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Novel strategies for antagonizing the phosphatidylinositol-3-kinase pathway in disease

University of British Columbia

The phosphatidylinositol 3-kinase (PI3K) signaling pathway is a critical regulator of cell physiology. This project aims to investigate several novel approaches to target the PI3K pathway. First, in order to determine the importance of PI3K regulators on normal cells, I investigated the effect of PTEN haploinsufficiency on glucose regulation in mice. Even a 50% reduction in PTEN expression was sufficient to increase phosphorylation of the downstream targets AKT and GSK3β. Next, I wanted to see if PI3K pathway could treat idiopathic thrombocytopenic purpura (ITP). Since the established ITP therapy (IVIg) is thought to signal through SH2-containing inositol 5’ phosphatase (SHIP), I tested the ability of a SHIP activator AQX-MN100 to reverse a murine model of ITP. In the classic model of ITP, AQX-MN100 was unable to rescue mice from antibody-mediated platelet destruction. However, prophylactic AQX-MN100 prevented the infection-mediated form of ITP. I then studied the potential uses of AQX-016A/AQX-MN100 in the hematopoietic malignancies multiple myeloma (MM) and mantle cell lymphoma (MCL). AQX-016A/AQX-MN100 successfully induced apoptosis of the cancer cell lines in vitro in both a time and dose dependant manner. I then investigated the potential of a small molecule ILK inhibitor to inhibit early prostatic dysplasia/hyperplasia in a murine model. Under the initial experimental parameters chosen, the ILK inhibitor was not able to inhibit dysplasia/hyperplasia. However, further studies are required to determine whether ILK inhibition may be an effective therapeutic strategy for treatment of prostate cancer. Finally, I attempted to potentiate the effects of PI3K pathway inhibitors with borrelidin, an inhibitor of tRNA synthetase, which successfully exhibited synergy with the PI3K inhibitor LY294002, but only exhibited additive effects with the ILK inhibitor. The results of this project show the validity of targeting members of the PI3K pathway either in alone or in combination with a synergistic pathway.

Text

2010-04-21

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/23966

Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/