Combination Regimens of nab-Rapamycin (ABI-009) Effective Against MDA-MB-231 Breast-Tumor Xenografts
| Autor: | N. Desai, O. D'Cruz, V Trieu |
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| Rok vydání: | 2009 |
| Předmět: | |
| Zdroj: | Cancer Research. 69:6106-6106 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Background: The mammalian target of Rapamycin (mTOR) is a key intracellular kinase integrating cell proliferation and survival and is an attractive target for cancer therapy. Nab-rapamycin (ABI-009) was developed using proprietary nab-technology and showed dose-linear pharmacokinetics, safety up to 90 mg/kg and effective antitumor activity at 40 mg/kg in the human-tumor-xenograft panel. The goal of this study was to test the effectiveness of different combination regimens for ABI-009 against MDA-MB-231 breast-tumor xenografts.Materials and methods: Subcutaneous human-breast (MDA-MB-231) tumors were grown in athymic nude mice and treated intravenously (IV) with ABI-009 alone at 40 mg/kg (3xwkly/4wks) and in combination with Erlotinib (50 and 100 mg/kg/day/4wks, IP), Cetuximab (20 and 40 mg/kg, 3xwkly/4wks, IP), Doxorubicin (2 and 5 mg/kg, wkly/10 wks, IV), Oxaliplatin (5 and 10 mg/kg wkly/4 wks, IV), SAHA (50 mg/kg, qdx7 or qdx14, IP), and Perifosine (30 and 60 mg/kg, 3xwkly/4wks, PO). The animal weights and tumor measurements were recorded three times weekly and adverse observations recorded.Results: ABI-009 was highly effective as a single agent against MDA-MB-231 breast tumor xenografts with 75% tumor-growth inhibition (TGI). Combination with Erlotinib resulted in TGI of 85% and 95% (50 and 100 mg/kg, respectively), 83% and 87% for Cetuximab (20 and 40 mg/kg, respectively), 83% and 90% for Doxorubicin (2.5 and 5 mg/kg, respectively), 82% and 85% for Oxaliplatin (5 and 10 mg/kg, respectively), 82% and 90% for SAHA (7 and 14 day treatment, respectively), and 92% and 96% for Perifosine (30 and 60 mg/kg, respectively). Notably, Erlotinib and Perifosine were found to synergize with ABI-009 resulting in maximum TGI and tumor growth delay.Discussion: ABI-009 (nab-rapamycin) alone was highly effective against MDA-MB-231 human-breast-tumor xenografts. Antitumor activity of ABI-009 was significantly increased in combination with kinase inhibitors, Erlotinib (EGFR-kinase inhibitor) and Perifosine (AKT inhibitor). Antitumor activity of ABI-009 was also significantly increased in combination with Doxorubicin – a topoisomerase inhibitor, and SAHA – an HDAC inhibitor, but not in combination with Oxaliplatin – a DNA crosslinker. In contrast, combination of ABI-009 with anti-EGFR monoclonal antibody, Cetuximab was not effective. The synergy of these combinations confirmed that rapamycin is active only on TORC1 and that suppression of TORC2 via AKT or PI3K pathways is a means of increasing activity of mTOR inhibitors with potential relevance to breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6106. |
| Databáze: | OpenAIRE |
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