Abstract 3875: Lymphatically directed MAPK/PI3K/mTOR inhibitor for treatment of cancer growth and metastasis
Authors: Galbán Stefanie , Espinoza Carlos , Luker Kathryn E. , Luker Gary D. , Dort Marcian Van , Ross Brian D. 
Published: August 2018

The Ras-ERK and PI3K/mTOR signaling pathways have profound effects on cancer cell survival, differentiation, proliferation, metabolism and motility. Due to the importance of these pathways, a myriad of compounds has been developed to inhibit key signaling nodes including MEK, PI3K and PI3K/mTOR inhibitors. Evidence has shown that extensive cross-talk and compensation between pathways occurs shifting therapeutic efforts towards strategies to target multiple pathways to improve therapeutic outcomes. However, clinical trials evaluating MAPK and PI3K combination therapies have revealed poor tolerability leading to early discontinuation. Here we show a multifunctional molecular inhibitor (ST-182) capable of simultaneous inhibition of MAPK, PI3K and mTOR pathways. Kinase assays were used to determine IC50s for MEK1, PI3K α, β, δ, γ and mTOR confirming in vitro targeting of these signaling nodes. Phosphorylation changes of ERK and AKT as surrogate markers for kinase inhibition were confirmed in multiple breast cancer cell lines and determined to be independent of their BRCA1 mutational status. Reverse phase protein array performed in MDA-MB-231 cells indicated both efficient MAPK and PI3K/mTOR pathway inhibition and along with differential regulation of epithelial-mesenchymal transition (EMT) pathways compared to combination therapy of single agents (MEK plus PI3K inhibitor). Using excised breast cancer tissue from orthotopic mammary tumor mouse models (MDA-MB-231 and AT-3), ST-182 was found to modulate MEK and PI3K/mTOR activities demonstrating in vivo bioavailability confirming simultaneous multifunctional inhibition of Ras/MEK/ERK and PI3K/AKT/mTOR pathways. Innovative Kinase Translocation Reporters (KTR) were used to confirm in vitro and in vivo inhibition of these pathways. Treatment of breast tumor bearing mice daily with ST-182 (400 mg/kg, PO) achieved a significant reduction in volumetric tumor growth versus control animals with no observed systemic toxicity. Furthermore, we observed a reduction in metastatic tumor load in these mouse models underpinning its regulation of EMT proteins. Pharmacokinetics evaluation of ST-182 following oral administration revealed unique physiochemical properties promoting direct lymphatic system uptake as the primary absorption route at an astonishing &gt;95% level rather than traditional portal vein absorption. Significant implications of lymph-directed uptake include circumventing first pass metabolism, enhanced bioavailability and reduction in systemic toxicities. This paradigm shift in drug development is anticipated to open up new opportunities for delivery of receptor tyrosine kinase (RTK) inhibitors using lymph-directed compounds to improve clinical outcome of breast cancer along with other tumor types.

Citation Format: Stefanie Galbán, Carlos Espinoza, Kathryn E. Luker, Gary D. Luker, Marcian Van Dort, Brian D. Ross. Lymphatically directed MAPK/PI3K/mTOR inhibitor for treatment of cancer growth and metastasis [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 3875.