Research

General Overview

We are fundamentally interested in why cancers develop, and we believe that learning about the roots of cancer development will lead to better cancer therapies, more cures and even cancer prevention. We've chosen to focus on different but related problems in cancer medicine.

The first area we study is Neurofibromatosis I (also known as NF1), which is a genetic syndrome that can lead to tumors in children. Individuals with NF1 can develop brain tumors and tumors along their spines (as well as cancers in other organs). This is an incurable disease that can lead to many complications and even death. We have developed experimental systems (described below) to study how mutations causing this disease actually lead to tumor formation, with the goal of using this information to develop better therapies.

A second major area of research is trying to understand why second cancers develop in some childhood cancer survivors. Children who survive cancer unfortunately have a much greater risk of developing a second cancer, which in many cases is a devastating development. Currently there is little that can be done to prevent this. My research focuses on analyzing these second cancers from childhood cancer survivors for problems in the genetic code. By studying the abnormalities in the genetic code of second cancers, we expect to understand the biological processes leading to second cancers, and one day prevent these complications so that survivors of pediatric cancers have the best chance possible of living healthy adult lives. Some of the tools and approaches we've developed are described in more detail below.

Areas of Investigation

Our research program focuses on two challenges in oncology: improving the treatment of malignant gliomas, and understanding the pathogenesis of therapy-induced malignancies, also known as second malignant neoplasms (SMNs). Central to both these areas are our studies on the function of neurofibromin, a tumor suppressor protein implicated in both brain tumors and SMNs. The long-term goals of these studies are to define key mechanisms contributing to the pathogenesis and therapeutic resistance of malignant gliomas and SMNs in order to develop effective strategies for managing and preventing these challenging diseases.

Approaches

We have generated mouse models to study SMN pathogenesis and neurofibromin function. Our methods for replicating clinically relevant radiation targeting and dosing recapitulate clinically-observed SMNs. The materials isolated from our models are novel reagents used in conjunction with primary cultures to study genetic and biochemical pathways responsible for pathogenesis. Our mouse models will be used to evaluate novel preventive strategies. In collaboration with clinical groups, we are assessing the relevance of our findings through comparative studies of human specimens.

Contributions

We developed clinically relevant approaches to study the underlying mechanisms of tissue specific responses to irradiation. Using these approaches developed mouse models of SMNs, including SMNs arising after cranial irradiation, a severe complication in pediatric brain tumor survivors. We found that neurofibromin loss confers sensitivity to radiation-induced tumorigenesis, and distinct patterns of malignancies in our mouse models arise in a dose-dependent manner. On-going studies are addressing how tissue-specific susceptibilities to radiation are mediated by neurofibromin in both physiologic and pathologic settings.