Abstract 1625: Discovery of a breast cancer targeting peptide with anti-tumor activity

Abstract

Abstract The American Cancer Society estimates 192,370 women will be diagnosed with breast cancer in the United States in 2009, and approximately 40,170 will die of this disease. Towards identifying new ligand-directed therapies for breast cancer, we have developed an in vivo screening method, where peptides that home specifically to the vascular component of tissues are selected after intravenous administration of an engineered combinatorial peptide phage library. We have used this technology for the identification of a new breast cancer targeting peptide and its receptor in a mouse model of highly aggressive and vascularized breast cancer. A random phage library displaying the cyclic sequence CX7C (X = any of the 20 natural amino acids) was injected intravenously in tumor-bearing mice after which phage was recovered from the tumor-tissue by bacterial infection and re-injected for a subsequent round of biopanning. After sequencing of the recovered phage from round 2 and 3 several candidate peptides were identified. One breast cancer targeting peptide (BCTP) was recovered from all tumors with the highest frequency. This peptide showed marked tumor homing as verified by immunohistochemistry (IHC). We used peptide affinity chromatography and tandem mass spectrometry (MS/MS) to identify the target receptor of BCTP. Strikingly, this newly discovered receptor plays an as yet unrecognized role in the pathology of breast cancer. BCPT exhibited strong binding to its receptor as verified by ELISA. To investigate if the BCTP receptor is a relevant candidate drug target in breast cancer, we obtained biopsy samples of breast cancer patients prior to chemotherapy. Strong immunoreactivity of the BCTP receptor was observed in the paraffin embedded tissue sections. Next, mammary tumor-bearing mice were injected twice per week with BCTP, control peptide or saline, systemically. BCTP treated mice demonstrated a marked decrease in tumor size of treated mice, compared to mice injected with PBS alone. We have identified, characterized and validated the peptide BCTP, specifically homing to highly aggressive, vascularized breast tumors. In addition to its tumor targeting capabilities this peptide possesses anti-tumor function in itself, inhibiting tumor growth and progression in tumor-bearing mice. More importantly, the target receptor expression has been verified in human biopsy samples of breast cancer, indicating that this protein might be a promising new drug target. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1625.