Authors:
Yayun Liang, Cynthia L. Besch Williford, Indira Benakanakere, Sandra L. Brandt, Philip E. Thorpe, and Salman M. Hyder
Summary:
Mutations in tumor suppressor p53 facilitate tumor cell survival and resistance to chemotherapeutic drugs. Consequently, restoring p53 function within tumors is a promising strategy for targeted cancer therapy. Furthermore, vascular targeting agents, for treatment of cancer are designed to cause selective shutdown of tumor blood vessels, offer yet another opportunity to reduce tumor load. Anionic phospholipids (AP), exposed on the surface of tumor endothelial cells, serve as an excellent marker for vascular disruption. Thus, treatment strategies which incorporate both of these pathways may result in improved and more potent responses. The aim of this study was to determine whether combination therapy targeting mtp53 and tumor blood vessels could be an effective therapeutic strategy for suppression of advanced breast cancer. We therefore tested therapeutic effects of PRIMA-1 which re-activates mtp53 and induces tumor cell apoptosis, and 2aG4, a monoclonal antibody that disrupts tumor vasculature by binding to AP on tumor endothelial cells, causing selective shutdown of tumor blood vessels. Two advanced breast tumor models that express mtp53, and are also Her-2/neu positive (BT-474) or negative (HCC-1428), were used to evaluate this combination therapy. Fluorescence staining and tumor blood vessel perfusion assays were performed to determine therapeutic mechanisms of action. Our results showed that (1) Combination treatment with PRIMA-1 and 2aG4 suppressed BT-474 tumor growth additively leading to complete arrest of tumor progression during treatment; (2) Some BT-474 tumors were completely eradicated when PRIMA-1 or 2aG4 was used alone; combination treatment led to synergistic loss of tumors in nude mice; (3) An increased anti-tumor effect was observed with PRIMA-1 plus 2aG4 treatment in HCC-1428 tumor model; HCC-1428 tumors did not progress with 2aG4 or PRIMA-1 treatment and regressed slightly when combination treatment was tested; however, combination therapy did not lead to complete remission of HCC-1428 tumors; (4) The incidence of lymph node metastasis in nude mice bearing BT-474 breast tumors was reduced by combined treatment using PRIMA-1 plus 2aG4. (5) No toxic effects were observed in any treatment groups. While seeking mechanistic explanations for anti-tumor effects we found that (a) PRIMA-1 induced exposure of AP in vitro in endothelial (HUVEC) cells, in BT-474, and extensively in HCC-1428 tumor cells; (b) PRIMA-1 plus 2aG4 treatment severely disrupted the ability of tumor blood vessels to perfuse in BT-474 and HCC-1428 tumors. These results indicate that PRIMA-1 plus 2aG4 combination therapy has a complementary and potent anti-tumor activity and could define a new strategy for suppression of advanced breast cancers.
Source:
2008 AACR Annual Meeting; 8:00 AM – 12:00 PM, Exhibit Hall B-F, 04/14/08