Molecular Markers of Response to Chemoradiation in Localized Esophageal Cancer

局限性食管癌放化疗反应的分子标志物

• 批准号: 7674679
• 负责人: Jaffer A. Ajani
• 金额: $ 13.86万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7674679
• 关键词: Adenocarcinoma; Biological Markers; Biopsy Specimen; Camptothecin; Cancer Patient; Carcinoma; Caucasians; Caucasoid Race; Clinical; Clinical Data; Cluster Analysis; Data; Dose; Esophageal carcinoma; Esophagus; Future; Gene Expression Profile; Gene Expression Profiling; Genes; Goals; In complete remission; Incidence; Investigation; Life; Literature; Malignant Neoplasms; Malignant neoplasm of esophagus; Modeling; Molecular Biology; Molecular Profiling; Neoplatin; Operative Surgical Procedures; Outcome; Pathologic; Patients; Predictive Value; Published Comment; Quality of life; Radiation; Randomized Controlled Clinical Trials; Resected; Residual Cancers; Residual state; Safety; Sample Size; Sampling; Specimen; Staging; Statistical Models; Subgroup; Survival Rate; Taxane Compound; Therapeutic; Toxic effect; United States; Validation; base; cancer diagnosis; cancer gene expression; chemotherapy; cohort; common treatment; cytotoxic; effective therapy; fluoropyrimidine; improved; molecular marker; public health relevance; response; taxane; therapy outcome

DESCRIPTION (provided by applicant): The overall goal of this proposal is to determine if molecular markers found in pretreatment biopsy specimens can predict pathologic complete response (pathCR) in patients with esophageal cancer (EC) undergoing preoperative chemoradiation (CTRT). PathCR is defined as no residual carcinoma in a resected specimen. Patients with EC have a 5-year survival rate of <20%. Localized carcinoma (stage II or III) is frequently treated with preoperative CTRT, but this empirical approach results in heterogeneous and often unpredictable outcomes. Approximately 25% of patients achieve a pathCR and tend to survive longer than do the 75% who achieve <pathCR (i.e., have residual cancer). Current clinical parameters do not reliably predict outcome from therapy and modifying the type CTRT has little impact on the proportion of patients with a pathCR. Moreover, preoperative CTRT and surgery have dire toxicity and life altering consequences. This lack of ability to individualize therapy is a major obstacle in improving patient outcomes. A rational approach to individualized therapy is likely to occur through understanding the molecular biology of this cancer. To that aim, we conducted a preliminary study in EC patients. In a 19-patient pilot profiling study using Affymetrix U133A GeneChip. microarray, unsupervised hierarchical cluster analysis segregated patient's cancers into two subgroups (5 of 6 pathCR clustered in subtype I and 1 of 6 in subtype II). These data suggest that pathCR might segregate from <pathCR based on molecular markers but our data needs confirmation in a larger patient sample. In an expanded cohort, we may also find an improved model for predicting pathCR which would itself require validation. We propose to assess the gene expression profile of 120 patients to assess if a high (e80%) positive predictive value for pathCR can be achieved. The Specific Aims of the proposal are 1. Determine the gene expression profile of the new cohort of 120 patients with esophageal cancer treated with preoperative chemoradiation. 2: Construct statistical models that have a high positive predictive value for pathCR by the gene expression profile of 120 patients. The modeling will include: (a) Identification of subtypes of esophageal cancer by gene expression profiles that are highly homogeneous; (b) Build pathCR prediction models based on specific to subtypes of esophageal cancer as defined in 2(a) and also in the homogeneously treated subgroups. Our attempts to individualize patient's therapy based on molecular biology can pave the way to allow administration of effective therapy, improve safety, and preserve the esophagus in some patients. PUBLIC HEALTH RELEVANCE: This proposal is an early attempt to individualize therapy based on molecular biology for patients with esophageal cancer. Our goal is to pave the way for a strategy in the future that will allow administration of effective therapy, improve safety, and preserve the esophagus in some patients.

