Abstract LB-302: Potent antitumor activity of XL184 (cabozantinib), a c-MET and VEGFR2 inhibitor, in colorectal cancer patient-derived tumor explant models.
Authors: Atreya Chloe E. , Song Eun-Kee , Messersmith Wells , Purkey Alicia , Bagby Stacey , Quackenbush Kevin , Kelley Robin K. , Kwak Eunice , Ryan David , Venook Alan , Arcaroli John J. 
Published: August 2014

Abstract
Background: The c-MET signaling pathway plays an essential role in tumorigenesis and is recognized as an important mediator of angiogenesis by inducing the expression of VEGF. In colorectal cancer (CRC), c-MET overexpression is a marker of local migration and invasion and may have prognostic significance. In addition, anti-VEGF therapy has been shown to promote tumor cell metastasis by a c-MET dependent mechanism. The objective of this study was to evaluate the activity of XL184 (cabozantinib), a potent inhibitor of both c-MET and VEGFR2, in CRC patient-derived tumor explant (PDTX) models.
Experimental Design: We used CRC PDTX models to investigate the efficacy of XL184 in spheroid cultures and in vivo in athymic nude mice. Spheroids with retained cell-cell contact were formed by culturing incompletely digested PDTXs in suspension. Spheroids were incubated for 3 days with 1-10 μM XL184. Spheroid area was measured by microscopy. In the mouse models, a total of 10 CRC PDTXs (3 KRAS wild-type and 7 KRAS mutant) were treated with XL184 (30 mg/kg daily, oral gavage) for 28 days. Mice were monitored daily for signs of toxicity and tumor size was evaluated twice per week by caliper measurements.
Results: Spheroids from PDTXs were entirely composed of tumor cells but, unlike cell lines, spheroids recruited stroma when implanted in mice. Although 10 μM XL184 did not inhibit spheroid formation, spheroid area significantly decreased following incubation for 3 days with 10 μM or 5 μM XL184 (p= 0.0012 and p= 0.0056, respectively). In our CRC PDTX in vivo models, XL184 was well tolerated and resulted in a significant decrease in tumor growth in CRC explants from all 10 patients, independent of KRAS status. Strikingly, two of the CRC explants exhibited tumor regression after 28 days of treatment with XL184.
Conclusion: XL184 showed potent antitumor activity in PDTX spheroid and mouse models. PDTX models may be particularly valuable for preclinical testing of inhibitors of stroma-modulated targets such as XL184, where activity is not reflected in cell lines. These promising data have contributed to the rationale and design of a clinical trial of XL184 in patients with advanced CRC. Our upcoming studies will focus on identifying predictive biomarkers of sensitivity or resistance to XL184.
Citation Format: Chloe E. Atreya, Eun-Kee Song, Wells Messersmith, Alicia Purkey, Stacey Bagby, Kevin Quackenbush, Robin K. Kelley, Eunice Kwak, David Ryan, Alan Venook, John J. Arcaroli. Potent antitumor activity of XL184 (cabozantinib), a c-MET and VEGFR2 inhibitor, in colorectal cancer patient-derived tumor explant models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-302. doi:10.1158/1538-7445.AM2013-LB-302