Molecular Biomarkers as Classifiers to Individualize Therapy of Esophagus Cancer

分子生物标志物作为食管癌个体化治疗的分类器

• 批准号: 7588248
• 负责人: Jaffer A. Ajani
• 金额: $ 18.34万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-02 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7588248
• 关键词: Age; Amendment; Area; Area Under Curve; Berry; Biological Assay; Biological Markers; Cancer Patient; Clinical; Clinical Data; Confidence Intervals; Data; Data Set; Decision Making; Development; Diagnosis; Dose; Drug resistance; Drug usage; Erinaceidae; Esophageal Neoplasms; Esophageal carcinoma; Esophagectomy; Esophagus; Exhibits; Future; Gender; Goals; Heterogeneity; Histopathologic Grade; Immunohistochemistry; In complete remission; Knowledge; Laboratories; Laboratory Research; Life; Location; Logistic Regressions; Malignant Neoplasms; Malignant neoplasm of esophagus; Methods; Methylation; Modeling; Molecular; Molecular Biology; NF-kappa B; Nomograms; Nuclear; Operative Surgical Procedures; Outcome; Pathologic; Patients; Pharmaceutical Preparations; Phase; Predictive Value; Probability; Procedures; Process; Protocols documentation; Quality of life; Radiation; Randomized Controlled Clinical Trials; Receiver Operating Characteristics; Resected; Residual Cancers; Resistance; Sampling; Specific qualifier value; Specificity; Specimen; Staging; Staining method; Stains; Suggestion; Survival Rate; Testing; Therapeutic; Tissues; Toxic effect; Uncertainty; United States; Validation; base; cancer diagnosis; clinically relevant; cohort; cytotoxic; improved; indexing; outcome forecast; partial response; predictive modeling; prognostic; prospective; public health relevance; response; tool; treatment strategy; validation studies

DESCRIPTION (provided by applicant): Despite the advances in therapy of cancer, patients with localized (stage II or III) esophageal carcinoma when treated with preoperative chemoradiation have a dismal prognosis (<20% 5-year survival rate). Treatment is associated with dire consequences. Currently, none of the clinical or therapeutic parameters can help to individualize therapy (select certain treatments or avoid others). It is known that response to chemoradiation (as judged by examining the resected specimen) varies. Pathologic complete response (pathCR), defined as the absence of residual cancer, or lack of response (=50% residual cancer or exCRTR) dictates patient outcome. Approximately 25% of patients achieve a pathCR and another 25% exhibit exCRTR. Patients with pathCR survive much longer than those with <pathCR and patients with exCRTR live much shorter than those with <exCRTR. If one could identify biomarkers that would distinguish these different outcomes before patients received treatment, we could begin to individualize therapy (avoid surgery in pathCR patients and avoid chemoradiation in exCRTR patients). We hypothesize that certain biomarker signatures may highly correlate with pathCR or exCRTR. Thus, the specific aims for R21 are (1) Establish the distribution and clinical relevance (pathCR and exCRTR) of NF-kB, Gli-1, and SHH in esophageal cancer patients undergoing preoperative chemoradiation; (2A) Assess the effect of specific classes of drugs used on clinical outcome and (2 B) Establish quantitative requirements for the expression of selected drug-resistance biomarkers, establish independent clinical relevance and then study if they improve the specificity of the emerging NF-kB, Gli-1, and SHH signature(s) (3) Establish IHC standardized quantitative assays of SHH, Gli1, NF-kB and selected drug- related biomarkers in our CLIA certified laboratory. Upon reaching the prespecified milestones, we will embark on R33 with the following specific aims (1) Prospectively validate the established NF-kB, SHH, Gli-1, and drug- resistance biomarkers' signature(s) for pathCR and exCRTR from the retrospective cohort (60 preliminary + 175 retrospective = 235) in 212 samples from prospective patients who will have preoperative chemoradiation. (2A) Establish a predictive model for various clinical outcomes (pathCR, partial response [1% to 50% residual cancer], and exCRTR) in 447 patients (derived from the preliminary, retrospective, and prospective cohorts) to derive the most promising biomarker signature(s). (2B) Add clinical parameters and classes of drug to the nomogram established in specific aim 2A. Thus, this proposal seeks to pave the path to individualized therapy for esophageal cancer using biomarker signatures. PUBLIC HEALTH RELEVANCE: The goal of this study (R21/R33) is to study untreated cancer tissue from esophageal cancer patients receiving preoperative chemoradiation to discover if certain molecular biomarker classifiers can help individualize therapy. This is being proposed in two phases: retrospective (R21) and prospective (R33). Only promising findings in the R21 will be validated in the R33 phase. In the R21 phase, the immunohistochemistry (IHC) of NFkB, Shh and Gli-1 as well as relevant drug-related biomarkers will be used to establish a distribution and clinical relevance (pathCR and exCRTR) of biomarker signatures. The IHC methods will be standardized and transferred from the research laboratory to a certified IHC clinical laboratory.

