Optimized targeted radiotherapy of pancreatic cancer

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 9% and is on track to become the 2nd leading cause of cancer deaths by 2030. This poor statistic is primarily due to the difficulty in screening for pancreatic cancer resulting in late-stage diagnosis. Currently about 20% of pancreatic cancers are localized at diagnosis and hence surgically removable. About 20-25% of patients have tumors that have further progressed and require chemotherapy and radiation therapy before some of them can have surgery. Most of the patients have metastatic disease, and the only currently available options are conventional chemotherapies. A major challenge for developing targeted therapies to treat PDAC has been the stroma which acts as a barrier to delivering drugs to the pancreatic cancer cells. Hence attempts to develop targeted therapies to PDAC need to have strategies to overcome this challenge. Tumor associated MUC1 (tMUC1) is present on over 90% of pancreatic ductal adenocarcinoma (PDAC) examined by immunohistochemistry, making it an extremely promising target. We have developed a tumor specific antibody, TAB004, which specifically detects tMUC1. The TAB004 antibody has also been fully humanized (hTAB004) to develop radionuclide imaging and targeted radiotherapy and we have demonstrated exceptional results in a triple negative breast cancer model. However, PDAC are known to have a desmoplastic stroma that constricts blood vessels that could deliver the radiotherapy to the cells. Hence a full-length antibody may not be the best targeting agent for pancreatic cancers compared to smaller molecules. In this project we propose to conduct a structured Design of Experiments (DOE) in which we will use the hTAB004 as well as a tandem scFv as targeting agents that will be labeled with a and b particle emitting radioisotopes. The tandem scFv will consist of hTAB004 scFv linked with the scFv of a Human/Mouse Serum Albumin (H/MSA) to ensure the construct does not rapidly clear via the kidneys. Such constructs (~50 kDa) have shown faster, and deeper tumor penetration compared to full length antibodies, with comparable uptake in the kidneys. Thus, one DOE variable (ligand size) will vary the tumor penetration and the other variable (radioisotope) will vary the radiation range. These are the most appropriate variables to study to develop an optimized radiopharmaceutical to target PDAC with minimal impact to normal cells. We will test these combinations in immune competent PDAC model having the appropriate stromal, hormonal, and immune milieu.