Pancreatic cancer (PC) is a highly metastatic disease with few effective treatment options. MUC1 is a glycoprotein that is over-expressed and aberrantly glycosylated in over 60% of PC and 100% of PC metastases. Tumor-associated MUC1 is a marker of an aggressive phenotype, as its expression is correlated with high metastases and poor prognosis. We have recently found that pancreatic cancer cells and tumors expressing high MUC1 have increased levels of neuropilin-1 (NRP-1), a co-receptor of VEGFA as compared to PDA with no or low MUC1. NRP-1 potentiates VEGF receptor signaling and pro-angiogenic activities. This may be indicative of enhanced intra-tumoral angiogenesis and disease progression. However, many drugs targeting angiogenesis have produced serious side effects, including hypertension, thrombotic events, and allergic reactions. Additionally, it i well accepted that drug delivery into the pancreas is difficult, as PC is highly desmoplastic with dense stroma. Thus, we hypothesize that MUC1 induces a pro-angiogenic tumor microenvironment by increasing levels of NRP-1 and subsequent VEGFA signaling. This may be the leading cause for the highly metastatic and aggressive tumor phenotype associated with MUC1. Second, we hypothesize that blocking the interaction between VEGF165 and NRP-1 within the tumor microenvironment will lead to therapeutic benefit. We will therefore first aim to study the effects of MUC1+ PDA cells on endothelial cell function in an NRP-1-dependent fashion in vitro. Second, we will determine if MUC1 creates a pro-angiogenic niche in vivo by up-regulating NRP-1 and VEGF signaling. Finally, we will deliver a VEGF165-NRP-1 inhibitory peptide directly to the MUC1-expressing pancreatic tumor microenvironment using a novel MUC1 antibody to deliver the peptide blocker. We propose to use appropriate PDA mouse models to study in vivo angiogenesis and drug delivery. In these mice, pancreatic tumors occur within the pancreas and recapitulate the human disease, progressing through the full spectrum of pancreatic intraepithelial neoplasia (PanINs) lesions to invasive adenocarcinoma with metastases. These mice either express human MUC1 (KCM) or are null for Muc1 (KCKO). By using these mouse models, we will be able to evaluate angiogenesis switch in an appropriate setting which will include the dense stromal component of the pancreas. Further, the use of the KCM mice will render our results highly translatable, as we are able to test our therapy targeting human MUC1. We recognize that such targeted delivery using a MUC1 antibody has never been attempted but if this works, it will revolutionize the way small molecules and peptides are delivered to the pancreas without unwanted side effects. If funded, this AREA grant will guarantee a strong research environment in the PI's lab, and will enhance the overall research environment that will help draw in the highest quality students, which is critical to successful development of a major research institution.
We hypothesize that a mucin glycoprotein namely MUC1 (which is aberrantly over expressed in >90% of metastatic pancreatic cancers) is driving metastatic spread by increasing levels neuropilin-1 (NRP-1) within the pancreatic tumor. NRP-1 reacts with tumor-vascular endothelial growth factor (VEGF) to cause increased angiogenesis and therefore increased metastatic spread. Thus, we propose to block NRP-1-VEGF interaction within the pancreatic tumor to achieve therapeutic benefit.
|Zhou, R; Curry, J M; Roy, L D et al. (2016) A novel association of neuropilin-1 and MUC1 in pancreatic ductal adenocarcinoma: role in induction of VEGF signaling and angiogenesis. Oncogene 35:5608-5618|