描述（由申请人提供）：尽管癌症治疗的进展，但在术前化学放疗治疗时，患有局部局部（II或III期）食管癌的患者的预后却令人沮丧（<20％5年生存率）。治疗与可怕的后果有关。当前，临床或治疗参数都无法帮助个性化治疗（选择某些治疗或避免其他治疗）。众所周知，对化学放疗的反应（通过检查切除的样品来判断）会有所不同。病理完全反应（PATHCR）定义为缺乏残留癌，或缺乏反应（= 50％残留癌症或Excrtr）决定了患者的预后。大约25％的患者获得了路径，另外25％的患者表现出脱节。患有路径的患者的生存时间比患有<PathCR的患者长得多，而患有EXCRTR的患者的寿命比<excrtr的患者短得多。如果可以识别出在患者接受治疗之前将这些不同结果区分开的生物标志物，我们可以开始个性化治疗（避免在PATHCR患者中进行手术，并避免使用脱发患者进行化学放疗）。我们假设某些生物标志物特征可能与PathCR或Excrtr高度相关。因此，R21的特定目的是（1）在接受术前化学疗法的食管癌患者中，建立NF-KB，GLI-1和SHH的NF-KB，GLI-1和SHH的分布和临床相关性（PATH和EXCRTR）； （2a）评估使用特定类别的药物对临床结果的影响，（2 b）为表达所选药物耐药性生物标志物的表达建立定量要求，建立独立的临床相关性，然后研究是否提高了新出现的NF-KB，GLI-1和SHH Signature的特异性，并建立IHC标准化的量子和Shhc Sandit-Sharb shark-shh-shh-shh-shim-ship shark shark shark-gli1，nf-nf-n.在我们的CLIA认证实验室中。达到预先指定的里程碑后，我们将以以下具体目的（1）前瞻性地验证已建立的NF-KB，SHH，GLI-1和耐药性生物标志物的签名（S）的签名（60 prespective cohort）（60个预感 + 175 + 175 + 175回顾者），从（2a）在447名患者（源自初步，回顾性和前瞻性人群）中，建立了各种临床结局（路径，部分至50％的残留癌）和EXCRTR的预测模型，以得出最有前途的生物标志性签名（S）。 （2b）将临床参数和类别的药物类别添加到特定目标2a中建立的诺夫图中。因此，该提案旨在使用生物标志物特征为食管癌的个性化治疗铺平道路。 公共卫生相关性：这项研究的目的（R21/R33）是研究接受术前化学放疗的食管癌患者的未经治疗的癌症组织，以发现某些分子生物标志物分类器是否可以帮助个性化治疗。这是两个阶段提出的：回顾性（R21）和前瞻性（R33）。 R21中只有有希望的发现才能在R33阶段进行验证。在R21阶段，NFKB，SHH和GLI-1的免疫组织化学（IHC）以及相关的与药物相关的生物标志物将用于建立生物标志物签名的分布和临床相关性（PATHCR和EXCRTR）。 IHC方法将被标准化并从研究实验室转移到经认证的IHC临床实验室。