Antitumor activity, and antiangiogenic activity of nanoparticle albumin-bound nab-rapamycin in combination with nab-paclitaxel.

Abstract

Abstract Abstract #3125 Background: Rapamycin inhibits downstream signals from the mammalian target of rapamycin (mTOR), a known kinase member of a signaling pathway that promotes tumor growth. Rapamycin's poor aqueous solubility and poor chemical stability have limited its development as an intravenous (IV) anticancer agent. Nab-rapamycin utilizes the albumin-bound technology to allow for IV administration of rapamycin and has demonstrated dose-linear pharmacokinetics and safety up to 90 mg/kg with effective antitumor activity at 40 mg/kg against a human panel of tumor xenografts. This study investigated the efficacy of combined therapy with nab-paclitaxel (Abraxane®) utilizing invasive human breast (MDA-MB-231) and colon (HT29) cancer xenograft models.
 Material and Methods: Xenograft transplants using luciferase-tagged MDA-MB-231 cells were implanted into mammary fatpad of SCID mice and allowed to reach 460 mm3 in size prior to IV administration of saline (vehicle, n = 9); nab-rapamycin, 3x wkly for 2 wks at 40 mg/kg (nab-rap-2W; n = 8); nab-rapamycin, 3x wkly for 4 wks at 40 mg/kg (nab-rap-4W; n = 8); Abraxane, qdx5 at 30 mg/kg (ABX; n = 8); nab-rap-2W + ABX (n = 9); or nab-rap-4W + ABX (n = 8). HT29 xenografts were also treated with nab-rap-4W (n = 8) and nab-rap-4W + ABX (10 mg/kg, qdx5, IP, n = 8). The in vivo antiangiogenic effect of nab-rapamycin was evaluated using the standard in vivo chick chorioallantoic membrane (CAM) assay with 3-day old embryos (n = 18).
 Results: Relative to vehicle controls, nab-rap-2W (P < 0.00011), nab-rap-4W (P < 0.0001), and ABX (P < 0.0001) were effective against MDA-MB-231 tumor xenograft models with tumor growth inhibition (TGI) of 60%, 66%, and 73% respectively. Additive antitumor effects were observed with combination of nab-rapamycin + ABX with TGI of 81% and 86% for nab-rap-2W + ABX and nab-rap-4W + ABX groups, respectively. For HT29 tumors, the combination of ABX and nab-rapamycin also showed greater TGI (89%) compared to nab-rapamycin alone (81%). In the chick CAM assay, nab-rapamycin demonstrated antiangiogenic efficacy at doses of 10 µg and above without affecting embryo viability.
 Conclusions: Combination therapy of nab-rapamycin and Abraxane was more effective at inhibiting breast and colon xenograft tumor growth than single therapy of either drug. The enhanced antitumor activity seen with combined nab-rapamycin-Abraxane may in part be due to the observed antiangiogenic activity of nab-rapamycin. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3125.