Related Experiment Video
Updated: Aug 27, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Consensus molecular subtype 4 (CMS4)-targeted therapy in primary colon cancer: A proof-of-concept study
Niek A Peters1, Alexander Constantinides1, Inge Ubink1
1Lab Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
Background:
Mesenchymal Consensus Molecular Subtype 4 (CMS4) colon cancer is associated with poor prognosis and therapy resistance. In this proof-of-concept study, we assessed whether a rationally chosen drug could mitigate the distinguishing molecular features of primary CMS4 colon cancer.
Methods:
In the ImPACCT trial, informed consent was obtained for molecular subtyping at initial diagnosis of colon cancer using a validated RT-qPCR CMS4-test on three biopsies per tumor (Phase-1, n=69 patients), and for neoadjuvant CMS4-targeting therapy with imatinib (Phase-2, n=5). Pre- and post-treatment tumor biopsies were analyzed by RNA-sequencing and immunohistochemistry. Imatinib-induced gene expression changes were associated with molecular subtypes and survival in an independent cohort of 3232 primary colon cancer.
Results:
The CMS4-test classified 52/172 biopsies as CMS4 (30%). Five patients consented to imatinib treatment prior to surgery, yielding 15 pre- and 15 post-treatment samples for molecular analysis. Imatinib treatment caused significant suppression of mesenchymal genes and upregulation of genes encoding epithelial junctions. The gene expression changes induced by imatinib were associated with improved survival and a shift from CMS4 to CMS2.
Conclusion:
Imatinib may have value as a CMS-switching drug in primary colon cancer and induces a gene expression program that is associated with improved survival.
Insights
Imatinib shows promise in treating mesenchymal Consensus Molecular Subtype 4 (CMS4) colon cancer. This therapy may switch CMS4 tumors to a more favorable CMS2 subtype, improving patient survival.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Mesenchymal Consensus Molecular Subtype 4 (CMS4) colon cancer presents a significant clinical challenge due to its association with poor prognosis and resistance to therapies.
- Identifying targeted therapeutic strategies for CMS4 is crucial for improving patient outcomes.
Purpose of the Study:
- To evaluate the efficacy of imatinib in mitigating the molecular characteristics of primary CMS4 colon cancer.
- To assess imatinib's potential as a drug to switch the molecular subtype of colon cancer.
Main Methods:
- The ImPACCT trial involved molecular subtyping of colon cancer using a validated RT-qPCR CMS4-test.
- A Phase-2 study administered neoadjuvant imatinib therapy to five CMS4 patients, with pre- and post-treatment biopsies analyzed via RNA-sequencing and immunohistochemistry.
- Gene expression changes were correlated with molecular subtypes and survival in an independent cohort of 3232 primary colon cancers.
Main Results:
- The CMS4-test identified 30% of biopsies as CMS4.
- Imatinib treatment led to significant suppression of mesenchymal genes and upregulation of epithelial junction genes.
- These molecular changes correlated with improved survival and a shift from CMS4 to CMS2 subtype.
Conclusions:
- Imatinib demonstrates potential as a CMS-switching agent in primary colon cancer.
- The drug induces a gene expression profile associated with enhanced patient survival.
More Related Videos
09:29Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
06:46Competing-Risk Nomogram for Predicting Cancer-Specific Survival in Multiple Primary Colorectal Cancer Patients after Surgery
Published on: September 27, 2024
