pathways, including vascular endothelial growth factor (VEGF) signaling, immune checkpoints, cytokine signaling, and the mechanistic target of rapamycin (mTOR) pathway. However, fewer than half of patients will respond to any one particular therapy, and the optimal sequencing of treatment remains unclear. Therefore, an area of urgent need in the care of patients with mRCC is the development of robust biomarkers that are predictive of treatment response. Small molecule inhibitors of VEGF receptors (VEGFR) have been the most preferred first-line treatment for mRCC patients for the past decade, and cabozantinib, a multi-kinase inhibitor of VEGFR, MET, and AXL was recently granted regulatory approval as frontline treatment. Preliminary studies from our group and others suggest that clear cell RCC (ccRCC) tumors characterized by high levels of expression of angiogenesis-associated genes and/or harboring somatic mutations in specific genes (i.e. PBRM1) may be more dependent on VEGF signaling and thus might better respond to VEGFR-targeted therapies. In addition, since tumor-associated angiogenesis may promote an immunosuppressive microenvironment and cabozantinib is known to have immuno-modulatory effects, we anticipate that the activation of specific immune pathways in the tumor microenvironment might be associated with response or resistance to this agent. In this application, we propose to assess candidate predictive biomarkers for response to cabozantinib by utilizing pre-treatment tumor specimens from patients with metastatic ccRCC (mccRCC) treated in the randomized phase III METEOR clinical trial that compared cabozantinib to the mTOR inhibitor everolimus. Specifically, we will test the hypothesis that expression of angiogenesis-associated genes is predictive of clinical response to cabozantinib (Aim 1). We will also assess tumor genetic alterations as predictive biomarker of clinical response to cabozantinib (Aim 2). Finally, we will explore gene signatures of immune pathways activation that might be associated with response or resistance to cabozantinib (Aim 3). The proposed prospective-retrospective study represents a unique opportunity for the development of clinically useful biomarkers that can significantly improve the treatment of patients with mRCC.