Therapeutic challenges at the preclinical level for targeted drug development for Opisthorchis viverrini-associated cholangiocarcinoma

ABSTRACT

Introduction

Cholangiocarcinoma (CCA) is a malignant tumor of bile duct epithelium with the highest incidence found in Thailand. Some patients are considered suitable for adjuvant therapy and surgical resection is currently the curative treatment for CCA patients. Tumor recurrence is still a hurdle after treatment; hence, finding novel therapeutic strategies to combat CCA is necessary for improving outcome for patients.

Areas covered

We discuss targeted therapies and other novel treatment approaches which include protein kinase inhibitors, natural products, amino acid transporter-based inhibitors, immunotherapy, and drug repurposing. We also examine the challenges of tumor heterogeneity, cancer stem cells (CSCs), the tumor microenvironment, exosomes, multiomics studies, and the potential of precision medicine.

Expert opinion

Because CCA is difficult to diagnose at the early stage, the traditional treatment approaches are not effective for many patients and most tumors recur. Consequently, researchers are exploring multi-aspect molecular carcinogenesis to uncover molecular targets for further development of novel targeted drugs.

KEYWORDS:

• Cholangiocarcinoma
• precision medicine
• chemotherapy
• amino acid transporter-based inhibitor
• immunotherapy
• drug repurposing
• tumor heterogeneity
• cancer stem cells
• tumor microenvironment
• multiomics study
• precision medicine

Article Highlights

• Chronic inflammation caused by Opisthorchis viverrini (Ov) infection is defined as the major risk factor for CCA development in Thailand.

• The use of chemotherapeutic drugs such as gemcitabine, cisplatin, and 5-fluorouracil (5-FU) as CCA adjuvant therapy can improve the survival outcome of CCA patients.

• Chemoresistance or a poor response to treatment is a problem.

• Novel therapeutic strategies, improved efficacy and reduction of side effects of conventional chemotherapy are desirable.

• Protein kinase inhibitors, natural products, amino acid transporter-based inhibitors, immunotherapy, and repurposed drugs have been preclinically studied and evaluated for CCA therapy.

• The challenges for new CCA drug development arise from factors such as tumor heterogeneity, cancer stem cells (CSCs), microbiota, tumor microenvironment, and exosomes.

• Multiomics advancement for CCA precision medicine treatment is urgently needed.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This study was supported by the grant of the National Research Council of Thailand through Fluke Free Thailand Project and the Basic Research Fund of Khon Kaen University under Cholangiocarcinoma Research Institute to W Loilome.