A Novel Association and Therapeutic Targeting of Neuropilin-1 and MUC1 in Pancreatic Cancer

Pancreatic cancer has the worst prognosis of all cancers and is the fourth leading cause of cancer-related deaths in the United States. The disease has a dismal 5-year survival rate of 5% and a mean life expectancy of 6 months, which is thought to be a result of the inherently aggressive nature of the disease in combination with diagnosis that typically occurs at the later stages. Therefore, it is important for research to focus on why pancreatic cancer is so aggressive and how to treat pancreatic cancer once it has spread.

Mucin1 (MUC1) is a protein present on over 60% of pancreatic tumors and on 100% of metastatic lesions from the pancreas. In pancreatic cancer, MUC1 is a marker of aggressive tumors that are highly metastatic leading to poor prognosis. Additionally, MUC1 is expressed in an altered form on pancreatic tumors, which allows for the specific detection of 'tumor-associated' MUC1. In a new, unpublished, observation, we have found that pancreatic tumors with high MUC1 have increased levels of Neuropilin 1 (NRP-1), which is a co-receptor for Vascular Endothelial Growth Factor (VEGF). Tumors induce new blood vessel formation (also known as angiogenesis) by enhancing the production of 'pro-angiogenic' factors, such as VEGF. NRP-1 is critical for VEGF-induced angiogenesis, and tumors that have high levels of NRP-1 have increased tumor growth, higher levels of angiogenesis, and poorer prognosis. Thus, we hypothesize that MUC1 is driving metastatic spread by increasing levels of NRP-1 within the pancreatic tumor, which reacts with tumor-VEGF to cause increased angiogenesis and therefore increased metastatic spread. Further, blocking NRP-1-VEGF interaction may lead to therapeutic benefit, as it is well established that tumor progression is dependent on the nutrients and oxygen provided by blood and therefore angiogenesis must occur for tumors to grow. Blood vessels within the tumor also supply a route of escape for the cancer and thus promote metastatic spread of the disease. In pancreatic tumors, higher levels of VEGF and blood vessels have been correlated to metastatic spread and disease progression, emphasizing the importance of angiogenesis in pancreatic cancer. Thus, understanding how NRP-1 expression affects VEGF-induced angiogenesis and further targeting of NRP-1-VEGF interaction will be extremely valuable in the context of MUC1 overexpressing pancreatic tumors.

We propose to test the hypothesis by, first, using human and mouse pancreatic cancer cell lines that are void or express high levels of MUC1. We will investigate the ability of these cells to cause endothelial cells to undergo changes that would occur in an angiogenic environment, such as proliferation, invasion, and vessel formation. Thereafter, we will use appropriate mouse models that develop spontaneous tumors of the pancreas with either human MUC1 or lacking MUC1 to assess angiogenesis and NRP-1 levels. It is critical to note that we propose to use models of pancreatic cancer where mice are genetically manipulated to spontaneously develop cancer in a manner similar to human disease. Investigation into an association between MUC1 and NRP-1 could unlock some of the keys to the aggressive nature of pancreatic cancer.

The last goal of our project is to therapeutically intervene in the angiogenic progress using targeted drug delivery. In the past, targeting angiogenesis has not proven to be beneficial in clinical trials. One possible explanation for this is that systemic delivery of the drugs that can lead to toxic side-effects and a low dose of drug actually reaching the tumor site. We propose to use a novel antibody, which recognizes tumor-associated MUC1 that is highly expressed on pancreatic tumors and metastatic lesions. We plan to attach a blocker of NRP-1-VEGF interaction to the MUC1 antibody with the goal of delivering the blocker directly to the tumor site sparing normal tissue. To test this system, we will use our mouse model of pancreatic cancer, which expresses the human form of the MUC1 gene. This allows us to use an antibody against the human form of MUC1 and increases the ability of this work to quickly move into the clinic. Thus, this goal is highly innovative and could generate promising preclinical data regarding targeted drug delivery in pancreatic cancer and the effects of inhibiting NRP-1-VEGF interaction in pancreatic cancer.

In summary, our proposal will investigate the relationship between MUC1 and NRP-1, which have both been shown to contribute to the aggressive nature of pancreatic cancer. We will do this using relevant in vitro culturing techniques and mouse models of pancreatic cancer that are unique to our lab. Further we propose to deliver a blocker of NRP-1-VEGF directly to the tumor using an antibody that is specific for tumor-associated MUC1. We aim to stop tumor growth, angiogenesis, metastases, and progression with this treatment.