Bruce G. Haffty, MD

2009-2010 BCRF Project:
Dr. Haffty's research interest focuses on molecular and genetic factors that may be associated with radiation resistance and local-regional recurrence following treatment of breast cancer, which continues to be a significant pattern of failure, particularly in young women with breast cancer. The p53 Binding Protein, 53BP1 is commonly expressed in breast cancers. Loss of expression of this protein may be associated with more aggressive behavior of cancers. The researchers reported last year that in a sample of 500 patients with early stage breast cancers that lack expression of 53BP1, correlates strongly with triple negative breast cancers, and also correlates strongly with distant metastasis among the triple negative cancers. This year they focused on genotyping of patients for polymorphisms in 53BP1 and report that in a cohort of women treated with breast conserving therapy, who were genotyped for a common polymorphism (genetic change) in the gene coding for 53BP1, a correlation between local relapse in the breast and patients homozygous for the polymorphism. They also completed a series of basic science experiments demonstrating that knocking down the 53BP1 gene with siRNA techniques enhanced radiation sensitivity and chemo-radiation sensitivity.

One of the key components of radiation sensitivity, and failure of radiation to control disease, involves a process of tumor cell death referred commonly to as apoptosis. The BCL-2 (B-Cell Lymphoma) family of proteins are central regulators of apoptosis and have been shown to be significant factors in the sensitivity of tumors to chemotherapy and radiation. Since BCL-2 is commonly expressed in breast cancer and is associated with radiation resistance, it is an attractive target for increasing radiation sensitivity. The Haffty team has shown in a preliminary pilot study, which was a result of work they conducted under the generous support by the BCRF funding from last year, that over-expression of BCL-2 was associated with increased local relapse rates in patients treated with breast conserving surgery and radiation (Yang et al., 2009). Recently orally active novel small molecule drugs that inhibit the anti-apoptotic family of BCL-2 proteins have been developed (ABT-263, ABT-737). These are available for human use and currently in Phase I/II studies, and are ideally suited as agents to potentially enhance radiation sensitivity and improve outcomes in patients undergoing radiation.

In the current grant cycle they will further explore the role of BCL-2 in improving outcomes in patients undergoing radiation therapy. Specifically, they will further evaluate, in a larger and separate cohort of patients, the correlation of the BCL-2 family of proteins with local-regional relapse and radiation resistance, they will evaluate the clinical significance of a genetic change (single nucleotide polymorphism) in the gene controlling BCL-2 in a cohort of patients treated with breast conserving surgery and radiation, and they will conduct basic science and translational research studies evaluating drugs that target BCL-2 in combination with radiation to determine the potential for enhanced radiation sensitivity using these targeted agents in combination with radiation. Simultaneously, with these studies, a Phase I dose escalation trial of the BCL-2 inhibitors in combination with palliative external beam radiation therapy will be conducted to determine the toxicity of the BCL-2 inhibitors in combination with radiation therapy.

Mid-Year Progress Report:
Dr. Haffty reports that he is extremely pleased with his group’s progress to date related to evaluation of novel molecular and genetic markers associated with failure of radiation therapy to adequately control local-regional disease, which continues to be a significant pattern of failure, particularly in young women with breast cancer. One of the key components of radiation sensitivity, and failure of radiation to control disease, involves a process of tumor cell death referred commonly to as apoptosis. The BCL-2 (B-Cell Lymphoma) family of proteins are central regulators of apoptosis and have been shown to be significant factors in the sensitivity of tumors to chemotherapy and radiation, and is commonly expressed in breast cancer. Since expression of BCL-2 may be associated with radiation resistance, it is an attractive target for increasing radiation sensitivity.

The Haffty team showed in a preliminary pilot study, which was a result of work they conducted with support by BCRF last year, that over-expression of BCL-2 was associated with increased local relapse rates in patients treated with breast conserving surgery and radiation 1. Recently orally active novel small molecule drugs that target BCL-2 have been developed (ABT-263, ABT-737). These are available for human use and currently in Phase I/II studies, but limited work has been done evaluating these agents in combination with radiation. Dr. Haffty and colleagues have been conducting a series of experiments, where they have targeted BCL-2 with these novel drugs in combination with radiation, and have demonstrated enhanced radiation sensitivity and increased tumor cell kill with the combination of BCL-2 targeting and radiation in breast cancers. Thus far they have completed staining of a number of proteins in the BCL-2 family in a large cohort of patients undergoing breast conserving surgery and radiation and are in the process of analyzing that data. In addition they have initiated a series of basic science experiments where they have targeted BCL-2 with molecular techniques and have observed enhanced radiation sensitivity, and have targeted BCL-2 with the commercially available drug and have observed enhanced radiation sensitivity.

In addition to the above, BCRF funding has allowed the researchers to explore another molecular marker, the metabotropic glutamate receptor (GRM1). They have found that targeting this receptor also enhances radiation sensitivity and increases apoptosis, in a similar fashion to targeting BCL-2. They are further exploring this avenue of investigation as well. The funding we have received from BCRF in the past year has generated several publications, and several others are in preparation.

Bio:
Bruce G. Haffty, MD, is currently Professor and Chairman, Dept of Radiation Oncology, UMDNJ-Robert Wood Johnson Medical School and New Jersey Medical School and Associate Director of Clinical Sciences, Cancer Institute of New Jersey. His medical school training was at Yale School of Medicine, followed by an internship in internal medicine, residency and chief residency in the Department of Therapeutic Radiology, Yale School of Medicine, Yale-New Haven Hospital. Since completion of residency, Dr. Haffty spent the majority of his academic career at Yale School of Medicine, Department of Therapeutic Radiology, where he was a Professor of Therapeutic Radiology, served as residency program director from 1992 through 2004, Vice Chairman and Clinical Director from 2002-2005. He moved to the Robert Wood Johnson Medical School and Cancer Institute of New Jersey in 2005.

Dr. Haffty's clinical areas of expertise include breast cancer and head and neck cancer, for which he is internationally recognized. He has had numerous research grants and conducts clinical and translational research in his chosen areas of expertise. He has published over 200 peer-reviewed articles, 30 book chapters, and numerous editorials and letters. He recently completed editing a comprehensive book, Handbook of Radiation Oncology. He is consistently listed as one of the country's leading physicians by Best Doctors in America, Ladies Home Journal, Good Housekeeping, America's Top Doctors, Top Doctors for Cancer, and Top Doctors in New York and New Jersey.

In addition to a busy clinical practice, Dr. Haffty has served on numerous national committees related to research and education in radiation oncology, serves on the Editorial Board of numerous Medical Journals, and has mentored many medical students, trainees and junior faculty in conducting clinical and translational research. He is currently an Associate Editor of the Journal of Clinical Oncology, serves on the Executive Committees of the National Accreditation Program for Breast Centers and American Radium Society, and Board of Directors of ASTRO. He is co-chairman of the BOOST program for RSNA, and currently serves as Chairman of the Residency Review Committee in Radiation Oncology, and a radiation oncology Trustee of the American Board of Radiology. Dr. Haffty is President of the American Radium Society, and President-Elect of the American Board of Radiology.