Validation of blood-based predictive biomarkers of therapeutic response to neoadjuvant chemoradiation therapy in patients with locally advanced rectal cancer

项目摘要/摘要 新辅助放化疗(NCRT)后再手术是标准护理的患者 局部进展期直肠癌(LARC)占新诊断直肠癌病例的60%。 尽管nCRT使许多患者受益，但目前尚不清楚谁会或不会对此做出积极的反应。关于 20%接受nCRT的患者将经历病理完全应答(PCR)，而约25%的患者将经历 没有反应。最近，几项临床试验评估了新的治疗方案及其结果。 提出新的治疗策略，这些策略以前不适用于LARC患者。随着可用 这些新的策略，关键是能够通过预测性生物标记物预先识别LARC患者， 对nCRT有反应或无反应的可能性更高。 我们的目标是优化和验证一种准确、精确和微创的高效检测方法。 评估生物标志物(S)在LARC环境下对nCRT疗效的预测作用。将被验证的化验 在这项提案中，是一种使用xMAP技术的Luminex多重分析。我们已经确定了六个候选人 将在这项研究中得到验证的生物标志物。在这里，使用优化和验证的分析，我们将实现 候选生物标记物(S)在真实世界临床实验室环境中的临床验证 标本。在这项研究结束时，我们将为患者实现一种微创的、基于血液的检测 治疗分层，这将为LARC患者(S)和医疗保健系统带来巨大好处。 使用xmap分析，我们正在检测dna损伤反应(Ddr)的候选生物标记物。 LARC患者外周血单核细胞(PBMC)冻存后细胞裂解物中的信号转导。在我们的 初步工作，这些生物标记物表达的变化与对 LARC患者的nCRT。这些候选生物标志物是通过我们最近的假设驱动的 由国防部资助的翻译研究。这项建议是通过两人的合作提出的 主要调查人员汇集了互补的专业知识。集结的多学科团队带来了 结合临床和基础科学、分析开发/验证及其临床部署方面的专业知识。 在这里，我们将分析性地验证我们的分析(UH2阶段)，然后通过使用 来自LARC患者的生物链霉菌(UH3期)。使用的生物杀虫剂来自LARC患者和健康人 来自Fox Chase生物样本资料库设施和LARC临床研究/试验评估的对照 治疗反应。在UH2阶段，我们将进行预分析(生物样品可变性)和分析 (例如，精确度、准确度)验证。在UH3阶段，我们将通过评估临床有效性来确定临床有效性 效用参数(例如，灵敏度/特异度、最佳截断值)，并与nCRT反应状态进行比较。 成功完成将产生有效的生物标记物/分析，用于临床研究分析 试验/研究。从长远来看，这项工作可能会改善LARC患者的患者分层治疗。

PROJECT SUMMARY/ABSTRACT Neoadjuvant chemoradiation therapy (nCRT) followed by surgery is the standard of care for patients with locally advanced rectal cancer (LARC), which accounts for ~60% of newly diagnosed rectal cancer cases. Although nCRT benefits many patients, it is currently not known who will or will not respond favorably. About 20% patients that receive nCRT will experience a pathologic complete response (pCR), while ~25% patients will exhibit no response. Recently, several clinical trials have assessed new treatment paradigms, and their results present new treatment strategies which were previously not available for LARC patients. With the availability of these new strategies, it is crucial to be able to a priori identify LARC patients, via a predictive biomarker, who have a higher likelihood of responding or not responding to nCRT. Our goal is to optimize and validate an efficient assay that is accurate, precise, and minimally invasive to assess biomarker(s) that will predict response to nCRT in the setting of LARC. The assay that will be validated in this proposal is a Luminex multiplexed assay that uses the xMAP technology. We have defined six candidate biomarkers that will be validated in this study. Here, using the optimized and validated assay we will then achieve the clinical validation of the candidate biomarker(s) in a real-world clinical laboratory setting using LARC patient specimens. At the end of this study, we will achieve a minimally invasive, blood-based assay for patient treatment stratification which will be of tremendous benefit to LARC patient(s) and the healthcare system. Using the xMAP assay, we are detecting candidate biomarkers of DNA damage response (DDR) signaling in cell lysates from cryopreserved peripheral blood monocytes (PBMCs) of LARC patients. In our preliminary work, the change in the expression of these biomarkers significantly associated with response to nCRT in LARC patients. These candidate biomarkers were identified through our recent hypothesis-driven translational study funded by the DOD. This proposal was developed through a collaboration between the two primary investigators bringing together complementary expertise. The assembled multi-disciplinary team brings together expertise in clinical and basic science, assay development/validation, and their clinical deployment. Here, we will analytically validate our assay (UH2 phase) and then establish the clinical validity by using biospecimens from LARC patients (UH3 phase). The biospecimens used are from LARC patients and healthy controls from the Fox Chase BioSample Repository Facility, and from LARC clinical studies/trials evaluating therapeutic response. In the UH2 phase we will perform pre-analytical (biospecimen variability) and analytical (e.g., precision, accuracy) validation. In the UH3 phase, we will establish clinical validity by evaluating clinical utility parameters (e.g., sensitivity/specificity, optimal cut-offs) and compare with nCRT response status. Successful completion will yield validated biomarkers/assays for use as investigational assays in clinical trials/studies. Over the long-term, this work may improve patient stratification for treatment in LARC patients.