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: 10448869
• 负责人: Sanjeevani Arora
• 金额: $ 25.88万
• 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/10448869
• 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; Foxes; Funding; Future; Goals; Healthcare Systems; Human; Immunoassay; Immunofluorescence Immunologic; In complete remission; Investigation; Laboratories; MDM2 gene; Malignant Neoplasms; Modality; Neoadjuvant Study; Neoadjuvant Therapy; Newly Diagnosed; Operative Surgical Procedures; Pathologic; Pathology; Patient Care; Patients; Performance; Phase; Primary Neoplasm; Proteins; Public Health; Radiation therapy; Reagent; Rectal Cancer; 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; base; biomarker validation; cancer clinical trial; candidate marker; candidate validation; cell immortalization; chemoradiation; clinical development; clinical translation; clinically actionable; cross reactivity; design verification; detection limit; experience; improved; lead candidate; minimally invasive; monocyte; multidisciplinary; multiplex assay; patient population; patient stratification; peripheral blood; predicting response; predictive marker; prognostic; quantitative imaging; rectal; response; response biomarker; standard of care; translational study; treatment response; treatment strategy; 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.

项目总结/文摘