Joshua LaBaer, MD, PhD

2009-2010 BCRF Project:
The LaBaer group is pursuing studies to identify and characterize genes that regulate critical events involved in the progression of breast cancer and understanding the development of resistance to anti-estrogen drug treatment. They derived matched drug sensitive and resistant breast cancer cells that allow them to ask what changes occur in a breast cancer cell when it becomes drug resistant. They found a signature of 67 genes that are differently expressed in resistant vs. sensitive cells. In two different clinical studies, women whose tumors matched the resistance pattern had a significantly greater likelihood of early relapse while on tamoxifen. Such signatures may prove useful in informing women about whether they need more aggressive surveillance while on tamoxifen or if alternatives should be considered.

They also used the collection of breast cancer related genes (BC1000) that was produced with BCRF support, to identify 31 proteins that make sensitive cells become resistant. One of these, called HSPB8, is a kinase that repeatedly made these cells resistant. Overexpression of this gene in women's tumors predicted poor clinical outcome in patients. When produced in tamoxifen sensitive cells, HSPB8 makes them resistant to the drug; whereas, reducing HSPB8 in resistant cells causes them to die by inducing autophagy, a process by which cells digest their own proteins in times of nutrient stress. Taken too far, autophagy can lead to cell death. Further studies in this period have shown that autophagy plays an important role in the cell death of cultured breast cancer cells when treated with tamoxifen and that rescue from autophagy may provide an escape mechanism from the drug. The researchers hope that defining gene pathways that are responsible for drug resistance will lead to combined treatments that will more effectively treat resistant cancers. In addition, the LaBaer group has continued to develop, maintain and distribute a large gene collection, the BC1000, for studies by the breast cancer community. This collection is available to all researchers in the scientific community at http://plasmid.med.harvard.edu/PLASMID/.

In the coming year, Dr. Labaer intends to characterize the functional role of HSPB8 through protein interactions and evaluate their role in breast cancer patients. In parallel he and his team will continue characterizing tamoxifen/ Fulvestrant sensitive and resistant MCF7 sub-clones by similar methods.

Mid-Year Progress Report:
The LaBaer group is pursuing studies to identify and characterize genes that regulate critical events involved in the development of resistance to anti-estrogens. They found a signature of 67 genes that respond differently to tamoxifen in breast cancer cells that are sensitive compared to resistant ones. When looking at the tumors of women with breast cancer in two different studies this gene signature predicted disease-free survival in tamoxifen treated patients. The researchers also used robotic approaches to test >500 human kinases (proteins that regulate the activity of other proteins) for their ability to make breast cancer cells resistant to tamoxifen. One of these, HSPB8, repeatedly conferred drug resistance and, by itself, predicted poor clinical outcome in one cohort of patients. In part, tamoxifen kills breast cancer cells by triggering autophagy, a process by which cells digest their own proteins.

Further studies revealed that producing HSPB8 protected breast cancers cells from tamoxifen by preventing autophagy. Conversely, reducing HSBP8 in cells induced autophagy and caused cell death. Expression levels of HSPB8 are reduced after resistant cells are treated with autophagy-inducing drugs, emphasizing the connection between HSPB8 and autophagy. The Labaer team has continued with the characterization of the functional role of HSPB8 in autophagy and tamoxifen resistance. Through the use of self assembling protein microarrays they are looking for interacting partners of HSPB8 to gain a better understanding of its role in cancer. In addition, the LaBaer group has continued to develop, maintain and distribute a large gene collection, the BC1000, for studies by the breast cancer community. This collection is available to all researchers in the scientific community at http://dnasu.asu.edu/DNASU.

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.

1981 - BS, University of California, Berkeley, California
1989 - PhD, University of California School of Medicine, San Francisco, California (Biochemistry and Biophysics)
1990 - MD, University of California School of Medicine