Detection of Colorectal Cancer Adaptive Mutability May Justify Combination of Targeted- and Immune-Therapies

结直肠癌适应性突变的检测可能证明靶向治疗和免疫治疗相结合的合理性

基本信息

  • 批准号:
    10289627
  • 负责人:
  • 金额:
    $ 6.88万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-20 至 2022-04-16
  • 项目状态:
    已结题

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 EGFR/RAS signaling pathway is a strong driver of CRC when constitutively activated via mutations (KRAS ~40%, BRAF ~10%, NRAS ~5%), but targeted molecular inhibitors, when used alone (EGFRi, BRAFi, MEKi or ERKi), have yielded disappointing survival benefit. To date, it remains difficult to identify the subset of patients who will meaningfully benefit from EGFR/RAS pathway-targeted therapies, likely due to complex resistance mechanisms. A widely held view is that resistance to targeted therapies is due to pre-existence of rare, drug-resistant mutant cells (subclones) that expand and repopulate the tumor following initial successful treatment leading to permanent, clonal resistance. Recently, however, adaptive mutability (AM) of CRC in response to targeted therapies has been reported as a novel, early resistance mechanism. This hypothesis proposes that blocking critical, hard-wired signaling pathways causes a “stress” reaction characterized by the of genotoxic, reactive oxygen species (ROS) and the suppression of DNA mismatch repair enzymes. These early drug-induced changes effectively cause a sub-clonal, hypermutable state that facilitates the eventual emergence of permanently drug-resistant clones. Microsatellite instability (MSI) and other mutator states (i.e. POLE-mutated tumors) are now known to provide a greater probability of checkpoint inhibitor responses. Thus, we hypothesize that the AM induced by EGFR/RAS pathway inhibitors may lead to rapid, sub-clonal, enhanced mutability, and a higher load of neoantigens producing an “MSI-like” state. This hypermutability, if detectable, would portend the higher likelihood of response to checkpoint inhibitors. Traditional analysis of tumor mutation burden (TMB) by NGS assessment of a cancer gene panel would not likely detect genome-wide sub-clonal TMB (scTMB). Standard TMB assays detect bountiful, clonally-expanded mutations fixed in the tumor from the time of its founding. Conversely, we propose that the mutations resulting from a rapid, drug-induced mutator phenotype will likely be present at low variant allele frequencies (i.e. subclonal) that are below the limit of detection of standard NGS approaches. In this proposal, we will test the hypothesis that scTMB occurs in response to targeted therapies, and can be detected using an ultrasensitive and highly specific genome-wide Duplex DNA sequencing assay as an indicator (biomarker) of a mutator state induced by targeted therapies. We propose that the presence of scTMB would predict responses to checkpoint inhibitors, and suggest a benefit to targeted therapies combined with checkpoint inhibitors. These studies will lead to a better molecular understanding of the newly identified “adaptive mutability” resistance mechanism, and potentially provide a solid rationale for the use of combination targeted- and immune-therapies in biomarker-selected patient subpopulations to improve response.
项目总结/文摘

项目成果

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TIMOTHY J YEATMAN其他文献

TIMOTHY J YEATMAN的其他文献

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{{ truncateString('TIMOTHY J YEATMAN', 18)}}的其他基金

CLINCIAL VALIDATION OF APC AND TP53 AS BIOMARKERS FOR CETUXIMAB RESPONSE
APC 和 TP53 作为西妥昔单抗反应生物标志物的临床验证
  • 批准号:
    10789666
  • 财政年份:
    2023
  • 资助金额:
    $ 6.88万
  • 项目类别:
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
  • 批准号:
    10610600
  • 财政年份:
    2022
  • 资助金额:
    $ 6.88万
  • 项目类别:
Detection of Colorectal Cancer Adaptive Mutability May Justify Combination of Targeted- and Immune-Therapies
结直肠癌适应性突变的检测可能证明靶向治疗和免疫治疗相结合的合理性
  • 批准号:
    10613171
  • 财政年份:
    2021
  • 资助金额:
    $ 6.88万
  • 项目类别:
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
  • 批准号:
    10289625
  • 财政年份:
    2021
  • 资助金额:
    $ 6.88万
  • 项目类别:
CLINCIAL VALIDATION OF APC AND TP53 AS BIOMARKERS FOR CETUXIMAB RESPONSE
APC 和 TP53 作为西妥昔单抗反应生物标志物的临床验证
  • 批准号:
    10373564
  • 财政年份:
    2019
  • 资助金额:
    $ 6.88万
  • 项目类别:
CLINCIAL VALIDATION OF APC AND TP53 AS BIOMARKERS FOR CETUXIMAB RESPONSE
APC 和 TP53 作为西妥昔单抗反应生物标志物的临床验证
  • 批准号:
    10381742
  • 财政年份:
    2019
  • 资助金额:
    $ 6.88万
  • 项目类别:
INDIVIDUALIZING COLON CANCER THERAPY USING HYBRID RNA AND DNA MOLECULAR SIGNATURE
利用混合 RNA 和 DNA 分子特征进行个体化结肠癌治疗
  • 批准号:
    8738408
  • 财政年份:
    2012
  • 资助金额:
    $ 6.88万
  • 项目类别:
INDIVIDUALIZING COLON CANCER THERAPY USING HYBRID RNA AND DNA MOLECULAR SIGNATURE
利用混合 RNA 和 DNA 分子特征进行个体化结肠癌治疗
  • 批准号:
    9133794
  • 财政年份:
    2012
  • 资助金额:
    $ 6.88万
  • 项目类别:
INDIVIDUALIZING COLON CANCER THERAPY USING HYBRID RNA AND DNA MOLECULAR SIGNATURE
利用混合 RNA 和 DNA 分子特征进行个体化结肠癌治疗
  • 批准号:
    8547787
  • 财政年份:
    2012
  • 资助金额:
    $ 6.88万
  • 项目类别:
INDIVIDUALIZING COLON CANCER THERAPY USING HYBRID RNA AND DNA MOLECULAR SIGNATURE
利用混合 RNA 和 DNA 分子特征进行个体化结肠癌治疗
  • 批准号:
    8918486
  • 财政年份:
    2012
  • 资助金额:
    $ 6.88万
  • 项目类别:

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