Abstract 2932: Evaluation of dual-acting PIM/PI3K inhibitor IBL-302 in preclinical breast cancer models
Authors: Kennedy Sean P. , Neill Michael O , Cunningham Darren , Blanco-Aparicio Carmen , Martinez Sonia , Eustace Alex , Hennessy Bryan 
Published: August 2018

Activating PI3K mutations have been identified in more than 30% of breast cancers (BC). These mutations have been associated with resistance (res) to trastuzumab (Tras) a HER2-binding monoclonal antibody. PIM kinase expression has been shown to be markedly elevated in PI3K treated BC samples suggesting that it could be a major res pathway for PI3K inhibitors in BC, potentially limiting their clinical utility. IBL-302 is a novel molecule that inhibits both PIM and PI3K signalling. This mechanism of action could afford significant benefit in the treatment of BC. We evaluated the preclinical activity of a IBL-302, in a range of BC models. IBL-302 was tested in the Sanger Institute GDSC screening panel of more than 700 different cancer cell lines in a CellTiter Glo anti-proliferation assay (72hr incubation). We subdivided a panel of 36 BC cell lines into their clinical subtype (HER2+ n=6, HR+ n=6 & TNBC n=24). IBL-302 had significantly lower IC50 in TNBC cell lines when compared to HR+ and HER2+ BC cell lines (r = 0.352, p = 0.038). Sensitivity to IBL-302 correlated significantly with PIM 1 expression (r= -0.45, p = 0.0045) and PIM 2 expression (r =- 0.3238, p = 0.0506) but no such relationship was observed for PIM 3.The HER2 gene or protein is amplified or overexpressed in ~25% of BC and promotes an aggressive phenotype, through the activation of the PI3K/AKT pathway. We utilised our HER2+ BC, Tras res cell lines which had previously been utilised in another PI3K / Tras refractory trial (NCT02705859). IBL-302 had anti-proliferative effects in HER2+ lines (SKBR3, HCC1954 and BT474 cells) including matched models of acquired Tras (SKBR-T, BT474-T) or lapatinib (SKBR-L, HCC1954-L) res. IBL-302 achieved IC50 ranging from (33.4 ± 2.9nM) in SKBR3-T cells to (136 ± 35.2nM) in SKBR3-L, but interestingly both acquired Tras res cell lines SKBR3-T and BT474-T cells were significantly more sensitive to IBL-302 than that observed in the matched SKBR3-P (p&gt;0.01) and BT474-P (p&gt;0.01) cells respectively. It was also observed that the combination of Tras and IBL-302 significantly increased the anti-proliferative effect in SKBR3-P (P&lt;0.01) and SKBR3-T cells (P&lt;0.01), relative to testing either drug alone. Treatment with IBL-302 (50mg/kg) PO for 21-days BT474 in xenograft model in BALB/c nude mice resulted in a significant decrease in tumour volume relative to the vehicle treated controls (P&lt;0.01). IBL-302 had no significant impact on bodyweight at this dose. These results demonstrate in vitro efficacy of IBL-302 in a range of BC cell lines, including lines with acquired res to Tras. We have also shown the in vivo single agent efficacy of IBL-302 in the subcutaneous BT474 xenograft model in BALB/c nude mice. We believe IBL-302 represents an exciting new entity a dual-acting, PIM/PI3K inhibitor, with potential for the treatment of BC and given the potential to overcome Tras res in vitro in HER2+ BC cells that it should be clinically investigated in this setting.

Citation Format: Sean P. Kennedy, Michael O Neill, Darren Cunningham, Carmen Blanco-Aparicio, Sonia Martinez, Alex Eustace, Bryan Hennessy. Evaluation of dual-acting PIM/PI3K inhibitor IBL-302 in preclinical breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2932.