Pancreatic cancer (PC) is highly lethal disease. At the time of diagnosis more than 80% of PC patients have either locally advanced or highly metastatic disease. Fatality of PC patients is associated with early metastasis (spreading to distant organs), induction of multiple organ failure, cachexia (loss of weight and muscle atrophy), and poor patient response to standard chemotherapy. PCs often overexpress and release into the blood unusual glycoproteins that include CA19-9 and CA125 (also known as MUC16). We have recently discovered that, in addition to serving as a biomarker, aberrantly glycosylated forms of the large mucin type glycoproteins that comprise the material recognized in the CA19-9 and CA125 assays have biological activity as growth factors or cytokines. Thus, we aim to define the way in which this newly discovered activity affects the tumor progression, early metastasis and systemic effects of cancer progression. Our preliminary data demonstrate that overexpression of tumor associated truncated carbohydrate antigens (Tn and STn) on the MUC16 (Tn/STn-MUC16) membrane mucin glycoprotein creates a ligand for growth factor receptors, which results in an activation of oncogenic signaling cascades through Akt and FAK that increases the malignant potential of PC cells. Treatment of cancer cells with monoclonal antibody (mAb) AR9.6 that binds to MUC16, blocks stimulation of the above described oncogenic signaling cascades. In addition, treatment of PC cells and tumor bearing animals with AR9.6 mAb inhibits in vitro cancer cell growth, and in vivo tumor growth and metastasis. Genetic deletion of aberrant glycoforms MUC16 in PC cells reduced tumor metastasis, reduced the phosphorylation of ErbB2, ErbB3, Akt and GSK3?, and increased the median survival of the animals. We hypothesize that aberrant glycoforms of MUC16 play a major role in PC growth, metastasis and survival. Therefore, we propose to determine the circulating levels of abnormally glycosylated MUC16, and correlate this to the status of altered receptor-ligand interactions and oncogenic signaling in clinical specimens, and to clinical outcomes such as the incidence of metastasis, organ failure, cachexia, and overall survival using a unique set of samples obtained from rapid autopsies of patients that died of PC (Aim 1). We will validate our hypothesis that abnormal glycosylation of mucin glycoproteins contributes to pancreatic tumor progression and metastasis using genetic engineered mouse models of PC that are further engineered to express aberrantly glycosylated mucins (Aim 2). We will elucidate the mechanism by which aberrant glycoforms of MUC16 mediate PC tumorigenesis, and determine the in vivo therapeutic efficacy of AR9.6 mAb alone and in combination with Gemcitabine treatment against PC (Aim 3).These studies will lead to a new understanding of factors that contribute to tumor progression, metastasis, and the effects of secreted tumor products on distant organ sites, including the formation of the metastatic niche and cachexia. Also, the studies in this proposal have the potential to lead to novel targeted therapeutic strategies against metastatic PC.
In addition to functioning as a biomarker for adenocarcinoma, aberrant glycoforms of MUC16 (Tn/STn-MUC16) have biological functions as growth factors or cytokines that may contribute to pancreatic tumor progression, formation of the metastatic niche, cachexia or organ failure in the late phases of the disease. A principal goal of this application is to determine the molecular mechanism by which altered glycosylation (truncated O-glycans) of MUC16 creates biologically active compounds that contribute to tumor progression, metastasis and systemic effects of cancer progression, and development of novel targeted therapeutic strategy against metastatic pancreatic cancer.
