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

卡博替尼治疗转移性肾细胞癌的组织预测生物标志物

• 批准号: 10084285
• 负责人: Toni Choueiri
• 金额: $ 23.95万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-10 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084285
• 关键词: Adverse event; Applications Grants; Area; Biological Markers; Clear Cell; Clear cell renal cell carcinoma; Clinical; Clinical Trials; Complex; Cytokine Signaling; Data; Databases; Development; Disease; Drug Targeting; Endothelial Growth Factors Receptor; FDA approved; FRAP1 gene; Gene Mutation; Genes; Genetic Transcription; Grant; Hand; Histologic; Hypoxia; Hypoxia Inducible Factor; Immune; Immune checkpoint inhibitor; International; KDR gene; Lead; Metastatic Renal Cell Cancer; Molecular; Mutation; Neoplasms in Vascular Tissue; Outcome; Pathway interactions; Patient Care; Patients; Phase; Phase III Clinical Trials; Positioning Attribute; Prediction of Response to Therapy; Predictive Value; Progression-Free Survivals; Protein Tyrosine Kinase; Randomized; Renal Cell Carcinoma; Resistance; Retrospective Studies; SDZ RAD; Selection for Treatments; Signal Transduction; Somatic Mutation; Specimen; Systemic Therapy; TNFSF15 gene; Testing; Therapeutic; Tissues; Toxic effect; Tumor Suppressor Genes; Tumor Tissue; Up-Regulation; Vascular Endothelial Growth Factors; Vegf Inhibitor; angiogenesis; base; bevacizumab; candidate marker; clinical biomarkers; clinical development; clinical predictors; cost; disorder risk; genetic signature; hazard; immune checkpoint; immunoregulation; improved; inhibitor/antagonist; objective response rate; patient population; patient subsets; phase III trial; predictive marker; primary endpoint; prospective; response; response biomarker; small molecule inhibitor; targeted treatment; transcription factor; trial comparing; tumor; tumor microenvironment; tumor-immune system interactions; ubiquitin ligase

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.

项目总结/摘要 多种全身疗法在治疗转移性肾细胞癌（mRCC）中是有效的，并且靶点是 几种不同的分子途径，包括血管内皮生长因子（VEGF）信号传导，免疫 检查点、细胞因子信号传导和雷帕霉素（mTOR）通路的机制靶点。然而，少于 一半的患者对任何一种特定的治疗都有反应， 不清楚因此，在mRCC患者的护理中迫切需要的领域是开发稳健的免疫抑制剂。 这些生物标志物可预测治疗反应。血管内皮生长因子受体（VEGFR）的小分子抑制剂 在过去的十年中，卡博替尼一直是mRCC患者最首选的一线治疗， VEGFR、MET和AXL的多激酶抑制剂最近被监管机构批准作为一线治疗。 我们小组和其他人的初步研究表明，透明细胞RCC（ccRCC）肿瘤的特征是 血管生成相关基因的高水平表达和/或在特定基因中携带体细胞突变 (i.e. PBRM 1）可能更依赖于VEGF信号传导，因此可能更好地响应VEGF靶向的 治疗此外，由于肿瘤相关的血管生成可以促进免疫抑制性免疫抑制。 已知卡博替尼具有免疫调节作用，我们预计， 肿瘤微环境中特异性免疫途径的激活可能与免疫应答相关， 抵抗这种药物。 在本申请中，我们提出通过以下方式评估对卡博替尼的响应的候选预测性生物标志物： 利用来自在本研究中治疗的转移性ccRCC（mccRCC）患者的治疗前肿瘤标本， 比较卡博替尼与mTOR抑制剂依维莫司的随机III期METEOR临床试验。 具体来说，我们将检验血管生成相关基因的表达预测临床预后的假设。 对卡博替尼的响应（目标1）。我们还将评估肿瘤遗传改变作为临床诊断的预测生物标志物。 对卡博替尼的反应（目的2）。最后，我们将探索免疫途径激活的基因特征， 可能与对卡博替尼的应答或抗性有关（目的3）。 拟议的前瞻性-回顾性研究为临床开发提供了一个独特的机会， 有用的生物标志物，可以显着改善mRCC患者的治疗。