A Vascular Targeted Pan PI-3 Kinase Inhibitor, SF1126 with Activity Against Multiple Myeloma In Vivo.

Background: Considerable evidence suggests an important role for the PI-3 kinase and AKT signaling pathways in survival and chemoresistance in multiple myeloma (MM) and other lymphoid malignancies. Our group and others have demonstrated that downregulation of p-AKT with combination therapy (bortezomib + lonafarnib; David et al, Blood, 2005) is a surrogate marker for myeloma apoptosis. It has been demonstrated that the compound, LY294002 has significant pan PI-3 kinase inhibitory properties but is not suitable for clinical use due to PK issues. SF1126 is a novel RGD targeted derivative of LY294002 that has been shown to have activity in a number of different tumor models. Herein, we evaluated the activity of SF1126 against the MM.1S and MM.1R MM cell lines in vitro and in vivo for sensitivity to PI-3 kinase inhibition. The results demonstrate that MM.1S and MM.1R tumor cell growth is sensitive to SF1126 with IC₅₀ of 7.5 and 10.8 uM, respectively. The effects of SF1126 on MM.1R signaling in vitro was examined with profound inhibition of HIF1a induction under hypoxia, the suppression of phosphorylation states of MDM2, ERK and RS6 kinase. The IC₅₀ for inhibition of p-AKT in MM.1S and MM.1R cells was determined to be 2.4 and 2.8 uM, respectively. SF1126 treatment (50 mg/kg/dose sc given every other day) inhibited MM.1R tumor growth in nude mouse xenografts 95% as compared to untreated controls on day 38 (p < .01). Microvessel density analysis of MM.1R tumor tissue demonstrated that SF1126 had significant antiangiogenic activity in vivo.

Conclusion: The results provide preclinical data to support SF1126 as a clinically viable antiangiogenic, pan PI-3 kinase inhibitor for Phase I clinical trials in the treatment of multiple myeloma. Further studies in primary myeloma cells and in combination with conventional agents will be presented.