Evaluation of antitumor activity and biomarkers for MBP-426 in human pancreatic cancer xenograft models in vivo

Elzbieta Izbicka, Armando Diaz, David Campos, Michael Wick, Chris Takimoto, M Nagasawa, C Hashimoto.

Inst. for Drug Development/CTRC, San Antonio, TX, Mebiopharm Co Ltd, Tokyo, Japan

MBP-426 is a novel oxaliplatin-encapsulated transferrin (Tf) -conjugated N-glutaryl phosphatidylethanolamine (NGPE)-liposome. MBP-426 demonstrated potent anticancer preclinical activity and has recently entered clinical trials. Direct drug binding to Tf receptor (TfR) was demonstrated in human cancer cells in vitro; the drug delivery is thought to be enhanced via uptake by TfR. This study investigated activity of MBP-426 alone and in combination with gemcitabine or erlotinib in the PANC-1 human pancreas tumor xenograft model. Significant endpoints included mean tumor growth inhibition or regression, weight loss, and agent toxicity. In groups treated with MBP-426 alone and in combination with gemcitabine we further evaluated expression of biomarkers (TfR, cleaved caspase-3, PARP, survivin, CD31, Hif1a in tumor tissue; VEGF, TNF-a, bFGF, IL-6, MMP-2 and MMP-9 in serum) by immunostaining and multiplexed immunoassays, respectively. In vivo treatment with gemcitabine (40 mg/kg) resulted in reversible weight loss and moderate tumor growth inhibition (TGI=25%); no weight loss or TGI was reported for 50 mg/kg erlotinib. MBP-426 alone was inactive but the group co-treated with 40 mg/kg gemcitabine and 4 mg/kg MBP-426 reported significant (p<0.01) TGI compared with gemcitabine alone. Similar TGI effects were seen in the 40 mg/kg gemcitabine/ 8 mg/kg MBP-426 combination group (p<0.01). The 40 mg/kg gemcitabine plus 4 mg/kg MBP-426 group was active. Combination with 50 mg/kg erlotinib and 4 or 8 mg/kg MBP-426 had additive TGI in the high dose combination. Comparable significant (p<0.01) TGI in the low dose combination group was indicative of drug activity. Except for significant weight loss and 6/9 deaths at high dose MBP-426 and gemcitabine, the drug was well tolerated. The expression of TfR in tumor tissue exhibited an apparently upward trend with increasing doses of MBP-426. Tissue biomarkers were unaffected by any drug treatment except for significant p<0.05) upregulation of cleaved caspase-3 (gemcitabine alone) and survivin (high dose of MBP-426 and gemcitabine). The reduction of MMP-2 was significant (>20% inhibition, p=0.011) in the 4 mg/kg MBP-426 plus gemcitabine treatment group. TNF-a was significantly suppressed by gemcitabine (50% inhibition, p=0.007), the low dose of MBP-426 alone (35% inhibition, p=0.043) and in combination with gemcitabine (38% inhibition, p=0.027). Taken together, these results demonstrate additive combinatorial effects of MBP-426 with gemcitabine and erlotinib in pancreatic adenocarcinoma in vivo. Serum TNF-a and MMP-2 levels might be pursued as potential biomarkers of drug efficacy in clinical trials. Supported by Mebiopharm