Abstract B139: Promising antitumor effects of SNX-5422 in combination with checkpoint inhibitors in an MC38 murine model

Abstract

Abstract Introduction: SNX-2112 is a potent antitumor compound. In vitro studies have shown that SNX-2112 appears to have epigenetic character (hypomethylation) and interferes with onco-metabolism. SNX-5422 is an orally active prodrug of SNX-2112, a highly selective inhibitor of Hsp90 that has shown antitumor activity in clinical trials. Heat-shock protein 90 (Hsp90), a molecular chaperone, is commonly elevated in tumor tissues and plays an important role in immune responses. Preclinical studies have suggested that Hsp90 inhibitors enhance antigen expression on tumor cells while retaining T-cell function, and therefore could possibly be utilized in immunotherapy to augment tumor targeting. Additionally, the characteristics of SNX-2112 interference with epigenetics and cancer metabolism may complement checkpoint inhibitors. For these reasons, the combination of SNX-5422 with checkpoint inhibitors was examined in preclinical studies. Methods: Murine colon cancer model MC38 was selected for in vivo studies. Tumor volume was measured following treatment with SNX-5422 alone and in combination with monoclonal antibodies against PD-1 (RMP1-14) [study 1], or PD-L1 (10F.9G2) or CTLA4 (9D9) [study 2]). In both studies, female C57BL/6 mice were inoculated subcutaneously at the right lower flank with MC38 tumor cells (1x106). SNX-5422 was dosed every other day for 3 doses followed by 2 days off for a total of 3 weeks. Checkpoint inhibitors were dosed twice weekly for 3 weeks. Treatments were initiated when the mean tumor size reached approximately 130 mm3 (study 1) or 119 mm3 (study 2). Final tumor volume was measured on Day 33 (study 1) or Day 32 (study 2). Results: In study 1, tumor volume was reduced by 45.1% with SNX-5422 (40 mg/kg) and by 24.0% with anti-PD-1 (100 µg/animal) (p=NS vs. control for both). The combination of these 2 agents reduced tumor volume by 66.8% (p=0.014 vs. control; p=0.052 anti-PD-1 vs. combination). Using a lower dose of SNX-5422 (25 mg/kg), the combination reduced tumor volume by 61.5% (p=0.021 vs. control; p=NS vs. higher dose combination). In study 2, tumor volume was reduced by 24.1% with SNX-5422 (40 mg/kg) (p=NS vs. control) and by 77%-83% with the checkpoint inhibitors (P≤0.006 vs. control). The combination of SNX-5422 (40 mg/kg) and anti-PD-L1 (10 mg/kg) reduced tumor volume by 75.2% (p=0.007 vs. control; p=0.012 SNX-5422 alone vs. combination). There was also a 76.0% reduction in tumor volume with the combination using SNX-5422 25 mg/kg (p=0.007 vs. control; p=NS vs. higher dose combination). Similarly, in combination with anti-CTLA4 (10 mg/kg), tumor volume was reduced by 77.5% (p=0.003 vs. control; p=0.015 SNX-5422 alone vs. combination). A 69.9% reduction in tumor volume was observed when using SNX-5422 25 mg/kg in the combination (p=0.006 vs. control; p=NS vs. higher dose combination). The positive effects on tumor volume were achieved without adversely affecting the body weight. Conclusion: SNX-5422 at either 25 mg/kg or 40 mg/kg, in combination with anti-PD1, demonstrated significant antitumor activity in the MC38 murine colon cancer model. Additionally, there was improved antitumor activity of SNX-5422 when combined with the immune checkpoint inhibitors PD-L1 as well as CTLA4. These results support further clinical development of SNX-5422 combined with checkpoint inhibitors in cancer therapy. Citation Format: Yanmei Sun, Xirou Hu, Everardus Orlemans. Promising antitumor effects of SNX-5422 in combination with checkpoint inhibitors in an MC38 murine model [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B139.