Targeting Disease Specific Tn Antigen in Pancreatic Cancer

Abstract public domain (NIH RePORTER)

ABSTRACT / PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease. Over 80% of PDAC patients have locally advanced or highly metastatic disease at diagnosis. FOLFIRINOX and Gemcitabine/Nab-Paclitaxel are currently used as the standard of care for advanced PDAC patients, but responses are incomplete. Thus, there is an urgent and unmet need to develop novel targeted therapeutic strategies against PDAC. More than 80% of PDACs express surface glycoproteins carrying the cancer-associated carbohydrate antigens Tn and Sialyl Tn (STn), whose expression does not normally occur in the pancreas or other tissue and is associated with poor prognosis and reduced overall survival of PDAC patients. In addition to serving as a prognostic biomarker, we discovered that Tn/STn antigens on glycoproteins alter biological activity regarding growth factors and cytokines. Our preliminary data demonstrate that overexpression of Tn/STn antigens enhances PDAC disease progression, and metastasis and reduces the overall survival of tumor-bearing animals. Also, induced expression of Tn/STn antigens on glycoprotein receptors and ligands results in the activation of oncogenic signaling cascades through the epidermal growth factor receptor (EGFR/ErbB1) and its downstream PI3K/AKT signaling cascades that increase the malignant potential of PDAC cells. Treatment of Tn+ cancer cells with a newly developed afucosylated monoclonal antibody (mAb) anti-Tn (aRemab6), induces complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). In addition, treatment of Tn+ tumor-bearing animals with aRemab6 inhibits in vivo tumor growth and metastasis via Natural Killer (NK) cell-mediated ADCC. We hypothesize that the cancer-specific expression of the Tn antigen plays a major role in PDAC growth, metastasis, and survival. Therefore, we propose (Aim 1) to determine the mechanisms by which Tn antigen enhances PDAC tumor progression and identify Tn-expressing glycoproteins by glycoproteomics in the mouse model and clinical specimens using a unique set of samples obtained from rapid autopsies of patients that died of PDAC. (Aim 2) We will validate the roles of NK cell in aRemab6-mediated ADCC and evaluate the aRemab6 antibody-induced antitumor immune response in genetically engineered spontaneous immunocompetent mouse models of PDAC that are further engineered to express Tn antigen on glycoproteins (KPC-CosmcKO). (Aim 3) We will determine the “off-tumor” toxicity of aRemab6 and evaluate the therapeutic efficacy of aRemab6 plus gemcitabine/Nab- Paclitaxel against the Tn antigen-expressing immunocompetent spontaneous KPC and KPC-CosmcKO tumor models. These models closely recapitulate the tumor biology of human PDAC tumors and will aid in translating these preclinical findings to human cancer. Together, these studies will lead to a new understanding of factors contributing to pancreatic tumor progression and metastasis. Also, the studies in this proposal have the potential to develop aRemab6-based targeted therapeutic strategy against metastatic PDAC.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Aberrant expression of tumor-associated carbohydrate antigens Tn and STn augment pancreatic ductal adenocarcinoma (PDAC) progression and metastasis and reduce overall survival via constitutive activation of the epidermal growth factor (EGF) receptor family and PI3K/AKT signaling pathways. The major goals of this application are to determine the mechanism by which aberrant expression of Tn/STn enhances PDAC progression and explore the effectiveness of a novel afucosylated anti-Tn antibody (aRemab6) plus gemcitabine/nab-paclitaxel combination as a therapy to treat lethal PDAC.