Development of a precision medicine pipeline to identify personalized treatments for colorectal cancer

Area of Science:

• Oncology
• Precision Medicine
• Cancer Therapeutics

Background:

• Metastatic colorectal cancer (CRC) presents a significant health challenge with limited treatment options focused on disease control and symptom palliation.
• Current therapeutic strategies for CRC often lack personalization, leading to variable patient responses.

Purpose of the Study:

• To develop and implement a precision medicine approach for discovering novel therapeutic strategies for metastatic colorectal cancer.
• To identify predictive biomarkers for treatment response in CRC patients.

Main Methods:

• Established six matched low-passage cell lines and patient-derived xenografts (PDX) from CRC patient tumors.
• Conducted high-throughput drug screening of 119 FDA-approved oncology drugs on CRC cell lines, followed by in vivo validation in matched PDXs.
• Utilized RNA-Sequencing (RNA-Seq) to identify molecular predictors of drug response.

Main Results:

• Observed significant inter-patient variability in response to standard-of-care agents.
• Identified co-targeting of fibroblast growth factor receptor (FGFR), SRC, platelet-derived growth factor receptor (PDGFR), or vascular endothelial growth factor receptor (VEGFR) signaling as an effective therapeutic strategy.
• Discovered potential molecular predictors correlating with response to these targeted pathways.

Conclusions:

• Matched low-passage cell lines and PDXs represent a robust preclinical model system for identifying novel CRC therapies.
• The study highlights the potential of targeting specific signaling pathways for improved treatment outcomes in metastatic CRC.
• Precision medicine strategies utilizing patient-derived models can accelerate the discovery of effective treatments for colorectal cancer.