Abstract 3258: Targeting premalignant lesions for early breast cancer detection and intervention
Authors: Mann Aman P. , Kotamraju Ramana , Teesalu Tambet , Ruoslahti Erkki 
Published: May 2015

Abstract
Breast cancer patients' outcome and survival depends on the timely diagnosis of early malignant lesions. The lack of molecular understanding of the early changes in breast tissue that facilitate tumor progression has limited the development of tools to non-invasively distinguish early stage disease from normal breast tissue. Therefore, probes to target and better understand early breast tumors are much needed. Our laboratory has pioneered in vivo screening of phage libraries to identify peptides that specifically recognize tumor vessels, including breast cancer vasculature. These peptides have been employed to specifically deliver drugs, diagnostic agents, and nanoparticles to breast tumors.
Breast cancer progression constitutes a multistep process through a series of intermediate hyperplastic and neoplastic stages to invasive carcinoma. In this study, we aimed to identify peptides that specifically recognize premalignant lesions in the mammary tissue. To achieve this goal, we utilized the power of phage display to probe hyperplastic lesions associated with premalignant disease in a transgenic MMTV-PyMT animal model. After multiple ex-vivo and in-vivo rounds of selection, we identified a peptide, Prem-1, that on intravenous administration, specifically homed to premalignant mammary lesions. Prem-1 also homed to fully developed breast tumors in the same animal model, suggesting that the putative receptor for Prem-1 is expressed throughout the progression of the disease. Interestingly, Prem-1 did not show any affinity to normal breast tissue. Furthermore, we also identified 2 other candidate peptides that showed significant homing to premalignant lesions with a very different binding pattern as compared to Prem-1. We hypothesized that all three peptides recognize early changes in the breast tissue microenvironment but each bind a different target receptor in the tissue. We are currently investigating these receptors and analyzing their expression in breast cancer progression. Secondly, we are testing the peptides identified herein for the delivery of therapeutic nanoparticles as a mode of early intervention in breast cancer progression. This project utilized the natural environment in the early breast tumor to probe for new markers for detection of early disease. Methods to detect and study early premalignant mammary lesions will expand our understanding of the natural history of the disease, especially the changes in breast tissue that likely lead to tumor development. Hence, the knowledge gained from this study would provide a basis for therapies aimed at suppressing or eradicating premalignant breast lesions. This would be particularly beneficial for women at high-risk of breast cancer based on their genetic predisposition (mutations in BRCA genes).
Citation Format: Aman P. Mann, Ramana Kotamraju, Tambet Teesalu, Erkki Ruoslahti. Targeting premalignant lesions for early breast cancer detection and intervention. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3258. doi:10.1158/1538-7445.AM2014-3258