Grants We Funded

Abstract

Project Summary: Radiation therapy is a common treatment in patients with breast cancer. However, despite its many benefits, radiation is known to cause fibrosis and increase complication rates in women who have undergone prosthetic-based breast reconstruction after mastectomy. The success of this procedure is highly reliant on the quality of the skin and soft tissue envelope that remains after mastectomy and radiation therapy. Despite of significant technological advances in medicine, radioprotective treatment options to preserve normal tissue are still limited. Therefore, there is a need to test potential therapeutic effect of radioprotective agents in a controlled setting to verify their effectiveness and build an evidence-based approach to mitigating the risks of radiation therapy in prosthetic-based reconstruction. Previous studies and our preliminary data suggest that use of acellular dermal matrix (ADM) as a tissue expander cover and topical application of deferoxamine (DFO) may improve clinical outcome of tissue expansion (TE) in the setting of radiation. Thus, the central objective of this proposal is to explore the potential therapeutic role of ADM and DFO in TE followed by radiation, better understand the molecular mechanisms leading to radiation-induced fibrosis, and how these molecular events differ between skin expanded with and without use of ADM. Therefore, we will: Aim 1) Characterize the early molecular and histological changes in skin exposed to radiation and evaluate how use of ADM during TE impacts these changes, and Aim 2) Determine whether TE efficacy can be improved in the setting of radiation by wrapping tissue expander with ADM and applying topical DFO. We will perform in-depth transcriptomic analysis at single cell resolution in collected skin samples. In addition, we will measure in vivo skin growth and perfusion, perform histological and molecular analyses, and evaluate the biomechanical properties of skin in a porcine model with and without tested modalities. The long-term goal of our research is to improve outcomes of TE when performed in the setting of radiation. Clinically, these findings can have a significant impact in improving reconstructive outcomes for women who undergo post-mastectomy radiation therapy, and other patients with cancers requiring adjuvant radiation.

Impact Statement: Post-mastectomy radiation therapy (PMRT) often results in serious skin injury, which limits or precludes tissue expansion (TE) that is necessary for satisfactory breast reconstruction. Clinical experience and experimental studies in murine model suggest that acellular dermal matrix and deferoxamine may mediate the risk of radiation-induced injury. However, their potential benefits on TE efficacy in the setting of radiation and underlying mechanisms by which these variables affect reconstructive outcome are unknown. Our study aims to identify these mechanisms in order to provide an evidence-based guidance for the surgeons to help them minimize complications and improve breast reconstruction outcomes in PMRT patients.

Biography
Dr. Joanna K. Ledwon, PhD, is a Research Assistant Professor of Pediatric Surgery at Northwestern University and Ann & Robert H. Lurie Children's Hospital. Dr. Ledwon earned a Bachelor’s degree in Biotechnology from the University of Szczecin and a Master's degree in Biotechnology from the University of Warsaw. She then earned a Doctorate of Medical Sciences degree in Medical Biology from the Centre of Postgraduate Medical Education in Poland. Her doctoral research was focused on the identification of genetic risk markers of breast, prostate and colon cancer using genome-wide association studies. Over the past six years in the Gosain Laboratory, Dr. Ledwon has supported the research team with her expertise in biomedical research and molecular biology on multiple projects. She has studied the genetic background and molecular mechanisms of craniosynostosis and used patient-derived MSC cell culture and zebrafish animal models. She has also provided technical skill and biological expertise to study the molecular response of skin during tissue expansion using a porcine model. Dr. Ledwon has also investigated the effect of ADM on mechanically induced skin growth and the dermal changes during tissue expansion in a porcine model. As a young faculty member with a strong academic interest in the molecular mechanisms of tissue growth and regeneration, Dr. Ledwon is passionate about advancing the field of plastic surgery through basic science and translational research.