Joshua LaBaer, MD, PhD

The LaBaer group is pursuing studies to identify and characterize genes that play a role in resistance to commonly prescribed drugs used to treat breast cancer such as tamoxifen, fulvestrant and Herceptin® (trastuzumab). In earlier phases of this project, Dr. LaBaer's team derived a series of cultured breast cancer cells that were either highly sensitive or naturally resistant to tamoxifen and studied the factors that lead to drug resistance. These cell lines have been distributed to several labs and are used as a model to study the development of resistance.

From the characterization of these clones, Dr. LaBaer's team identified 227 genes that responded to tamoxifen in the sensitive cells but did not respond in the resistant ones. Regardless of their differential responses to tamoxifen in the matched cells, all of these genes still responded to estrogen, which suggests that they may share some common regulator that is disrupted in the resistant cells. The investigators discovered that three regulators are increased in the resistant cells. They continue characterizing these sub-clones at genomic and proteomic levels to better understand tamoxifen resistance. To extend this work, they also have begun to study how alterations in driver genes such as TP53 collaborate with other mutated genes and cause breast carcinogenesis. The successful treatment of cancer may require a combined approach that addresses both known cancer protein pathways, e.g. p53, as well as the modifier pathways that collaborate with p53 to cause cancer.

Dr. LaBaer's group has continued to develop, maintain and distribute a large gene collection, originally the BC1000 but now more than 10,000 human genes or studies by the breast cancer community, which recently expanded in this last period with the addition of more than 12,000 genes from their collaborators in the ORFeome Collaboration. This entire collection is available to all researchers in the scientific community at http://dnasu.asu.edu/DNASU/.

Mid-year Progress: Currently, Dr. LaBaer's team is combining and analyzing multi-layered data from genomic, proteomic, and transcriptomic profiling of tamoxifen-sensitive and -resistant cell lines to generate a global picture of molecular mechanisms underlying tamoxifen resistance.

Preliminary data showed that whereas sensitive cells share similar genomic profiles, the resistant counterparts are more variable, showing distinct profiles and suggesting a more diverse genetic background. Indeed, the researchers have confirmed that regardless of their differential responses to tamoxifen in the matched cells, certain genes and proteins still responded to estrogen, which suggests that they may share some common regulator that is disrupted in the resistant cells. Dr. LaBaer's group is currently performing a computational analysis to identify the gene sets and the pathways involved in biological processes that could play a role in tamoxifen resistance. To extend their knowledge in breast carcinogenesis, the researchers have begun to study how alterations in driver genes such as TP53 collaborate with other mutated genes and initiated cancer. Genomic studies indicate that breast cancer has a striking prevalence of somatic TP53 mutations (35%), which are particularly common in basal-like tumors. Patients with these aggressive basal-like tumors have few treatment options and respond poorly to current therapies. Successful treatment of basal cancer patients may require a combined approach that addresses both known cancer protein pathways, e.g. p53, as well as the modifier pathways that collaborate with p53 (most common mutated) to cause cancer.

Bio:
Dr. Joshua LaBaer is one of the nation's foremost investigators in the rapidly expanding field of personalized medicine. Formerly director of the Harvard Institute of Proteomics (HIP), he was recently recruited to ASU's Biodesign Institute as the first Piper Chair in Personalized Medicine.

Dr. LaBaer's efforts involve leveraging the Center's formidable resources for the discovery and validation of biomarkers - unique molecular fingerprints of disease - which can provide early warning for those at risk of major illnesses, including cancer and diabetes. This work is carried out in conjunction with the Partnership for Personalized Medicine, a multi-institution effort that includes the Translational Genomics Research Institute (TGen) in Phoenix and the Fred Hutchinson Cancer Research Institute in Seattle.

Dr. LaBaer completed his internship and residency at the Brigham and Women's Hospital and a clinical fellowship in Oncology at the Dana-Farber Cancer Institute, both in Boston. He is a board certified physician in Internal Medicine and Medical Oncology and was an Instructor and Clinical Fellow in Medicine at Harvard Medical School. He has contributed more than 60 original research publications, reviews and chapters. Dr. LaBaer is an associate editor of the Journal of Proteome Research, Analytical Biochemistry, and a member of the Scientific Advisory Boards for the Proteome Society, Promega Corporation, Lumera-Plexera Corporation, Barnett Institute, and a founding member of the Human Proteome Organization. In addition, he serves on the Board of Scientific Advisors to the Director of the National Cancer Institute.

Dr. LaBaer received his bachelor of science degree from University of California, Berkeley, and his medical degree from University of California School of Medicine. He also has a doctoral degree in Biochemistry and Biophysics from University of California, San Francisco.