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

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.

Current and Emerging Therapeutic Targets for the Treatment of Cholangiocarcinoma: An Updated Review

“…Antibody–drug conjugates (ADCs) are novel drug delivery mechanisms with two primary components: An antibody capable of targeting proteins expressed on the cell surface as well as a ‘payload’ of a cytotoxic chemotherapeutic agent [ 55 ]. Several promising cell surface protein targets have been identified that are under pre-clinical investigation for the treatment of cholangiocarcinoma.…”

“…Yashima et al conducted a pre-clinical study evaluating an ADC comprised of an HER-2-targeting antibody in conjunction with a trastuzumab emtansine payload in the CCA cell line. The study demonstrated that cell death was increased in HER-2 overexpressing CCA cells when compared to HER-2 negative cells by IHC GPC-1 is a cell surface proteoglycan receptor that contributes to cellular growth and proliferation by acting as a co-receptor with other pro-growth cellular receptors [ 55 ]. GPC-1 overexpression has been demonstrated in up to 47% of CCA tumor specimens [ 56 ].…”

A NRF2 Regulated and the Immunosuppressive Microenvironment Reversed Nanoplatform for Cholangiocarcinoma Photodynamic‐Gas Therapy

“…Photodynamic therapy (PDT) is an effective modality for tumor treatment, [ 1 , 2 , 3 ] and its application in the management of malignancies, such as cholangiocarcinoma (CCA), [ 4 , 5 , 6 ] has demonstrated definitive therapeutic benefits. Besides its direct cytotoxicity toward tumor cells, PDT exhibits immunomodulatory properties supported by accumulating evidence.…”