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

局部晚期直肠癌患者新辅助放化疗治疗反应的血液预测生物标志物的验证

• 批准号: 10615862
• 负责人: Sanjeevani Arora
• 金额: $ 25.3万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10615862
• 关键词: Academic Medical Centers; Adjuvant; Basic Science; Biological Assay; Biological Markers; Biological Specimen Banks; Blinded; Blood; Blood specimen; CHEK1 gene; CHEK2 gene; Calibration; Cancer Center; Cancer Patient; Cell Line; Cells; Characteristics; Chemotherapy-Oncologic Procedure; Clinical; Clinical Research; Clinical Sciences; Clinical Trials; Collaborations; Cryopreservation; DNA Damage; Disease-Free Survival; Evaluation; Exhibits; Fox Chase Cancer Center; Funding; Future; Gamma-H2AX; Goals; Healthcare Systems; Human; Immunoassay; Immunofluorescence Immunologic; In complete remission; Laboratories; MDM2 gene; Malignant Neoplasms; Modality; Neoadjuvant Study; Neoadjuvant Therapy; Newly Diagnosed; Operative Surgical Procedures; Pathologic; Pathology; Patient Care; Patients; Performance; Phase; Phosphorylation; Primary Neoplasm; Proteins; Public Health; Radiation therapy; Reagent; Rectal Cancer; Rectum; Reproducibility; Research; Research Design; Research Personnel; Sampling; Sensitivity and Specificity; Signal Transduction; Specimen; Standardization; Surrogate Endpoint; TP53 gene; Technology; Testing; Validation; Variant; Whole Blood; Work; assay development; biomarker validation; cancer clinical trial; candidate marker; candidate validation; cell immortalization; chemoradiation; clinical development; clinical translation; clinically actionable; cross reactivity; detection limit; experience; improved; lead candidate; minimally invasive; monocyte; multidisciplinary; multiplex assay; novel therapeutic intervention; patient population; patient stratification; peripheral blood; predicting response; predictive marker; quantitative imaging; rectal; response; response biomarker; segregation; standard of care; translational study; treatment response; treatment stratification

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.

项目概要/摘要 新辅助放化疗 (nCRT) 随后进行手术是以下患者的标准治疗方法 局部晚期直肠癌（LARC），约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做出有利反应。关于 20% 接受 nCRT 的患者将出现病理完全缓解 (pCR)，而约 25% 的患者将出现病理完全缓解 (pCR) 没有表现出任何反应。最近，一些临床试验评估了新的治疗范例及其结果 提出了以前无法用于 LARC 患者的新治疗策略。随着可用性 在这些新策略中，至关重要的是能够通过预测生物标志物先验地识别 LARC 患者，这些患者 对 nCRT 做出反应或不做出反应的可能性较高。 我们的目标是优化和验证准确、精确且微创的高效检测方法 评估可预测 LARC 背景下 nCRT 反应的生物标志物。将被验证的测定 该提案中是使用 xMAP 技术的 Luminex 多重检测。我们已经确定了六位候选人 将在本研究中验证的生物标志物。在这里，使用经过优化和验证的检测，我们将实现 使用 LARC 患者在真实临床实验室环境中对候选生物标志物进行临床验证 标本。在这项研究结束时，我们将为患者实现微创、基于血液的检测 治疗分层将对 LARC 患者和医疗保健系统带来巨大好处。 使用 xMAP 测定，我们正在检测 DNA 损伤反应 (DDR) 的候选生物标志物 LARC 患者冷冻保存的外周血单核细胞 (PBMC) 细胞裂解物中的信号传导。在我们的 初步工作表明，这些生物标志物表达的变化与对药物的反应显着相关。 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确定的 由国防部资助的转化研究。该提案是通过两者合作制定的 主要研究者汇集了互补的专业知识。聚集的多学科团队带来 汇集了临床和基础科学、检测开发/验证及其临床部署方面的专业知识。 在这里，我们将分析验证我们的测定（UH2 阶段），然后使用以下方法确定临床有效性： 来自 LARC 患者的生物样本（UH3 期）。使用的生物样本来自 LARC 患者和健康人 来自 Fox Chase BioSample Repository Facility 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（生物样本变异性）和分析 （例如，精度、准确性）验证。在UH3阶段，我们将通过评估临床有效性来建立临床有效性 效用参数（例如敏感性/特异性、最佳截止值）并与 nCRT 反应状态进行比较。 成功完成将产生经过验证的生物标志物/测定，可用作临床研究测定 试验/研究。从长远来看，这项工作可能会改善 LARC 患者治疗的患者分层。