Biomarkers to Predict Repsonse to Multi-RTK Targeted Therapy in Advanced Colorectal Cancer
Abstract
Colorectal cancer (CRC) remains a key Military Health Focus Area, as it continues to be the second leading cause of cancer-related mortality in military and Veteran communities as well as general population. Cetuximab, an antibody targeting the receptor tyrosine kinase (RTK) epidermal growth factor receptor (EGFR) is approved by the Food and Drug Administration for advanced CRC. However, cetuximab is effective in less than 10% of selected cases and resistance frequently arises. We recently identified a new mode of cetuximab resistance that was dependent on upregulation of activity of the glutamate transporter SLC1A7. Moreover, this resistance could be overcome by addition of a small molecule inhibitor, DL-threo-beta-benzyloxyaspartate in vitro. In this proposal, we aim to optimize the combination for its maximal efficacy and identify individuals that are most likely to respond to this combination treatment. We propose to determine the role of glutamate uptake via the glutamate transporter SLC1A7 in colorectal cancer progression and cetuximab resistance. Additionally, using validated patient-derived xenografts and derivative organoids, we aim to generate and test a transcriptional molecular signature that distinguishes individuals with this cetuximab resistance mechanism. Combined, these studies will enhance the efficacy of drug combinations in the targeted population. These novel inclusion criteria will also preserve quality of life in individuals by identifying and limiting use of ineffective treatments.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110694
Entities
People
- Bhuminder Singh
Organizations
- United States Army
- Vanderbilt University