Related Experiment Videos
Targeting c-MET in gastrointestinal tumours: rationale, opportunities and challenges
Conor A Bradley1, Manuel Salto-Tellez1,2, Pierre Laurent-Puig3
1Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7AE, UK.
Abstract:
Data from many preclinical studies, including those using cellular models of colorectal, gastric, gastro-oesophageal and gastro-oesophageal junction cancers, indicate that the hepatocyte growth factor (HGF)-hepatocyte growth factor receptor (c-MET) pathway is vital for the growth, survival and invasive potential of gastrointestinal cancers. Following the availability of data from these various studies, and data on c-MET expression as a biomarker that indicates a poor prognosis in patients with gastrointestinal cancer and increased c-MET expression, inhibitors targeting this pathway have entered the clinic in the past decade. However, the design of clinical trials that incorporate the use of HGF/c-MET inhibitors in their most appropriate genetic and molecular context remains crucial. Recognizing and responding to this challenge, the European Commission funded Framework 7 MErCuRIC programme is running a biomarker-enriched clinical trial investigating the efficacy of combined c-MET/MEK inhibition in patients with RAS-mutant or RAS-wild-type metastatic colorectal cancer with aberrant c-MET expression. The design of this trial enables the continued refinement of the predictive biomarker and co-development of companion diagnostics. In this Review, we focus on advances in our understanding of inhibition of the HGF/c-MET pathway in patients with gastro-intestinal cancers, the prominent challenges facing the clinical translation and implementation of agents targeting HGF/c-MET, and discuss the various efforts, and associated obstacles to the discovery and validation of biomarkers that will enable patient stratification in this context.
Insights
Targeting the hepatocyte growth factor (HGF)-hepatocyte growth factor receptor (c-MET) pathway shows promise for gastrointestinal cancers. Biomarker-driven clinical trials are crucial for optimizing HGF/c-MET inhibitor efficacy and patient stratification.
Area of Science:
- Oncology
- Molecular Biology
- Clinical Trials
Background:
- The hepatocyte growth factor (HGF)-hepatocyte growth factor receptor (c-MET) pathway is critical for gastrointestinal cancer progression.
- Aberrant c-MET expression is linked to poor prognosis in gastrointestinal cancer patients.
- HGF/c-MET inhibitors have been developed and entered clinical use.
Purpose of the Study:
- To review advances in understanding HGF/c-MET pathway inhibition in gastrointestinal cancers.
- To discuss challenges in the clinical translation of HGF/c-MET inhibitors.
- To explore biomarker discovery and validation for patient stratification.
Main Methods:
- Literature review of preclinical and clinical studies on HGF/c-MET pathway in gastrointestinal cancers.
- Analysis of ongoing biomarker-enriched clinical trials, such as the MErCuRIC programme.
- Discussion of challenges in biomarker validation and companion diagnostics development.
Main Results:
- Preclinical data strongly support the role of the HGF/c-MET pathway in gastrointestinal cancer growth and invasion.
- Clinical trials are investigating combined c-MET/MEK inhibition in specific patient populations.
- Refinement of predictive biomarkers and companion diagnostics is ongoing.
Conclusions:
- Effective clinical translation of HGF/c-MET inhibitors requires careful patient stratification based on biomarkers.
- Biomarker-driven trials are essential for optimizing treatment strategies in gastrointestinal cancers.
- Continued research is needed to overcome obstacles in biomarker discovery and validation.