Colorectal cancer (CRC) is one of the most diagnosed cancers in the world. Even though screening, surgery and oncology have greatly advanced, CRC is still one of the leading causes of cancer deaths, with 700,000 annual mortalities in both men and women. Environmental and lifestyle factors brought up by industrialization, such as an altered diet, lack of physical activity, increase in alcohol consumption, and circadian disruption, have greatly affected the burden of CRC. These factors increase the CRC risk, at least partly, by pathologically altering the colonic environment, including composition of the gut microbiota, referred to as dysbiosis. Colonic dysbiosis can promote pro-carcinogenic immune signaling cascades, leading to pro-tumorigenic inflammation, carcinogen production, and altered cellular responses in susceptible host resulting to development and/or progression of CRC. Nutraceuticals such as prebiotic molecules and probiotic bacterial species can help maintain intestinal microbial homeostasis and thus mitigate this pathological processes. Therefore, prebiotics and probiotics can hinder the effects of dysbiosis by encouraging anti-carcinogenic, anti-inflammatory immunity, the maintenance of the intestinal epithelial barrier, pro-apoptotic mechanisms, and carcinogen inactivation. In addition to its implications in preventing CRC, because of the mechanisms affected, nutraceuticals are being discovered as potential adjuncts to immune checkpoint inhibitors in the treatment of CRC. In this review, we provide an overview of the potential implications of prebiotics and probiotics in the prevention and treatment of CRC.

Pancreatic ductal adenocarcinoma (PDA) is an extremely lethal malignancy arising from the pancreas. The treatment of PDA is complicated by ineffective treatments and a lack of biomarkers predictive of treatment success. We have designed a patient-derived organoid (PDO) based high-throughput drug screening assay to model treatment response to a variety of conventional and investigational treatments for PDA. Consecutive patients undergoing endoscopic ultrasound-guided fine-needle biopsy for tissue diagnosis of PDA at Rush University Medical Center were offered to participate in the study. Biopsies were immediately processed to develop organoids. Fifteen PDOs were screened for sensitivity to 18 compounds, including conventional PDA chemotherapies and FDA-approved investigational targeted therapies in cancer using Cell-titer GLO 3D (Promega) cell viability assay. The area under the curve (AUC) was calculated and normalized to the maximum area under the curve to generate a normalized AUC between 0 and 1. Molecular profiling of PDOs was conducted using RNA-seq. Human PDA transcriptomic was extracted from The Cancer Genome Atlas (TCGA). The drug response curves were reproducible. We observed variation in response to conventional therapies overall as well as among individual patients. There were distinct transcriptome signatures associated with response to the conventional chemotherapeutics in PDA. The transcriptomic profile of overall resistance to conventional therapies in our study was associated with poor survival in PDA patients in TCGA. Our pathway analysis for targeted drugs revealed a number of predictors of response associated with the mechanism of action of the tested drug. The multiplex organoid-based drug assay could be used in preclinical to inform patient stratification and therapeutic selection in PDA. When combined with omics data, ex vivo response to treatment could help identify gene signatures associated with response to novel therapies.

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