Molecular Imaging Of Glutamine (Gln) Metabolism In Ras Wildtype (Wt) Metastatic Colorectal Cancer (Mcrc)

Background: Gln metabolism plays a critical role in cancer. In CRC, the epidermal growth factor receptor (EGFR) and Gln cooperate to provide signal transduction and fuel for mitogen activated protein kinase-dependent cell growth. Our preclinical data illustrate that Gln abrogates EGFR inhibition and blockade of Gln metabolism restores EGFR sensitivity, forming the basis of a phase I/II clinical trial exploring dual EGFR and Gln metabolism in mCRC (NCT03263429). As a biomarker correlate, we are performing dual tracer PET imaging of Gln flux (11C-Gln) and Gln to glutamate conversion (18F-FSPG). We hypothesize that tumors dependent on Gln will exhibit high 11C-Gln uptake at baseline, while inhibition of Gln metabolism will reduce 18F-FSPG uptake. Notably, this is the first-in-human study with 11C-Gln. Methods: Adult patients (pts) with previously treated anti-EGFR, RAS WT, mCRC are enrolling and receive panitumumab (6 mg/kg Day 1 and 15) and CB-839 (800 mg twice daily) in 28-day treatment cycles. 11C-Gln and 18F-FSPG scans are performed at baseline and Cycle 1 Day 28. Lesion to blood pool ratio (LBR) is calculated for each target lesion and compared with change in tumor size as measured by RECIST 1.1 after 2 cycles of therapy. Results: The study is ongoing. To date, we have collected pre- and post-therapy PET data on 4 pts; individual lesion data for 2 pts are presented in the table. A mixed response with 11C-Gln uptake was observed for Pt #1, which could reflect different underlying lesion pathology; varying degree of lesion size change was also observed in this patient. The greatest decrease in 18F-FSPG uptake corresponded to the lesion with the smallest growth. For Pt #2, 11C-Gln uptake at baseline was highest in the lesion with the largest decrease in tumor size at Day 56; 18F-FSPG uptake was greatly reduced in all lesions, which corresponded to decreases in tumor size. Best overall response was progressive disease and partial response for Pt #1 and #2, respectively. Conclusions: Quantitative biomarkers that predict response early in the course of therapy are a means to achieve the promise of precision medicine. Our preliminary clinical imaging data suggest that the employed investigational PET molecular imaging tracers have potential for prioritizing patients for combined EGFR/Gln targeted therapy and to predict response early in the treatment course. Additional PET data for all pts and summary statistics will be presented. Citation Format: Jennifer Gray Whisenant, Gary Smith, Allison Cohen, Kristen K. Ciombor, Dana Cardin, Cathy Eng, Laura Goff, Satya Das, Tiffany Hickman, Anna Fisher, Adria Payne, Robert Coffey, G. Dan Ayers, Jordan D. Berlin, H. Charles Manning. Molecular imaging of glutamine (Gln) metabolism in RAS wildtype (WT) metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4260.