330 POSTER Preclinical evidence for the effectiveness of mTOR inhibitor, nanoparticle albumin-bound (nab®) rapamycin as an anticancer agent

Trieu, V.; De, T. K.; Yang, Andrew; Cordia, Jon; Grim, B.; Ci, Sherry; Nguyen, Paul M.; Desai, Nikesh

doi:10.1016/s1359-6349(08)72264-x

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“…Pre-clinical studies of nab -rapamycin (ABI-009) in breast and colon cancer in in vivo models demonstrated anti-tumor activity, suggesting potential clinical utility. Moreover nab -rapamycin was well tolerated (no observed hypercholesterolemia and hypertriglyceridemia) overcoming the limitations posed by the poor water solubility of rapamycin (36). Specifically the binding of water-insoluble rapamycin to nanoparticle albumin permits albumin-mediated transcytosis of rapamycin by microvessel endothelial cells and the SPARC-albumin interaction may further increase accumulation of albumin-bound drug in the tumor.…”

Section: Discussionmentioning

confidence: 99%

Dual Inhibition of Akt/Mammalian Target of Rapamycin Pathway by Nanoparticle Albumin-Bound–Rapamycin and Perifosine Induces Antitumor Activity in Multiple Myeloma

Cirstea

Hideshima

Rodig

et al. 2010

Molecular Cancer Therapeutics

156

120

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The PI3K/Akt/mTOR pathway mediates multiple myeloma (MM) cell proliferation, survival, and development of drug resistance, underscoring the role of mTOR inhibitors such as rapamycin with potential anti-MM activity. However, recent data demonstrate a positive feedback loop from mTOR/S6K1 to Akt, whereby Akt activation confers resistance to mTOR inhibitors. We confirmed that suppression of mTOR signaling in MM cells by rapamycin was associated with upregulation of Akt phosphorylation. We hypothesized that inhibiting this positive feedback by a potent Akt inhibitor perifosine would augment rapamycin-induced cytotoxicity in MM cells. Perifosine inhibited rapamycin-induced p-Akt, resulting in enhanced cytotoxicity in MM.1S cells even in the presence of IL-6, IGF-1 or bone marrow stromal cells. Moreover, rapamycin induced autophagy in MM.1S MM cells as evidenced by electron microscopy and immunocytochemistry, was augmented by perifosine. Combination therapy increased apoptosis detected by Annexin/PI analysis and caspase/PARP cleavage. Importantly, in vivo antitumor activity and prolongation of survival in a MM mouse xenograft model after treatment was enhanced with combination of nab-rapamycin and perifosine. Utilizing the in silico predictive analysis we confirmed our experimental findings of this drug combination on PI3K, Akt, mTOR kinases, and the caspases. Our data suggests that mutual suppression of the PI3K/Akt/mTOR pathway by rapamycin and perifosine combination induces synergistic MM cell cytotoxicity, providing the rationale for clinical trials in patients with relapsed / refractory MM.

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Section: Discussionmentioning

confidence: 99%