Abstract A02: SM08502, a novel, small-molecule CDC-like kinase (CLK) inhibitor, downregulates the Wnt signaling pathway and demonstrates antitumor activity in pancreatic cancer cell lines and in vivo xenograft models

Abstract

Abstract Aberrant activation of the Wnt signaling pathway, a highly conserved signaling cascade implicated in multiple cancer hallmarks, is common in pancreatic cancer (PC) and may functionally support proliferation and tumor-forming capacity of PC cells as well as immune evasion. It may also promote fibrogenesis in the PC tumor microenvironment (TME), which is often characterized by a dense, fibrotic stroma that can contribute to treatment resistance. SM08502 is a novel, oral, small-molecule pan-CLK inhibitor that has been shown to potently inhibit the Wnt signaling pathway in preclinical colorectal cancer models. The purpose of these studies was to test the in vitro and in vivo activity of SM08502 in preclinical models of PC. SM08502 was tested against 14 PC cell lines in vitro and the compound’s antitumor potential was analyzed in Capan-1 and HPAFII xenografts in nude mice. In vitro studies included cell viability (all lines), colony formation, apoptosis, and Wnt-related gene expression assays in Capan-1, Panc1, and HPAFII. Xenograft mouse model assays included assessment of tumor growth inhibition (TGI) relative to vehicle controls for both cell lines. Additionally, xenografts of Capan-1 and HPAFII with and without co-implantation of cancer-associated fibroblasts (CAFs) were performed to model tumor stroma effects. SM08502 inhibited cell viability in all 14 cell lines (regardless of KRAS status) (EC50=0.072-0.526 μM). In Capan-1, HPAFII, and Panc1 cells, 1 μM SM08502 inhibited colony formation as well as Wnt-related gene expression by ≥50% relative to vehicle controls. In addition, SM08502 induced apoptosis as shown by elevated caspase 3/7 activity. In the HPAFII xenograft mouse model, SM08502 (25 mg/kg QD) significantly inhibited tumor growth (TGI=93%, p=0.011) and induced RECIST-defined regression in 3 of 5 mice. Notably, SM08502 administered intermittently (QOD) also significantly inhibited tumor growth (TGI=82%, p=0.011), but no regressions were observed. In the stroma modeling experiments, tumor xenografts with CAF co-implants grew larger (Capan-1, ~45%; HPAFII, ~64%) than xenografts without CAF. Despite increased tumor growth in the presence of CAFs, SM08502 (25 mg/kg QD) induced significant TGI vs. control in Capan-1 (80% and 65%; p<0.01) and HPAFII (85% and 71%; p<0.05) xenografts with or without CAF, respectively, indicating that CAFs do not affect the activity of SM08502. These data demonstrate that SM08502 potently inhibits Wnt pathway-related gene expression, has strong in vitro and in vivo antitumor activity, and shows potential to overcome the tumor-protective effects of stroma in PC. A phase 1 study assessing safety, tolerability, and pharmacokinetics of SM08502 in subjects with advanced solid tumors is ongoing (NCT03355066). Citation Format: Carine Bossard, Nathalia Cruz, Brian Eastman, Chi-Ching Mak, K.C. Sunil, Betty Tam, Gail Bucci, Josh Stewart, Timothy Phalen, Steven Cha. SM08502, a novel, small-molecule CDC-like kinase (CLK) inhibitor, downregulates the Wnt signaling pathway and demonstrates antitumor activity in pancreatic cancer cell lines and in vivo xenograft models [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A02.