The third leading cause of cancer-related deaths in the United States is pancreatic cancer, more than 95% of which is pancreatic ductal adenocarcinoma (PDA). The incidence rate of PDA nearly matches its mortality rate and the best treatment till date is surgical resection for which only 25% are eligible. Tumor recurrence and metastasis are the main causes of cancer-related mortality. MUC1 is a transmembrane glycoprotein expressed on most epithelial cells. It is overexpressed and aberrantly glycosylated in cancer and is known as tumor-associated MUC1 (tMUC1). More than 80% of PDAs express tMUC1. A monoclonal antibody called TAB004 has been developed specifically against human tMUC1 extracellular domain. We report that treatment with TAB004 significantly reduced the colony forming potential of multiple PDA cell lines while sparing normal pancreatic epithelial cell line. Binding of TAB004 to tMUC1 compromised desmosomal integrity, induced ER stress and anoikis in PDA cells. The mechanisms underlying TAB004's antitumor effects were found to be reduced activation of the EGFR-PI3K signaling pathway, and degradation of tMUC1, thereby reducing expression of its transcriptional targets, c-Src and c-Myc. This reduction in oncogenic signaling triggered anoikis as indicated by reduced expression of antiapoptotic proteins, PTRH2 and BCL2. TAB004 treatment slowed the growth of PDA xenograft compared to IgG control and enhanced survival of mice when combined with 5-FU. Since TAB004 significantly reduced colony forming potential and triggered anoikis in the PDA cells, we suggest that it could be used as a potential prophylactic agent to curb tumor relapse after surgery, prevent metastasis and help increase the efficacy of chemotherapeutic agents.

Chimeric antigen receptor (CAR) T cells have shown remarkable success in treating hematologic cancers. However, this efficacy has yet to translate to treatment in solid tumors. Pancreatic ductal adenocarcinoma (PDA) is a fatal malignancy with poor prognosis and limited treatment options. We have developed a second generation CAR T cell using the variable fragments of a novel monoclonal antibody, TAB004, which specifically binds the tumor-associated-MUC1 (tMUC1). tMUC1 is overexpressed on ~85% of all human PDA. We present data showing that TAB004-derived CAR T cells specifically bind to tMUC1 on PDA cells and show robust killing activity; however, they do not bind or kill normal epithelial cells. We further demonstrated that the tMUC1-CAR T cells control the growth of orthotopic pancreatic tumors in vivo. We witnessed that some PDA cells (HPAFII and CFPAC) were refractory to CAR T cell treatment. qPCR analysis of several genes revealed overexpression of indoleamine 2, 3-dioxygenases-1 (IDO1), cyclooxygenase 1 and 2 (COX1/2), and galectin-9 (Gal-9) in resistant PDA cells. We showed that combination of CAR T cells and biological inhibitors of IDO1, COX1/2, and Gal-9 resulted in significant enhancement of CAR T cell cytotoxicity against PDA cells. Overcoming PDA resistance is a significant advancement in the field.

Gastrointestinal cancers (GI) account for 26% of cancer incidences globally and 35% of all cancer-related deaths. The main challenge is to target cancer specific antigens. Mucins are heavily O-glycosylated proteins overexpressed in different cancers. The transmembrane glycoprotein MUC1 is the most likeable target for antibodies, owing to its specific overexpression and aberrant glycosylation in many types of cancers. For the past 30 years, MUC1 has remained a possible diagnostic marker and therapeutic target. Despite initiation of numerous clinical trials, a comprehensively effective therapy with clinical benefit is yet to be achieved. However, the interest in MUC1 as a therapeutic target remains unaltered. For all translational studies, it is important to incorporate updated relevant research findings into therapeutic strategies. In this review we present an overview of the antibodies targeting MUC1 in GI cancers, their potential role in immunotherapy (i.e., antibody-drug and radioimmunoconjugates, CAR-T cells), and other novel therapeutic strategies. We also present our perspectives on how the mechanisms of action of different anti-MUC1 antibodies can target specific hallmarks of cancer and therefore be utilized as a combination therapy for better clinical outcomes.

The complex interactions between genes and the environment play important roles in disease susceptibility and progression. One of the chronic diseases that is affected by this gene-environment interplay is cancer. However, our knowledge about these environmental factors remains limited. The microorganisms that inhabit our bodies have recently been acknowledged to play a crucial role as an environmental factor, to which we are constantly exposed. Studies have revealed significant differences in the relative abundance of certain microbes in cancer cases compared with controls. It has been reported that changes in the composition of normal gut microbiota can increase/decrease cancer susceptibility and progression by diverse mechanisms including, but not limited to, inflammation—a well-known hallmark of carcinogenesis. The microbiota can also affect the response to various treatments including immunotherapy. The microbiome-immune-cancer axis will continue to provide insight into the basic mechanisms of carcinogenesis. In this review, we provide a brief understanding of the mechanisms by which microbiota affects cancer development, progression, and treatment.

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human cancers. Transforming Growth Factor Beta (TGF-β) is a cytokine that switches from a tumor-suppressor at early stages to a tumor promoter in the late stages of tumor development, by yet unknown mechanisms. Tumor associated MUC1 is aberrantly glycosylated and overexpressed in >80% of PDAs and is associated with poor prognosis. MUC1 expression is found in the early stages of PDA development with subsequent increase in later stages. Analysis of human PDA samples from TCGA database showed significant differences in gene expression and survival profiles between low and high MUC1 samples. Further, high MUC1 expression was found to positively correlate to TGF-βRII expression and negatively correlate to TGF-βRI expression in PDA cell lines. We hypothesized that MUC1 overexpression induces TGF-β mediated non-canonical signaling pathways which is known to be associated with poor prognosis. In this study, we report that MUC1 overexpression in PDA cells directly activates the JNK pathway in response to TGF-β, and leads to increased cell viability via up-regulation and stabilization of c-Myc. Conversely, in low MUC1 expressing PDA cells, TGF-β preserves its tumor-suppressive function and inhibits phosphorylation of JNK and stabilization of c-Myc. Knockdown of MUC1 in PDA cells also results in decreased phosphorylation of JNK and c-Myc in response to TGF-β treatment. Taken together, the results indicate that overexpression of MUC1 plays a significant role in switching the TGF-β function from a tumor-suppressor to a tumor promoter by directly activating JNK. Lastly, we report that high-MUC1 PDA tumors respond to TGF-β neutralizing antibody in vivo showing significantly reduced tumor growth while low-MUC1 tumors do not respond to TGF-β neutralizing antibody further confirming our hypothesis.