APC + TP53 Combinatorial Mutations Emerging as Biomarkers to Predict EGFRI Sensitivity

APC TP53 组合突变作为预测 EGFRI 敏感性的生物标志物

基本信息

批准号：
10610600
负责人：
TIMOTHY J YEATMAN
金额：
$ 17.12万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-16 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10610600
关键词：
APC mutation Affect Annexins Apoptosis BRAF gene Biological Assay Biological Markers Cancer Etiology Categories Cell Line Cell Survival Cellular Assay Cessation of life Cetuximab Clinical Clinical Trials Colorectal Cancer Complex Consensus DNA sequencing Data Data Set Databases Development Engineering Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Exploratory/Developmental Grant FDA approved Feedback Future Gene Expression Gene Expression Profile Genes Human Hybrids KRAS2 gene Lead Ligands MEKs Measures Modeling Mutate Mutation Organoids Pathway interactions Patients Pharmaceutical Preparations Proto-Oncogene Proteins c-akt Ras/Raf Receptor Inhibition Receptor Signaling Role Secondary to Signal Pathway TP53 gene Therapeutic Validation base bevacizumab cell growth chemotherapy clinical investigation colon cancer cell line colon cancer patients combinatorial drug sensitivity drug-sensitive exome sequencing inhibitor therapy metastatic colorectal molecular marker molecular subtypes mutant mutational status novel novel marker panitumumab phospholipase C gamma pre-clinical predicting response response response biomarker targeted treatment therapeutic target transcriptome treatment response tumor tumor diagnosis

项目摘要

PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is a major cause of cancer deaths which is curable if detected early. Unfortunately, many CRC tumors are diagnosed at more advanced stages where cure rates remain low with 20% five-year survival. The epidermal growth factor receptor (EGFR) is a major FDA-approved therapeutic target in metastatic CRC that may be underutilized. To date, it is still difficult to identify patients who may benefit from EGFRi therapy. In fact, the only identified biomarkers for EGFRi therapy are mutations in downstream genes that activate the RAS pathway (KRAS (40%), NRAS (5%), and possibly BRAF (10%)). Unfortunately, these biomarkers are negative predictors that are only ~50% accurate in predicting non-responders. Thus, accurate prediction of EGFRi sensitivity is still problematic. We have recently employed a novel hybrid approach using a predictive cetuximab sensitivity (CTX-S) gene expression signature score in 468 CRC tumors with coincident global gene expression and exome sequencing data to identify mutations beyond those in KRAS/BRAF/NRAS that might predict EGFRi responders. We found that tumors harboring the combination of APC + TP53 mutations are predicted to be the most sensitive to cetuximab (CTX). Whereas most CRC tumors (70%) have truncating mutations in APC and mutations in TP53 are present in 50% of CRC tumors, co-mutation of both genes is present in ~25% of CRC and heretofore has never been rigorously measured in clinical trials. Thus, we hypothesize co- mutated APC + TP53 as a new composite biomarker to identify CTX sensitive tumors that would allow greater response rates in WT RAS/RAF patients and potentially extend therapy to some mutant KRAS patients. To understand and validate the full potential of this novel biomarker, here we seek to determine the cellular impact of the APC and TP53 mutations that increase the tumor sensitivity to EGFR inhibition. Further, we seek to identify additional early/intermediate biomarkers of response correlating with the presence of these mutations. Finally, we will determine if these mutations alter the gene expression–based consensus molecular subtype (CMS). Tumors with CMS2 are predicted to have greater sensitivity to EGFR inhibition and appear to strongly correlate with APC + TP53 mutations in our human datasets. We seek to determine if mutations in APC + TP53 can convert molecular subtypes CMS1,3,4 to CMS2, coincident with enhancing EGFRi sensitivity. This application will provide the necessary pre-clinical validation of novel molecular biomarkers to best predict which CRC tumors will be responsive to EGFRi, and to support subsequent future clinical validation that may lead to expanded application of an under-used, FDA-approved targeted therapy.

项目摘要/摘要结直肠癌（CRC）是癌症死亡的主要原因，如果早期检测到可以治愈。很遗憾，许多CRC肿瘤在更高级的阶段被诊断为较低，五年五年生存。表皮生长因子受体（EGFR）是转移性FDA批准的主要治疗靶标 CRC可能未被充分利用。迄今为止，仍然很难识别可能从EGFRI治疗中受益的患者。实际上，EGFRI治疗的唯一确定的生物标志物是下游基因的突变，它激活了 RAS途径（KRAS（40％），NRA（5％）和可能的BRAF（10％））。不幸的是，这些生物标志物是在预测非反应器方面仅准确50％的负预测因子。那，准确的预测 EGFRI敏感性仍然是有问题的。我们最近使用预测性雇用了一种新型的混合方法西妥昔单抗敏感性（CTX-S）基因表达签名评分在468个CRC肿瘤中具有一致的全球基因表达和外显子组测序数据以识别KRAS/BRAF/NRA中的突变，可能预测EGFRI响应者。我们发现携带APC + TP53突变组合的肿瘤是预计对西妥昔单抗（CTX）最敏感。而大多数CRC肿瘤（70％）截断在50％的CRC肿瘤中存在APC和TP53突变的突变，两个基因的共同致密染在约25％的CRC和迄今为止，在临床试验中从未经过严格测量。因此，我们假设共同突变的APC + TP53作为一种新的复合生物标志物，以识别CTX敏感肿瘤，可以更大 WT RAS/RAF患者的反应率，并可能将治疗扩展到一些突变的KRAS患者。到了解和验证这种新型生物标志物的全部潜力，在这里我们寻求确定细胞影响 APC和TP53突变增加了肿瘤对EGFR抑制的敏感性。此外，我们试图确定反应的其他早期/中间生物标志物与这些突变的存在相关。最后，我们将确定这些突变是否改变了基因表达基于基于基因的共有分子亚型（CMS）。预计患有CMS2的肿瘤对EGFR抑制具有更大的敏感性，并且似乎密切相关在我们的人类数据集中使用APC + TP53突变。我们试图确定APC + TP53中的突变是否可以将分子亚型CMS1,3,4转换为CMS2，与增强EGFRI敏感性一致。此应用程序将提供新型分子生物标志物的必要临床前验证，以最好地预测哪些CRC肿瘤将对EGFRI敏感，并支持随后的未来临床验证，这可能会扩大应用不足的FDA批准的靶向疗法的应用。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy.

DOI：
10.1186/s12885-022-09344-3
发表时间：
2022-03-10
期刊：
BMC cancer
影响因子：
3.8
作者：
Yang M;Davis TB;Pflieger L;Nebozhyn MV;Loboda A;Wang H;Schell MJ;Thota R;Pledger WJ;Yeatman TJ
通讯作者：
Yeatman TJ

Ras Pathway Activation and MEKi Resistance Scores Predict the Efficiency of MEKi and SRCi Combination to Induce Apoptosis in Colorectal Cancer.

DOI：
10.3390/cancers14061451
发表时间：
2022-03-11
期刊：
Cancers
影响因子：
5.2
作者：
Davis TB;Gupta S;Yang M;Pflieger L;Rajan M;Wang H;Thota R;Yeatman TJ;Pledger WJ
通讯作者：
Pledger WJ