描述（由申请人提供）：该提案的总体目标是确定在接受术前化学化学（CTRT）的食管癌（EC）患者中，预处理活检标本中发现的分子标记是否可以预测病理完全反应（PATHCR）。路径Cr被定义为切除的样品中无残留癌。 EC患者的存活率为5年<20％。局部癌（II期或III期）经常用术前CTRT治疗，但是这种经验方法会导致异质性且通常无法预测的结果。大约25％的患者达到了路径，并且往往比达到<PathCR的75％（即患有残留癌）的生存时间更长。当前的临床参数不能可靠地可靠地预测治疗的结果，并且修改CTRT对PATHCR患者的比例几乎没有影响。此外，术前CTRT和手术具有可怕的毒性和改变生活的后果。缺乏个性化治疗的能力是改善患者预后的主要障碍。通过了解该癌症的分子生物学，可能会发生一种合理的个性化治疗方法。为此，我们对EC患者进行了初步研究。在使用Affymetrix U133A Genechip的19名患者试点分析研究中。微阵列，无监督的层次群集分析将患者的癌症隔离为两个亚组（在亚型I中以6个路径群集中的5个中的5个，亚型II中的6个中的1个）。这些数据表明，PATHCR可能会根据分子标记与<路径分离，但我们的数据需要在较大的患者样本中确认。在扩展的队列中，我们还可以找到一个改进的模型来预测PathCR，这本身需要验证。我们建议评估120名患者的基因表达谱，以评估是否可以实现高（E80％）阳性预测值。该提案的具体目的是1。确定用术前化学放疗治疗的120例食管癌患者的新队列的基因表达谱。 2：构建统计模型，该模型具有120名患者的基因表达谱，对路径的阳性预测值很高。该建模将包括：（a）通过高度均匀的基因表达谱鉴定食管癌的亚型； （b）在2（a）和同质处理的亚组中定义的基于针对食管癌亚型的特定亚型的路径预测模型。我们试图基于分子生物学来个性化患者疗法的尝试可以为允许进行有效治疗，提高安全性并保留某些患者食管的方式铺平道路。公共卫生相关性：该建议是基于食管癌患者的分子生物学个性化治疗的早期尝试。我们的目标是为未来的策略铺平道路，以便在某些患者中进行有效治疗，改善安全性并保护食道。

项目成果

Low metabolic activity in primary gastric adenocarcinoma is associated with resistance to chemoradiation and the presence of signet ring cells.

• DOI: 10.1007/s00595-020-02018-2
• 发表时间: 2020-10
• 期刊: SURGERY TODAY
• 影响因子: 2.5
• 作者: Harada, Kazuto;Patnana, Madhavi;Wang, Xuemei;Iwatsuki, Masaaki;Murphy, Mariela A. Blum;Zhao, Meina;Das, Prajnan;Minsky, Bruce D.;Weston, Brian;Lee, Jeffrey H.;Bhutani, Manoop S.;Estrella, Jeannelyn S.;Shanbhag, Namita;Ikoma, Naruhiko;Badgwell, Brian D.;Ajani, Jaffer A.
• 通讯作者: Ajani, Jaffer A.

Recent trend in gastric cancer treatment in the USA.

美国胃癌治疗的最新趋势。

• DOI: 10.20517/2394-4722.2017.74
• 发表时间: 2018
• 期刊: Journal of cancer metastasis and treatment
• 作者: Harada,Kazuto;Baba,Hideo;Ajani,JafferA
• 通讯作者: Ajani,JafferA

Risk of peritoneal metastases in patients who had negative peritoneal staging and received therapy for localized gastric adenocarcinoma.

• DOI: 10.1002/jso.24912
• 发表时间: 2018-03
• 期刊: Journal of surgical oncology
• 影响因子: 2.5
• 作者: Mizrak Kaya D;Nogueras-González GM;Harada K;Amlashi FG;Roy-Chowdhuri S;Estrella JS;Das P;Lee JH;Weston B;Bhutani MS;Matamoros A Jr;Thomas I;Lin Q;Badgwell BD;Ajani JA
• 通讯作者: Ajani JA

Integrated genomic profiling and modelling for risk stratification in patients with advanced oesophagogastric adenocarcinoma.

• DOI: 10.1136/gutjnl-2020-322707
• 发表时间: 2021-11
• 期刊: GUT
• 影响因子: 24.5
• 作者: Hao, Dapeng;He, Siyuan;Harada, Kazuto;Pizzi, Melissa Pool;Lu, Yang;Guan, Pujun;Chen, Lu;Wang, Ruiping;Zhang, Shaojun;Sewastjanow-Silva, Matheus;Abdelhakeem, Ahmed;Shanbhag, Namita;Bhutani, Manoop;Han, Guangchun;Lee, Jeffrey H.;Zhao, Shuangtao;Weston, Brian;Murphy, Mariela Blum;Waters, Rebecca;Estrella, Jeannelyn Santiano;Roy-Chowdhuri, Sinchita;Gan, Qiong;Lee, Ju-Seog;Peng, Guang;Hanash, Samir M.;Calin, George Adrian;Song, Xingzhi;Zhang, Jianhua;Song, Shumei;Wang, Linghua;Ajani, Jaffer A.
• 通讯作者: Ajani, Jaffer A.

Attenuation of YAP1 can potentially target cancer stem cells to overcome drug resistance.

YAP1 的减弱有可能靶向癌症干细胞以克服耐药性。

• DOI: 10.18632/oncoscience.449
• 发表时间: 2018
• 期刊: Oncoscience
• 作者: Harada,Kazuto;Song,Shumei;Ajani,JafferA
• 通讯作者: Ajani,JafferA