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UBC Theses and Dissertations

Inhibition of the phosphoinositide 3-kinase pathway in multiple myeloma mediated through-activation of SHIP Kennah, Michael


Multiple myeloma (MM) is a B-lymphocyte neoplasia that remains incurable due in part to intrinsic and acquired drug resistance, despite the numerous conventional therapies available. The growth, survival and anti-apoptosis signals resulting from adhesion and cytokine-mediated interactions between the malignant clones and the bone marrow microenvironment are transduced chiefly through the elevated phosphoinositide 3-kinase (PI3K) signaling pathway, which has been demonstrated essential for disease progression. Many biologically-based therapeutics are in development for MM, but the therapies aimed at abrogating this cascade have shown modest success and often have problems with toxicity. A novel alternate approach in controlling this signaling is activation of an endogenous negative regulator, the inositol phosphatase SHIP. A benefit of targeting SHIP is its restricted expression to hematopoetic cells, thereby limiting potential toxicity to surrounding tissues. Further, the PI3K pathway is involved in the development of drug resistance, and abrogating the cascade can re-sensitize MM cells to conventional therapeutics. Here we demonstrate activation of SHIP is sufficient to inhibit proliferation and induce apoptosis of MM cells in vitro, while having no significant effects on non-hematopoetic cancer cells or lymphocytes lacking SHIP. We also show that SHIP activators enhance the cytotoxicity of current chemotherapeutic agents and provide preliminary results of efficacy in a murine xenograft model. These results not only provide the basis for the further study of a new therapeutic agent to improve MM patient outcome but also propose a new model for studying signal transduction through activating the endogenous negative regulators of the PI3K pathway.

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