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Noopur Raje, MD
Massachusetts General Hospital Cancer Center
Boston, MA, USA
by Lynne Lederman, PhD
The complex Akt signaling cascade, which is important in myeloma and other cancers, is central to many pathways coupled to cell surface receptors having down stream effects on the cell cycle, survival, protein synthesis, and cell growth. IL-6, which induces signaling in myeloma cells via phospho-STAT 3 and MAP kinase, also induces phospho-Akt in a dose and time dependent manner. Akt activity can be blocked by compounds including LY295002, a specific PI3 kinase inhibitor, which overcomes the protective effects of IL-6. Activated or overexpressed Akt is related to drug resistance, e.g., to Apo2L/TRIAL, doxorubicin, and bortezomib. There are several compounds that inhibit Akt or PI3 kinase in development or early trials in myeloma, including Enzastaurin, an oral protein kinase (PK) C inhibitor, Perifosine (KRX-0401), a synthetic phospholipids that inhibits phosphorylation of Akt and downstream target proteins, mTOR (mammalian target of rapamycin) family inhibitors, e.g., RAD –1 and CCI 779, and SGN40, a humanized monoclonal antibody to CD40 that inhibits Akt phosphorylation. Additional trials of these compounds, including in combination with novel agents such as lenalidomide or bortezomib, are planned or ongoing.