Extrahepatic Cholangiocarcinoma (eCCA) represents a formidable challenge in oncology, characterized by its aggressive nature, late diagnosis, and limited therapeutic options. At Protheragen, our extensive experience in biological research and drug development positions us at the forefront of advancing preclinical therapeutic strategies for this devastating disease.
Overview of Extrahepatic Cholangiocarcinoma (eCCA)
Extrahepatic Cholangiocarcinoma (eCCA) is a malignancy that originates from the epithelial cells lining the bile ducts outside the liver. It constitutes a substantial portion of all cholangiocarcinomas and exhibits a wide range of clinical and pathological characteristics based on its anatomical location, such as perihilar (Klatskin tumors) or distal bile duct cholangiocarcinomas. Often, eCCA is diagnosed at advanced stages due to its subtle and insidious nature, typically presenting with symptoms like obstructive jaundice, abdominal pain, and weight loss. The prognosis for patients with eCCA remains poor, highlighting the urgent need for more effective diagnostic and therapeutic strategies.
Fig.1 The tumor microenvironment in extrahepatic cholangiocarcinoma. (Yang Y.,
et al., 2023)
Pathogenesis of Extrahepatic Cholangiocarcinoma (eCCA)
The pathogenesis of eCCA is multifaceted, involving genetic, epigenetic, and environmental factors. Key mechanisms include:
eCCA often features mutations in pivotal genes such as TP53, KRAS, and ARID1A. These mutations can wreak havoc on cell cycle regulation, thereby fueling tumor growth.
Aberrant DNA methylation and histone modification are frequently seen in eCCA. They can silence tumor suppressor genes and activate oncogenes, thus contributing to tumorigenesis.
Certain chronic inflammatory conditions, like primary sclerosing cholangitis (PSC) and chronic biliary infections, are closely linked to an elevated risk of eCCA. This underscores the significant role that chronic inflammation plays in its development.
Emerging evidence indicates that metabolic diseases, such as type 2 diabetes and nonalcoholic fatty liver disease, are notable risk factors for eCCA. This highlights the intricate interplay between metabolic pathways and the process of tumorigenesis.
Diagnostics Development for Extrahepatic Cholangiocarcinoma (eCCA)
Molecular Diagnostics
Advances in molecular diagnostics, including next-generation sequencing (NGS) and cell-free DNA (cfDNA) analysis, enable the detection of specific genomic alterations in eCCA. These techniques provide valuable information for personalized therapeutic planning and monitoring of therapeutic response.
Biomarkers
Non-invasive biomarkers, such as serum carbohydrate antigen 19-9 (CA19-9) and microRNAs (miRNAs) derived from bile cytologic samples, show promise for the early detection of eCCA. For instance, increased levels of miR-31-5p, miR-378d, miR-182-5p, and miR-92a-3p have been observed in eCCA cases compared to controls.
Therapeutics Development for Extrahepatic Cholangiocarcinoma (eCCA)
- Adjuvant Therapy: Adjuvant chemotherapy and radiotherapy have been shown to improve survival in patients with resected eCCA. For instance, adjuvant therapy with S-1, a mixture of tegafur, gimeracil, and oteracil potassium, has been shown to improve survival among patients with resected eCCA in a phase 3 randomized clinical trial.
- Targeted Therapies: Molecularly targeted therapies, such as EGFR/ERBB2 inhibitors, are being explored for the therapeutic of eCCA. While EGFR inhibitors have shown limited efficacy in advanced CCA, targeting ERBB2, which is more commonly altered in eCCA, may represent a promising approach. For example, a case report suggested a combination of Trastuzumab and pertuzumab was curative for a patient with ERBB2-amplified eCCA.
- Immunotherapy: Immune checkpoint inhibitors, such as Pembrolizumab and Nivolumab, are being evaluated in clinical trials for the therapeutic of eCCA. These agents aim to reinforce antitumor immunity by blocking intrinsic suppressors, such as CTLA4, PD1, or PDL1, in the immunosuppressive tumor microenvironment.
Table 1. Robust clinical trials of extrahepatic cholangiocarcinoma. (Yang Y., et al., 2023)
| Approach |
Agents |
Sample size |
Clinical trial ID |
| Adjuvant chemotherapy |
Gemcitabine |
225 |
UMIN 00000820 |
| Adjuvant chemotherapy |
Gemcitabine and Capecitabine |
69 |
SWOG 0809 |
| Endoscopic radiofrequency ablation |
NA |
65 |
NCT02592538 |
| Endoscopic radiofrequency ablation |
NA |
174 |
NCT01844245 |
| Endoscopic radiofrequency ablation |
S-1 |
75 |
NCT02592538 |
| Chemotherapy plus targeted therapy |
Gemcitabine and Oxaliplatin plus Erlotinib |
133 |
NCT01149122 |
| Chemotherapy plus targeted therapy |
Gemcitabine and Oxaliplatin plus Cetuximab |
122 |
NCT01267344 |
| Chemotherapy plus targeted therapy |
Cisplatin and Gemcitabine plus Panitumumab |
90 |
NCT01320254 |
| Chemotherapy plus targeted therapy |
Gemcitabine and Oxaliplatin plus Panitumumab |
85 |
NCT01389414 |
| Immunotherapy |
Pembrolizumab |
104 |
NCT02628067 |
| Immunotherapy |
Nivolumab |
54 |
NCT02829918 |
| Immunotherapy |
Atezolizumab plus Cobimetinib |
77 |
NCT03201458 |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Protheragen offers comprehensive diagnostics and therapeutics development services for eCCA. Our services encompass a wide range of capabilities, from biomarker discovery and validation to the evaluation of novel therapeutic agents. Utilizing state-of-the-art technologies and a multidisciplinary approach, Protheragen aims to accelerate the development of effective solutions for this challenging malignancy.
Disease Models
- TFK-1, EGI-1, and QBC939 Cell Lines
- Patient-Derived Organoids (PDOs)
- Patient-Derived Xenografts (PDX) Models
- KRAS or TP53 Genetically Engineered Mouse Models (GEMMs)
Protheragen's competitive advantage lies in our ability to offer a seamless integration of preclinical research services, from early-stage discovery to advanced therapeutic evaluation. Our comprehensive approach ensures that clients receive high-quality data and insights, enabling informed decision-making and efficient progress in their eCCA research programs. If you are interested in our services, please feel free to contact us.
Reference
- Yang, Yongheng, and Xiaolu Zhang. "An overview of extrahepatic cholangiocarcinoma: from here to where?." Frontiers in Oncology 13 (2023): 1171098.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
