General Overview

We are fundamentally interested in why cancers develop, how to prevent cancers and how to improve health for individuals diagnosed with cancer. 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 key issues in cancer medicine described below.

Cancer development and Aging

My laboratory studies carcinogenesis, or the biological processes that lead to cancer formation, which involves mechanisms that are shared with aging. A major research effort undertaken by my laboratory has been to systematically study, using both experimental systems and clinical materials, radiation-induced mutagenesis and in so doing gain insight into how mutagenic exposures complement or amplify age-associated changes. Individuals who have received cancer therapy, particularly as children, can be at heightened risk for developing second cancers. One of our goals is to prevent this complication in cancer survivors and we have developed multi-disciplinary research to study treatment-associated malignancies.

Over the years, we developed multiple mouse models of radiation-induced malignancies and analyzed these malignancies with whole exome sequencing to identify distinctive trinucleotide-based mutational signatures. We also analyzed human radiation-induced malignancies and performed comparative studies to show significant similarities between the mutational profiles in human and mouse radiation-induced malignancies. Radiation-associated mutational signatures correlate to a mutational signature that associated with aging. This observation and the growing evidence that mutational processes in normal cells accumulate with age has led to more questions about the relationship between aging and cancer formation that we are now studying. We have on-going studies to investigate how the age at which radiation exposure occurs influences mutational and cancer trajectory in aging individuals.

Cancer Metabolism

In the last several years, my laboratory developed a focus on tumor metabolism and elucidating metabolic mechanisms required for tumor progression in vivo. We used CRISPR technology to perform a systems level analysis of in vivo tumor metabolic requirement, which reveal striking tumor metabolic dependencies that distinguish primary and metastatic tumors. We are coupling these studies with investigations to develop imaging modalities optimized for evaluating in vivo tumor metabolism. Our objective is to measure quantitative imageable metabolic signatures in tumors (primary and metastatic) growing in vivo and investigate how mitochondrial and respiratory function play context-specific roles in supporting in vivo growth. Our overarching goal is to investigate the mechanisms supporting tumor growth and progression in order to develop therapies that exploit cancer-specific metabolic dependencies and open new paradigms in cancer management.

Neurological complications in Cancer

Individuals with cancer, particularly elderly patients, commonly develop neurological complications that can impact immediate and longterm well-being. We have developed models to study the effects of cancer therapy on the nervous system and are using these to understand how neurological complications develop and how these can be prevented. For example, one line of investigation involves testing whether biomarkers can predict in individuals with cancer those who are at risk for developing neurocognitive decline after brain radiation therapy.