Activity of GDC-0941, an inhibitor of phosphoinositol 3 kinase (PI3K), in gastrointestinal stromal tumor (GIST) xenograft and duration of response after discontinuation of treatment in combination with imatinib.

Abstract

10020 Background: Oncogenic signaling in GISTs is sustained mainly via PI3K/AKT rather than RAS/MAPK pathway. We tested the efficacy of GDC-0941 (GDC) alone and in combination with imatinib (IM) in IM-sensitive GIST xenograft. Methods: Nude mice were grafted bilaterally with human GIST bearing KIT exon 11 mutation. They were orally dosed over 19 days in 4 groups: A (control); B (GDC-0941 75mg/kg/d); C (IM 50mg/kg/bid); D (GDC+IM, doses/schedule=B+C). In addition, xenografts re-growth after treatment withdrawal was evaluated. Micro-FDG-PET assessed standardized uptake values (SUV) and tumor/lesion glycolysis (TLG) over 8 weeks. Histopathology included H&E, KIT and Ki-67 staining. KIT signaling status was assessed by Western blot. Results: IM and GDC+IM reduced tumor volume by 86% and 95%, respectively, while GDC had no significant effect. IM and GDC treatments showed only grade 1 or grade 1&2 histologic response (HR), while grade 3 HR was observed in 75% of tumors under GDC+IM. Compared to control, mitotic activity decreased 2-fold under GDC, while it was not detectable in the other arms. Apoptotic activity was respectively 3- and 15-fold higher than control under IM and GDC+IM, being almost unaffected under GDC alone. After 24 hrs, SUV decreased in all treated groups, and remained low particularly under IM. The highest reduction in TLG was observed under GDC+IM. In GDC and IM groups, inhibition of AKT was visible but incomplete. Only GDC+IM induced complete PI3K/AKT pathway knockdown. After treatment discontinuation, immediate tumor re-growth was observed in IM group, whereas GDC+IM treatment yielded long-lasting volumetric effect (98% and 15% of baseline, respectively, after 4 weeks of treatment end). SUV and TLG increased constantly under IM, whereas same parameters remained low in GDC+IM. Mitotic index in GDC+IM was still 2-fold lower than in controls. Conclusions: The combination of GDC-0941 and imatinib has extensive antitumor efficacy in GIST xenograft, inducing more substantial apoptosis and durable effects than imatinib alone. This effect was sustained even after treatment withdrawal. No significant financial relationships to disclose.