The mTOR Inhibitor RAD001 (Everolimus) Inhibits Myeloma Tumor Growth In Vivo and Enhances the Anti-MM Effects of Bortezomib and Arsenic Trioxide.

The mammalian target of rapamycin (mTOR) is an intracellular protein that acts as a central regulator of multiple signaling pathways (IGF, EGF, PDGF, VEGF, amino acids) that mediate abnormal growth, proliferation, survival and angiogenesis in cancer. mTOR is a critical component of the PI3K/Akt pathway, a key cell survival pathway that is dysregulated in many cancers including multiple myeloma (MM). mTOR is an important therapeutic target because it is a “rate-limiting” bottleneck in the key signaling pathway that regulates cell survival, proliferation, and angiogenesis. RAD001 (everolimus) is a novel oral mTOR pathway inhibitor. Recent data suggests that RAD001 has direct effects on tumor cell proliferation and may have antiangiogenic activity due to inhibition of tumoral VEGF production and effects on vascular endothelial and smooth muscle cell biology. We first evaluated the in vivo effects of single agent RAD001 in mice bearing the human MM tumor LAGλ-1. Tumor-bearing mice receiving RAD001 at 3, 10, or 30 mg/kg once daily five times per week (M-F) via oral gavage showed marked inhibition of tumor growth at all doses (P<0.0001) and reduction of paraprotein levels (P<0.0001) compared to mice receiving placebo. Next, we evaluated the in vivo anti-MM effects of RAD001 in combination with arsenic trioxide (ATO) and RAD001 in combination with bortezomib. Each severe combined immunodeficient (SCID) mouse was implanted with a fragment (2 – 4 mm³) of the LAGλ-1 tumor into the left hind limb muscle. The tumors were allowed to grow for 10 days at which time human IgG levels were detectable in the mouse serum, and mice were blindly assigned into treatment groups. Tumor-bearing mice received RAD001 at 1, 3, or 10 mg/kg once daily five times per week via oral gavage, ATO (3 mg/kg) once daily five times per week via intraperitoneal injection, bortezomib (0.5 mg/kg) once daily twice weekly via intravenous injection, or a placebo. Mice receiving RAD001/ATO combination therapy exhibited decreased hIgG levels and tumor volume compared to those mice receiving single agent and placebo therapy. Additionally, those mice receiving the RAD001/bortezomib combination treatment displayed similar MM tumor growth inhibition including decreased hIgG levels and tumor volume as the RAD001/ATO-treated mice. These preliminary in vivo results are encouraging with combination RAD001+ATO and RAD001+bortezomib therapy for the treatment of MM and additional studies are being performed to further optimize the clinical development of RAD001 in combination with other anti-MM treatments for patients with MM.