Exploration of Novel Mutation Biomarkers to Repurpose EGFRi for Mutant KRAS Colorectal Cancer

探索新的突变生物标志物，将 EGFRi 重新用于突变 KRAS 结直肠癌

• 批准号: 10199678
• 负责人: Vaia Florou
• 金额: $ 22.18万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10199678
• 关键词: BRAF gene; Bar Codes; Biological Assay; Biological Markers; Blood; Caring; Cetuximab; Clinical; Clinical Data; Clinical Trials; Clinical assessments; Colon; Colorectal Cancer; Cyclophosphamide; DNA; DNA sequencing; Data; Disease Progression; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Evaluation; FDA approved; Future; Gene Expression; Gene Expression Profile; Genes; Genotype; KRAS2 gene; Label; Laboratories; Lead; Leadership; Left; Link; Measures; Methodology; Molecular; Monitor; Mutation; Neoplasm Metastasis; Outcome; Patients; Pharmaceutical Preparations; Phase; Prognosis; Progression-Free Survivals; Reporting; Residual Neoplasm; Resistance; Role; Side; Signal Transduction; Southwest Oncology Group; TP53 gene; Testing; The Cancer Genome Atlas; Therapeutic; Tissues; Tumor Suppressor Genes; base; clinical practice; cohort; colon cancer patients; cost effective; design; ds-DNA; effective therapy; improved; innovation; insertion/deletion mutation; metastatic colorectal; molecular subtypes; mutant; novel; novel strategies; panitumumab; personalized medicine; pre-clinical; predictive test; primary endpoint; prospective; randomized trial; response; secondary endpoint; standard of care; success; therapeutic target; tumor

PROJECT SUMMARY/ABSTRACT Metastatic colorectal cancer (CRC) has very poor prognosis with median survival of less than 36 months. The epidermal growth factor receptor (EGFR) is a major therapeutic target in metastatic CRC. EGFR inhibitors (EGFRi) such as cetuximab and panitumumab are FDA approved only in patients with WT KRAS/NRAS. MUTANT “RAS” patients have been historically thought to be non-responsive, and more recently, right-sided patients have been considered insensitive as a group, limiting the utility of this drug class. Moreover, while FDA approved for first-line therapy, these agents are seldom used. Using a novel approach fusing gene expression and DNA sequencing, our laboratory recently reported the identification of MUTANT APC + TP53 as a strong predictor of EFGRi sensitivity for WT RAS, but also— surprisingly---for MUTANT KRAS patients. Therefore, we have developed the provocative hypothesis that some MUTANT KRAS CRC patients might benefit from EGFRi. Here we propose an early phase “signal finding” clinical trial to prospectively validate the potential of MUTANT APC + TP53 as biomarkers to predict cetuximab sensitivity, and repurpose/expand the utility of EGFRi to a molecular subset of MUTANT KRAS patients that have been historically overlooked. Moreover, some of these patients may harbor right-sided tumors. For this purpose, two specific aims have been proposed: AIM 1. To perform a “signal-finding”, single agent cetuximab, 3rd-line clinical trial to prospectively assess the potential for APC(A) + TP53(P) mutations to predict EGFRi sensitivity in MUTANT KRAS patients. Based on early historical trials, few if any mutant KRAS patients responded to cetuximab. However, no patients were selected based on mutational profiles. Here we propose, based on intriguing pre-clinical data, that molecular subpopulations harboring APC + TP53 mutations may benefit from EGFRi. A minimally-positive result from a “signal finding” trial, requiring only a few responding/stable patients, would lead to a larger randomized trial. Given the fact that there are really no effective therapies for mutant KRAS patients, particularly in the 3rd line, a cost-effective exponential statistical design has been proposed. AIM 2. Evaluation of an ultrasensitive cfDNA duplex sequencing assay for predicting initial response and monitoring disease progression and minimal residual disease in metastatic CRC. Substantially expanding the utility of an already FDA approved drug—particularly to the “undruggable” MUTANT KRAS genotype---would be considered a breakthrough moment for 40% of metastatic CRC patients, with a major impact on clinical practice. Success in this “signal finding” trial would lead to more definitive trials in the future that would change clinical practice.

项目总结/摘要 转移性结直肠癌（CRC）的预后非常差，中位生存期不到36个月。的 表皮生长因子受体（EGFR）是转移性CRC的主要治疗靶点。EGFR抑制剂 FDA仅批准在WT KRAS/NRAS患者中使用EGFRi，如西妥昔单抗和帕尼单抗。 突变型“RAS”患者历来被认为是无反应的，最近被认为是右侧的 患者作为一个群体被认为是不敏感的，限制了这类药物的效用。虽然FDA 这些药物虽然被批准用于一线治疗，但很少使用。 我们的实验室最近报道了一种融合基因表达和DNA测序的新方法， 鉴定突变APC + TP 53作为WT RAS的EFGRi敏感性的强预测因子，而且- 令人惊讶的是，对于KRAS突变患者来说。因此，我们提出了一个挑衅性的假设， 突变型KRAS CRC患者可能受益于EGFRi。在这里，我们提出了一个早期阶段的“信号发现” 前瞻性验证突变APC + TP 53作为预测西妥昔单抗生物标志物的潜力的临床试验 敏感性，并将EGFRi的用途重新定位/扩展到突变KRAS患者的分子亚群， 在历史上被忽视了。此外，其中一些患者可能患有右侧肿瘤。为此 目的，提出了两个具体目标： AIM 1.进行一项“信号发现”、西妥昔单抗单药、三线临床试验，以前瞻性评估 APC（A）+TP 53（P）突变预测突变型KRAS患者中EGFRi敏感性的潜力。 根据早期历史试验，很少有突变KRAS患者对西妥昔单抗有应答。然而，没有病人 是根据突变谱选择的在这里，我们提出，基于有趣的临床前数据， 携带APC + TP 53突变的分子亚群可能受益于EGFRi。最小阳性结果 从“信号发现”试验，只需要少数反应/稳定的患者，将导致更大的随机 审判鉴于事实上，对于突变型KRAS患者，特别是第三代KRAS患者， 线，提出了一种成本效益指数统计设计。 AIM 2.用于预测初始响应的超灵敏cfDNA双链体测序测定的评价 以及监测转移性CRC中的疾病进展和微小残留病。 实质性地扩大了已经FDA批准的药物的效用-特别是“不可用药”的突变体 KRAS基因型--将被认为是40%的转移性CRC患者的突破性时刻， 影响临床实践。这项“信号发现”试验的成功将导致未来更明确的试验 会改变临床实践