We are currently conducting two clinical trials using 11C-glutamine and (S)-4-(3-18F-Fluoropropyl)-L-glutamic acid (18F-FSPG) in the setting of metastatic WT RAS colorectal cancer (CRC). 11C-glutamine and 18F-FSPG report on two different aspects of glutamine metabolism, glutamine influx and glutamate efflux respectively. Imaging data will be correlated to treatment response and genetic (RNA-seq) and immunohistochemistry (IHC) data.
In collaboration with Vanderbilt University Medical Center, we are conducting a Phase II clinical trial combining an anti-EGFR antibody, panitumumab, with a glutaminase (GLS1) inhibitor, CB-839 (NCT03263429). Patients participating in this trial are imaged pre- and post-treatment with 11C-glutamine and 18F-FSPG. The baseline PET imaging provides a measure of glutamine avidity of the tumors and can be used to predict response to treatment. Post-treatment imaging is being evaluated as an early biomarker of response to treatment by evaluating the change in uptake of the PET tracers.
We are also evaluating baseline glutamine PET imaging with 11C-Glutamine and 18F-FSPG in patients with metastatic WT RAS CRC undergoing treatment with EGFR-targeted antibody therapy (NCT03275974). PET imaging is being evaluated as a predictive biomarker of response which would enable selection of patients for this therapy.
Preclinically, we are using patient-derived xenograft (PDX) models of colorectal cancer (CRC) in imaging and treatment studies. To model the clinical trials, we are evaluating treatment with anti-EGFR antibodies (cetuximab and panitumumab) in combination with drugs targeting glutamine metabolism (V-9302 and CB-839) as well as single agent controls. V-9302 is a small molecule inhibitor of ASCT2, the primary glutamine transporter in cancer cells (Schulte et al. Nat Med. 2018; 24(2):194-202. doi: 10.1038/nm.4464). On the other hand, CB-839 targets glutaminase, the enzyme responsible for conversion of glutamine to glutamate. Although both drugs target glutamine metabolism, they have distinct mechanisms of action. PET imaging is performed using 18F-4-fluoro-glutamine and 18F-FSPG at baseline and post-treatment. We are also using RNA-seq data from these PDXs to develop imaging-derived gene signatures associated with treatment response. These gene signatures could provide rationale of patient selection for treatment with glutaminolysis inhibitors.
To access additional information and data associated with our co-clinical trial visit the MIRACCL website.