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; 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.

项目摘要/摘要 新辅助化学放疗治疗（NCRT），然后进行手术是 局部晚期直肠癌（LARC）占新诊断的直肠癌病例的约60％。 尽管NCRT对许多患者有利，但目前尚不知道谁会或不会做出好评。关于 20％接受NCRT的患者会经历病理完全反应（PCR），而约25％的患者将 没有任何反应。最近，一些临床试验评估了新的治疗范例及其结果 提出了新的治疗策略，这些策略以前不适合LARC患者使用。与 这些新策略，至关重要的是，能够通过预测性生物标志物来识别LARC患者 对NCRT做出反应或不响应的可能性更高。 我们的目标是优化和验证准确，精确和微创的有效测定 评估将在LARC环境中预测对NCRT的反应的生物标志物。将被验证的测定 在此提案中，是使用XMAP技术的Luminex多路复用测定法。我们定义了六个候选人 在本研究中将验证的生物标志物。在这里，使用优化和经过验证的测定，我们将实现 使用LARC患者的现实世界临床实验室设置中候选生物标志物的临床验证 标本。在这项研究结束时，我们将为患者获得最低侵入性的基于血液的测定 治疗分层对LARC患者和医疗保健系统有很大的好处。 使用XMAP分析，我们正在检测DNA损伤响应（DDR）的候选生物标志物 LARC患者的冷冻保存外周血单核细胞（PBMC）的细胞裂解物中的信号传导。在我们的 初步工作，这些生物标志物表达的变化与反应显着相关 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的 由国防部资助的翻译研究。该建议是通过两者之间的合作制定的 主要研究人员将补充专业知识汇总在一起。组装的多学科团队带来 临床和基础科学，测定开发/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相），然后通过使用 LARC患者（UH3期）的生物测量。所使用的生物测量来自LARC患者和健康 FOX Chase BioSample存储库设施的对照，以及评估LARC临床研究/试验 治疗反应。在UH2阶段，我们将执行分析前（生物测试变异性）和分析性 （例如，精度，准确性）验证。在UH3阶段，我们将通过评估临床来建立临床有效性 实用程序参数（例如灵敏度/特异性，最佳截止性），并与NCRT响应状态进行比较。 成功完成将产生经过验证的生物标志物/测定，以用作临床研究的研究试验 试验/研究。从长远来看，这项工作可以改善LARC患者治疗的患者分层。