University of Pennsylvania Philadelphia, Pennsylvania
Perelman Professor and Chair, Department of Cancer Biology Abramson Family Cancer Research Institute Perelman School of Medicine
Addressing cancer recurrence by identifying and validating therapeutic targets unique to dormant tumor cells.
Despite advances in treatment, up to 30 percent of patients will experience a breast cancer recurrence with metastatic disease over their lifetimes, sometimes many years after treatment of their primary cancer. Two factors are likely responsible for many breast cancer recurrences: the presence of residual cancer cells that survive and persist following initial treatment and tumor cell dormancy, a phenomenon whereby tumor cells lay dormant and are undetectable. Related to this, obesity is associated with an increased risk of breast cancer recurrence and death, potentially because it promotes the survival of dormant cancer cells or their ability to resume growth after treatment. While tumor dormancy and cancer recurrence are responsible for many breast cancer deaths, the mechanisms underlying these processes are largely unknown.
Dr. Chodosh is working to identify interventions for breast cancer survivors that can reduce the risk of recurrence and improve long-term outcomes. He and his team have identified several new candidate genes that are believed to play important functional roles in tumor dormancy and recurrence. Recently, the team has demonstrated that the gene PAQR8 plays a role in promoting the survival and recurrence of dormant tumor cells by enabling breast cancer cells to become resistant to a variety of therapies, including chemotherapy, anti-estrogen therapy, and anti-HER2 therapy. They have shown this gene to be both necessary and sufficient to promote tumor cell survival by blocking the HER2 pathway in novel laboratory models. The team has also made observations suggesting that the impact of obesity on promoting breast cancer recurrence may be mediated through obesity-induced changes to the immune system.
In the next year, the team will continue to test the involvement of dormancy and recurrence in a set of candidate genes identified by state-of-the-art gene editing techniques. They will use this technology to investigate the impact of specific genes on cancer cell fitness during dormancy and recurrence and continue analyses of primary and recurrent tumors in their novel laboratory models. Lastly, the team will identify immune cell types that may be required for suppressing recurrence of dormant cells and if they are differentially affected by obesity.
Therapeutic approaches that specifically target the unique biological vulnerabilities of dormant residual cancer cells in breast cancer patients who have completed treatment but still harbor microscopic residual disease, represents a new frontier in breast cancer research.
Lewis A. Chodosh, MD, PhD is the Chair of the Department of Cancer Biology at the Perelman School of Medicine, Associate Director for Basic Science, Director of Tumor Biology, and co-Director of the 2-PREVENT Translational Center of Excellence at the Abramson Family Cancer Research Institute at the University of Pennsylvania. He is a physician-scientist who received a BS in Molecular Biophysics and Biochemistry from Yale University, an MD from Harvard Medical School, and a PhD in Biochemistry from MIT in the laboratory of Dr. Phillip Sharp. He performed his clinical training in Internal Medicine and Endocrinology at Massachusetts General Hospital and conducted postdoctoral training with Dr. Philip Leder at Harvard Medical School. Dr. Chodosh joined the faculty of the University of Pennsylvania in 1994, where he is currently a Professor in the Departments of Cancer Biology, Cell & Developmental Biology, and Medicine. Dr. Chodosh also serves as Editor-in-Chief of Breast Cancer Research, and he was inducted into the National Academy of Medicine in 2017.
His research focuses on the mechanisms of tumorigenesis and tumor progression, particularly with respect to the problem of breast cancer dormancy and recurrence. Dr. Chodosh has made numerous contributions to the understanding of the molecular and cellular underpinnings of cancer progression and has developed multiple genetically engineered models for human cancer that are in wide use throughout the scientific community.
2003
The William P. Lauder Award
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