(10.) The Gut Microbiome and Responses to Neoadjuvant Chemoradiation in Rectal Cancer Patients

 描述（由申请人提供）：结直肠癌是美国第三大最常见的癌症类型，也是男性和女性癌症相关死亡率的第二大原因。直肠癌位于盆腔深处的直肠，据估计，2015年将有大约40，000例直肠癌新发病例。局部晚期直肠癌的治疗不同于结肠癌，因为标准方法是新辅助化疗，特别是5-FU，结合手术前放疗。这种方法被证明可以降低局部复发率，局部复发率可能会导致严重的发病率和死亡率。新辅助放化疗后病理完全缓解的实现也与患者结局的改善相关。化疗和放疗均可引起肠粘膜的变化，特别是肠上皮屏障功能的变化和炎症反应的诱导。此外，化疗和放疗也会影响肠道微生物组的组成，这反过来又会影响对化疗疗效至关重要的免疫反应。因此，我们假设新辅助治疗期间肠道微生物组的组成和肠道微生物组活性的变化与肿瘤反应相关。在拟议的工作中，我们将在新辅助化疗-放射治疗之前、期间和之后从局部晚期直肠癌患者中获取粪便样本，并分别通过16 S细菌测序和质谱法确定微生物组的组成和功能活性。总体目标是确定是否存在对实现完全病理学缓解重要的特定细菌种群或功能，如通过新辅助治疗完成后手术切除的肿瘤标本的组织学评价所评估的。这些研究将为未来的工作奠定基础，通过操纵肠道微生物组来改善肿瘤对化学辐射的反应和患者的预后。

 DESCRIPTION (provided by applicant): Colorectal cancer is the third most common type of cancer in the United States and the second leading cause of cancer-related mortality among men and women combined. Rectal cancers are located in the rectum deep in the pelvis, and it is estimated that there will be approximately 40,000 new cases of rectal cancer in 2015. The treatment of locally advanced rectal cancers is different from colon cancer in that the standard approach is neoadjuvant chemotherapy, specifically with 5-FU, combined with radiation prior to surgery. This approach was shown to reduce the rate of local recurrence that can cause substantial morbidity and mortality. The achievement of pathologic complete response after neoadjuvant chemo-radiation has also been associated with improved patient outcomes. Both chemotherapy and radiation can cause changes in the intestinal mucosa, in particular changes in intestinal epithelial barrier function and induction of inflammatory responses. In addition chemotherapy and radiation can also affect the composition of the gut microbiome, which, in turn, can affect immune responses that are important for chemotherapy efficacy. Thus, we hypothesize that the composition of the gut microbiome and changes in the activities of the gut microbiome during neoadjuvant therapy are associated with tumor responses. In the proposed work, we will obtain stool samples from locally advanced rectal cancer patients before, during, and after completion of neoadjuvant chemo-radiation and determine the composition and functional activities of the microbiome through 16S bacterial sequencing and mass spectrometry, respectively. The overall goal will be to determine if there are specific bacterial populations or functions that are important for achieving complete pathologic response as assessed by histologic evaluation of tumor specimens surgically removed after completion of neoadjuvant therapy. These studies will lay the foundation for future work to improve tumor responses to chemo-radiation and patient outcomes by manipulation of the gut microbiome.