Abstract 1323: Targeting tMUC1 for the diagnostics and treatment of pancreatic cancer
Authors: Wu Shuta , Fowler Anthony J. , Ogle Craig , Mukherjee Pinku 
Published: July 2016

Background:

Pancreatic Cancer is (PC) is the 4th leading cause of cancer-related deaths in the United States with 94% of PC patients dying within 5 years of diagnosis. Treatment options for PC patients are limited as PC is diagnosed at a late stage from the lack of early symptoms and inaccessibility of the pancreatic region. Typical early detection methods involve ultrasound tests or cholangiopancreatography which can be intrusive or use radioactive materials.

Typical treatments involve ablation, chemotherapy, or a combination of chemotherapy with radiation. But these methods can have adverse side and off-target effects due to systemic delivery of drugs

There is a need to diagnose pancreatic cancer efficiently and to target the delivery of anti-cancer treatments at optimal dosages to avoid adverse side-effects in patients.

Pancreatic Ductal Adenocarcinoma (PDA) represents 90% of PCs and over 80% of PDAs over-express tumor-associated Mucin-1 (tMUC1), a membrane-tethered glycoprotein protein. Tumor-associated MUC1 exhibits changes to its glycosylation pattern that expose its protein core, thus making it identifiable to the TAB004, a specific antibody we developed and have shown to only recognizes this form of MUC1.

Thus, we hypothesize that TAB004 antibody can be utilized as a targeting agent to accurately diagnose PDA and to enable the use of highly cytotoxic anti-cancer treatments at localized concentrations, which would make the treatment more effective at lower doses overall.

Methods:

We determined the specificity and internalization of TAB004 (OncoTab Inc) in several MUC1-expressing PDA cell lines in vitro using confocal and high resolution fluorescence microscopy. NuLink kit (NuChemie) was used in TAB004-PLGA nanoparticle (NPs) conjugation. Confirmation of NPs to TAB004 conjugation (NP-TAB) was determined using flow cytometry. NP-TAB and NPs internalization was compared using confocal microscopy in vitro in several tMUC1-expressing PDA cell lines. Viability of cell lines was determined using the Dojindo CCK -8 Cell Proliferation Assay and Cytotoxicity Assay in response to NPs and NP-TAB treatments. Imaging of mice injected with TAB004 conjugated with ICG (Dojindo ICG labeling Kit-NH2), NPs with ICG, and NP-TAB with ICG was performed using and IVIS Spectrum.

Results:

TAB004 was specific for and internalized significantly more in tMUC1 expressing cell lines. NP-TAB persist longer in tMUC1 expressing cells in vitro. TAB004 was able to target tMUC1 expressing orthotopic PDA tumors. NP-TAB had significantly increased accumulation at the tumor site than NPs. Further experiments are currently being performed in vivo in an appropriate mouse model of PDA to determine treatment efficacy.

Conclusion:

TAB004 is a promising targeting agent for diagnosing and treating tMUC1 expressing PDA. Given that tMUC1 is associated with aggressive form of PDA and patients with MUC1-positive PDA have poor prognosis, these results are significant and clinically relevant.

Citation Format: Shuta Wu, Anthony J. Fowler, Craig Ogle, Pinku Mukherjee. Targeting tMUC1 for the diagnostics and treatment of pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1323.