James N. Ingle, MD

2011-2012 BCRF Project:
(made possible by generous support from Play For P.I.N.K.)

Tamoxifen remains one of the most important drugs for the treatment of breast cancer. Recent information indicates that a patient's genetic make-up is related to tamoxifen's metabolism and the amount of benefit a patient receives. Dr. Ingle and colleagues focused their efforts on the actions of tamoxifen and its metabolites on breast cancer cells with estrogen receptor (ER)a (ERa, which is currently used in patient care) and ERB (ERB, the second whose role in patient care is still unknown). The researchers found evidence suggesting that ERB may play an important role in a breast cancer's sensitivity to endocrine (hormonal) therapy. They have developed a new antibody to ERB that they will use in the study of patient samples. The results of these studies should provide leads to further improve the treatment of women with breast cancer.

In 2010-2011, the Mayo team's main focus was on the role of ERB in breast cancer and its value as a marker in hormone therapy and therapeutic classification. These studies are essential in order to determine the value of ERB in predicting sensitivity to tamoxifen therapy when given to patients with ERa-positive breast cancers. Their progress has enabled the researchers to begin new studies to determine the effect of ERB and its variants on outcomes in women treated with tamoxifen. The team has also published findings that ERB sensitizes breast cancer cells to the anti-estrogenic effects of endoxifen, a new endocrine agent developed by the National Cancer Institute. Lastly, they have developed cell models of ERB and its variants and will utilize them to determine the value of ERβ and its four variants in predicting response to different endocrine therapies.

Mid-year Progress: Dr. Ingle's team has finished the development of an antibody against ERB that recognizes all the forms of this receptor (ERB1-5) and identified one commercially available antibody that recognizes only ERB1. They have now begun studying numerous collections of breast cancer samples in order to determine if ERB has value in predicting disease progression or a patient's responsiveness to hormonal therapy.

For 2011-2012, Dr. Ingle's team set three primary research aims, the first two of which were expanded based on recent results. First, following the completion of the development and characterization of their novel ERB monoclonal antibody, the researchers published a manuscript in the Journal of Cellular Biochemistry, where they provided evidence that much of the controversy regarding the roles of ERB in breast cancer may be explained by variability in antibody sensitivity and specificity. Secondly, Dr. Ingle and colleagues have launched a phase I clinical trial on endoxifen, which based on previous BCRF-funded studies had shown to be effective against breast cancer cells that express ERB. This work was published in Breast Cancer Research in 2011. The expansion of this clinical trial cohort is expected to begin in the summer of 2012. This team's third research aim revolves around the examinations of the various ERB variants. Initial studies have demonstrated that expression of these variants has the ability to modify ERa and ERB1 responses following estrogen treatment.

Bio:
Dr. Ingle is Professor of Oncology and Foust Professor in Mayo Clinic College of Medicine. He is the Leader of Breast Cancer Research in the Mayo Clinic Comprehensive Cancer Center and serves as Program Co-Leader of the Women's Cancer Program with responsibility for breast cancer. Dr. Ingle is the Director of the Mayo Clinic Breast Cancer Specialized Program of Research Excellence.

Dr. Ingle chaired the Breast Committee of the North Central Cancer Treatment Group for 22 years (1977-1999). His primary interests are pharmacogenomics and translational research involving endocrine therapy of breast cancer and the biology of endocrine sensitivity. He has 283 peer-reviewed publications. He has served on numerous national and international bodies such as the National Institutes of Health (1990, Conference Vice-Chair)) and St. Gallen (2003-2011) Consensus Conference Panels on early breast cancer, serving as Co-Chair of the 2009 St. Gallen Conference. He currently serves on the Breast Cancer Steering Committee of the National Cancer Institute's Coordinating Center for Clinical Trials.