Promising Highly Targeted Therapies for Cholangiocarcinoma: A Review and Future Perspectives

SIMPLE SUMMARY: The challenging early detection of cholangiocarcinoma and the limited availability of less-invasive anticancer therapies contribute to its poor prognosis. Some highly targeted therapies have been explored for cholangiocarcinoma, such as antibody-drug conjugates (ADCs), photodynamic therapy (PDT) with/without systemic chemotherapy, and experimental photoimmunotherapy (PIT). PIT stands out as a novel and promising therapy with less invasiveness; however, it has not yet been performed in human cases of cholangiocarcinoma. In this article, we focus on and review ADC, PDT, and PIT as highly targeted therapies, including experimental therapies for cholangiocarcinoma, and indicate their future prospects. ABSTRACT: To overcome the poor prognosis of cholangiocarcinoma (CCA), highly targeted therapies, such as antibody-drug conjugates (ADCs), photodynamic therapy (PDT) with/without systemic chemotherapy, and experimental photoimmunotherapy (PIT), have been developed. Three preclinical trials have investigated the use of ADCs targeting specific antigens, namely HER2, MUC1, and glypican-1 (GPC1), for CCA. Trastuzumab emtansine demonstrated higher antiproliferative activity in CCA cells expressing higher levels of HER2. Similarly, “staphylococcal enterotoxin A-MUC1 antibody” and “anti-GPC1 antibody-monomethyl auristatin F” conjugates showed anticancer activity. PDT is effective in areas where appropriate photosensitizers and light coexist. Its mechanism involves photosensitizer excitation and subsequent reactive oxygen species production in cancer cells upon irradiation. Hematoporphyrin derivatives, temoporfin, phthalocyanine-4, talaporfin, and chlorine e6 derivatives have mainly been used clinically and preclinically in bile duct cancer. Currently, new forms of photosensitizers with nanotechnology and novel irradiation catheters are being developed. PIT is the most novel anti-cancer therapy developed in 2011 that selectively kills targeted cancer cells using a unique photosensitizer called “IR700” conjugated with an antibody specific for cancer cells. PIT is currently in the early stages of development for identifying appropriate CCA cell targets and irradiation devices. Future human and artificial intelligence collaboration has potential for overcoming challenges related to identifying universal CCA cell targets. This could pave the way for highly targeted therapies for CCA, such as ADC, PDT, and PIT.