食管癌的代谢组学和BH3分析：精准治疗的新评估方法
Metabolomic and BH3 profiling of esophageal cancers: novel assessment methods for precision therapy.
作者信息
Taylor Ripley R, Surman Deborah R, Diggs Laurence P, Trepel Jane B, Lee Min-Jung, Ryan Jeremy, Davis Jeremy L, Steinberg Seth M, Hernandez Jonathan M, Hoang Choung, Kenney Cara M, Bond Colleen D, Kunst Tricia F, Letai Anthony, Schrump David S
机构信息
Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Building 10; 4-3952, 10 Center Drive, MSC 1201, Bethesda, MD, 20892-1201, USA.
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
出版信息
BMC Gastroenterol. 2018 Jun 22;18(1):94. doi: 10.1186/s12876-018-0823-x.
BACKGROUND
Esophageal cancers accounted for nearly 16,000 deaths in 2016. The number of patients with esophageal cancers increases every year. Neoadjuvant chemoradiotherapy (nCRT) prior to esophagectomy is a standard treatment for esophageal cancers. The patients who have no residual tumor (pathological complete response (pCR)) at surgery are the most likely to experience long term survival. Accurately determining which patients will have a pCR will improve prognostic information for patients and families, confirm lack of response to nCRT, or avoid surgery if no residual tumor is present. Imaging, endoscopy, and liquid biomarkers have all failed to detect pCR without performing an esophagectomy.
METHODS
In this study, we are enrolling patients with esophageal adenocarcinoma and squamous cell carcinoma. Patients will undergo standard evaluation including CT scans, laboratory tests, endoscopy with biopsies, and evaluation by a thoracic surgeon. Tissue biopsy is required for enrollment that will be sent for BH3 profiling and metabolomics. Patients will be treated with standard nCRT followed by surgery. Patients with metastatic disease are not eligible. Surgery at the National Cancer Institute will be minimally-invasive robotic surgery. Patients will remain on study indefinitely with regular clinic visits and imaging tests.
DISCUSSION
The mitochondria are critically involved in the intrinsic pathway apoptosis. Bcl-2 homology domain 3 (BH3) profiling is a technique to measure a cell's susceptibility to apoptosis. BH3 profiling measures the relative interactions of proteins that induce or block apoptosis. The collective balance of these proteins determines whether a cell is near the threshold to undergo apoptosis. If the cell is near this threshold, then the tumor may be more likely to die when treated with nCRT. The mitochondria secrete metabolites that may be detectable as biomarkers. Metabolomics is a global assessment of all metabolite changes that has been performed for detection, monitoring, prognosis, and treatment response in cancers. Stratification of patients based on whether pCR occurs or not may elucidate metabolomic signatures that may be associated with response. We are asking whether BH3 profiling or a metabolomic signature will correlate with tumor death after nCRT for esophageal cancer.
TRIAL REGISTRATION
NCT03223662 ; Clinicaltrials.gov. July 21, 2017.
背景
2016年食管癌导致近16000人死亡。食管癌患者数量逐年增加。食管癌切除术前的新辅助放化疗（nCRT）是食管癌的标准治疗方法。手术时无残留肿瘤（病理完全缓解（pCR））的患者最有可能实现长期生存。准确确定哪些患者会出现pCR将改善患者及其家属的预后信息，确认对nCRT无反应，或在无残留肿瘤时避免手术。影像学、内镜检查和液体生物标志物在未进行食管癌切除的情况下均无法检测到pCR。
方法
在本研究中，我们正在招募食管腺癌和鳞状细胞癌患者。患者将接受包括CT扫描、实验室检查、内镜活检以及胸外科医生评估在内的标准评估。入组需要进行组织活检，活检组织将送去进行BH3分析和代谢组学分析。患者将接受标准的nCRT，随后进行手术。有转移性疾病的患者不符合条件。美国国立癌症研究所的手术将采用微创机器人手术。患者将通过定期门诊就诊和影像学检查无限期参与研究。
讨论
线粒体在细胞内凋亡途径中起关键作用。Bcl-2同源结构域3（BH3）分析是一种测量细胞对凋亡敏感性的技术。BH3分析测量诱导或阻断凋亡的蛋白质之间的相对相互作用。这些蛋白质的总体平衡决定细胞是否接近凋亡阈值。如果细胞接近该阈值，那么肿瘤在用nCRT治疗时可能更易死亡。线粒体分泌的代谢产物可作为生物标志物被检测到。代谢组学是对所有代谢产物变化的全面评估，已用于癌症的检测、监测、预后和治疗反应评估。根据是否发生pCR对患者进行分层可能会阐明与反应相关的代谢组学特征。我们正在研究BH3分析或代谢组学特征是否与食管癌nCRT后的肿瘤死亡相关。
试验注册
NCT03223662；Clinicaltrials.gov。2017年7月21日。
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