Developing novel targeted diagnostics and therapeutics for cholangiocarcinoma

Cholangiocarcinomas (CCAs) are a rare group of cancers with dismal prognosis. New therapeutic options are therefore warranted. Nanomedicine has the potential to improve cancer diagnosis and therapy (theranosis) but has infrequently been explored in CCA.
The aim of this study was to develop a targeted theranostic system for CCA. An orthotopic murine model of CCA to test these systems in a more accurate model of the disease was first generated. Potential biomarkers for theranosis were identified, one of which, tenascin C (TNC), was explored further.
To facilitate the development of orthotopic CCA models, bioluminescent extra-hepatic CCA cell lines were generated using lentiviral infection. Clone TFKluc2B2, was selected for the orthotopic model. These cells were injected under high-frequency ultrasound (HF-US) guidance into peri-cholecystic area of the murine liver. The optimised method yielded 90% success for tumour establishment with the ability to image tumour growth by longitudinal bioluminescent imaging and tumour volume measurement using HF-US.
Potential biomarkers for theranosis in cholangiocarcinoma were identified and evaluated using a systematic approach and a modified scoring system (TASC-T score). Matrix metalloproteinase 9, claudin 18, TNC, carbonic anhydrase 9 and epidermal growth factor receptor showed the highest theranostic potential. TNC was evaluated in 54 human CCA and paired para-cancerous normal liver specimens. Significantly higher TNC immunolabelling was observed in CCA tissue.
Fluorescent-labelled TNC affimers (peptide-based antibody mimetics), were evaluated for their ability to target TNC-positive murine tumours in vivo. A trend towards increased fluorescence was seen in tumours of the TNC affimer group compared to control affimer. Gold nanoparticles and two chemotherapeutic agents (gemcitabine and irinotecan) were also evaluated as part of a potential theranostic system that would include photothermal therapy and targeted drug delivery.
This work provides the rationale for a nanoparticle-based theranostic system to be developed for improved therapeutics in CCA.