Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR) and has been shown to have antineoplastic activity in addition to its use as an immunosuppressive agent for the prevention of organ transplant rejection. We report the use of everolimus for the compassionate treatment of four elderly, nontransplant patients presenting with multiple basal cell carcinomas (BCC). All patients had a long history of BCC, had refused surgery as a current treatment option, and did not respond to alternative treatments (including topical 5-fluorouracil and imiquimod). Patients were treated with oral everolimus (1.5–3.0？mg daily) for 12 months or longer: a complete and sustained response was seen in one case, and partial responses were seen in two other cases. Everolimus was well tolerated in these elderly patients. These promising preliminary data suggest that further dose-finding, controlled clinical studies are warranted to evaluate the antineoplastic effects of everolimus in patients affected by BCC who cannot or will not undergo surgery. 1. Introduction The protein kinase family is involved in many critical regulatory cell functions. One pathway that plays a key role in signal transduction involves phosphatidylinositol-3-kinase (PI3K), which activates a cascade of other kinases, eventually providing a signal for cell proliferation. The downstream effector of PI3K is the mammalian target of rapamycin (mTOR), which plays a key regulatory role in protein translation by modulating the activity of other kinases via phosphorylation [1, 2]. Two agents that target mTOR are now commercially available: sirolimus and its derivative everolimus, and both drugs are approved for use as part of immunosuppressive regimens following renal or heart transplantation. In addition to their immunosuppressive properties, these proliferation signal inhibitors (PSIs) also have substantial antineoplastic activity, resulting from a number of different mechanisms. Firstly, there is now evidence that growth factors and oncogenic proteins can activate PI3K, and this leads, via mTOR, to the phosphorylation and activation of a number of protein kinases that promote cancer cell proliferation and survival. Inhibition of mTOR activity can block this signaling cascade and thus interfere with tumor cell proliferation [3]. Secondly, vascular endothelial cell proliferation and angiogenesis are under the control of vascular endothelial growth factors (VEGFs), which act, at least in part, through the PI3K-mTOR signaling pathway. By blocking this pathway, PSIs may also exert antineoplastic
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