SUN-LB055 Targeting Mutant p53 Alone or in Combination with a Phosphatidylserine Specific Antibody Suppresses Growth and Metastasis of Human Breast Cancer: A Strategy Towards Enhancing Personalized Medicine

Mutations in the tumor suppressor p53 gene are frequently associated with various cancers, including human breast cancer. Unlike wild-type p53 (wtp53), mutant p53 protein (mtp53) fails to promote apoptosis, resulting in tumor cell survival and resistance to chemotherapeutic drugs. Consequently, restoration of p53 function is a promising strategy for targeted cancer therapy. The aim of this study was to determine whether administration of APR-246, a small molecule that restores p53 function, either alone or in combination with 2aG4, an antibody that disrupts tumor blood vessels by targeting phosphatidylserine (high levels of which are present in tumor blood vessels) effectively suppresses breast cancer growth and metastasis. We previously reported that the proposed therapy is effective against hormone-dependent breast cancers which express mtp53, though not against breast cancer cells expressing wtp53. Furthermore, APR-246 alone and in combination with 2aG4 dramatically reduced xenograft blood vessel density, an important observation since blood vessels provide a major route for tumor metastasis. Most patients who succumb to breast cancer, and in particular, those with triple-negative breast cancer (TNBC) do so following metastasis to distant organs. TNBCs are devoid of chemotherapeutic targets; consequently, patients are administered toxic, non-specific drugs. However, since more than 80% of TNBCs express mtp53 it was our goal to determine whether APR-246/2aG4 might offer a new targeted approach through which to suppress metastatic TNBC. Female nude mice (n = 10-11/ group) were injected with MDA-MB-435 cells that metastasize efficiently to the lungs. Five days later APR-246 administration began; mice were injected i.v. with 100 mg/kg APR-246 every other day (11 treatments), followed by twice a week for a further 8 treatments. 2aG4 or C44 control antibody was administered i.p (100 μg/mouse) at the same time as APR-246. Compared with vehicle-treated mice, the number of metastatic colonies/lung were significantly reduced (P < 0.05, ANOVA) in animals given APR-246 or 2aG4 alone, or a combination of the two. This might be explained by induction of tumor cell apoptosis in the lungs. While treatment with APR-246 or 2aG4 alone reduced the number of MDA-MB-435-induced metastatic colonies, it took a combination of the two to significantly lower the incidence of metastasis (combination therapy brought about a 50% reduction in incidence of metastasis compared with controls; p<0.05; GENMOD). Throughout our studies no animals exhibited weight loss, indicating that treatments did not cause drug-induced toxicity. Based on our findings, we contend that the growth and metastasis of breast tumors that express mtp53 might effectively be controlled by simultaneous targeting of mtp53 protein and tumor blood vessels. Supported by a COR Faculty Research Grant. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.