Abstract 524: Characterizing the in vitro and in vivo effects of the PIM kinase inhibitor HS140 in triple-negative human breast cancer

Abstract

Triple-negative breast cancer (TNBC) lacks expression of the estrogen receptor (ER), the progesterone receptor (PR) and the ERBB2 (also known as HER2) receptor, making it the worse subtype of all breast cancers. Currently, there are no molecular targeted therapies for this cancer and chemotherapy is only successful in a limited number of patients. Recent studies suggest that members of the oncogenic PIM kinase family, especially PIM-1, play a significant role in the growth of TNBC. However, there is very limited information on the role other PIM family members have in the growth and development of TNBCs. As an attempt to address this concern, we treated a panel of TNBC cell lines with HS140, a PIM-2 kinase inhibitor developed in the laboratory. Using cytotoxicity assays, we were able to demonstrate a decrease in anchorage-dependent growth of cell lines at different concentrations of HS140. Also, a triple negative breast cancer GEMM (C3TAg) was used for an efficacy study. Mice (FVB/N background) have C(3)SV40 T-antigen resulting in inactivation of p53 and Rb. Nine mice received HS140 treatment (80mg/kg BIW IP) and 14 left untreated for control (non-treatment [NT]). All mice were monitored for weight loss and timespan to tumor development 5 times weekly. Tumor volumes at 21 days were significantly (Mann-Whitney, p=0.0002) reduced in the treated cohort with a mean of 109mm3 (range of 0-5000) compared to untreated 1393mm3 (0-239). We observed no toxicities with body mass stable at the treatment dose of 80mg/kg. Additionally, three mice from untreated and three mice from treated cohorts were chosen for blood sampling pre- and post-treatment via a submandibular bleed; no significant differences were noted in WBC, RBC, PLT, or HGB between untreated and treated cohorts. Overall, these results suggest that other members of the PIM kinase family, including PIM-2, have an important function in the growth and development of TNBC and may serve as a potential molecular target for future therapeutics. Citation Format: Michael Cobb, Lucas Hunter, David Carlson, David Darr, Timothy Haystead, Antonio T. Baines. Characterizing the in vitro and in vivo effects of the PIM kinase inhibitor HS140 in triple-negative human breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 524. doi:10.1158/1538-7445.AM2017-524

Preclinical evaluation of a novel triple-acting PIM/PI3K/mTOR inhibitor, IBL-302, in breast cancer

“…1). This has already been described by Brasó-Maristany et al and others who identified increased PIM 1 expression in TNBC that correlated with increased proliferation and protection from apoptosis [12,51].…”

“…Overall, considering the encouraging evidence surrounding PIM kinase inhibitors in combination with other inhibitors in cancer therapy [31,32,63], and evidence suggesting targeting multiple pathways simultaneously will rescue sensitivity [18,20,22,51], as well as the in vitro and in vivo studies of IBL-302 in preclinical breast cancer models presented in this paper, we believe that the dual PI3K/mTOR and PIM inhibitor IBL-302 should be investigated further in breast cancer. We thus plan, to take the compound to phase I clinical trial evaluation in heavily pretreated breast cancer patients.…”