Abstract 3672: Preclinical assessment of MET modulation by a VEGFR inhibitor/MET inhibitor combination that shows additive antitumor efficacy
Authors: Srivastava Apurva K. , Hollingshead Melinda H. , Weiner Jennifer , Park Sook Ryun , Kinders Robert J. , Kummar Shivaani , Tomaszewski Joseph , Parchment Ralph E. , Doroshow James H. 
Published: August 2012

Abstract
Background: Suppression of VEGFR signaling promotes activation of the MET signaling pathway, which may compensate for the VEGFR blockade, potentially leading to cellular invasion and metastasis. These findings have led to the hypothesis that VEGFR inhibitors will be more effective when combined with MET inhibitors in the clinic. This hypothesis is currently being tested in a clinical trial of Pazopanib with Tivantinib (ARQ197) at the NCI. We have replicated this trial in a xenograft model to evaluate the pharmacodynamic (PD) response of MET and HIF-1α using newly developed and validated quantitative assays and relate the biomarker response to anti-tumor efficacy. Methods: Ectopic SNU5 (human gastric cancer cell line) xenografts were staged to 200 mm3 in athymic nude mice and treated for 8 days with vehicle, Pazopanib (100 mg/kg/day, QD), Tivantinib (200 mg/kg/day, QD), and combinations of Pazopanib (QD) with two dose levels of Tivantinib (200 mg/kg/day QD and 400 mg/kg/day BID). Trucut needle biopsies (18Ga) were collected at 4 hours and 24 hours after Tivantinib administration on Day 8 and processed according to procedures developed to minimize analyte degradation. Tumor lysates were evaluated for MET, pY1235MET, pY1356MET, and HIF-1α using ELISA assays. Tumor volumes were measured at baseline and on Day 8. Results: PD-biomarker analysis in biopsy specimens revealed that treatment with Tivantinib alone did not significantly change MET, pY1235MET, and pY1356MET levels. Pazopanib treatment did not significantly increase total MET levels, but significantly increased pY1235MET and pY1356 MET at 4 hours after the Day 8 dose. The Pazopanib-induced activation of pY1235MET and pY1356MET was prevented by Tivantinib (p&lt;0.05) in combination (BID schedule). Analysis of intratumoral levels of HIF-1α is currently underway. Compared to the vehicle treated group, single agent Tivantinib and Pazopanib inhibited tumor growth measured on Day 8 by 19% (p&lt;0.05) and 20% (p&lt;0.05), respectively, whereas the combination of Pazopanib and Tivantinib achieved 38-46% inhibition of tumor growth (p&lt;0.05). The combination regimen was more effective when Tivantinib was administered BID than QD. Conclusions: The combination of Pazopanib with Tivantinib exhibited additive anti-tumor activity that was greater than either agent alone. Enhanced efficacy of combination therapy was associated with Tivantinib block of Pazopanib-induced activation of MET. These results confirm the hypothesis underlying clinical trials of combinations of VEGFR with MET inhibitors. The study is being expanded with additional xenograft models and treatment schedules to confirm and further examine the generality of these findings. Funded by NCI Contract #HHSN261200800001E.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3672. doi:1538-7445.AM2012-3672