Brent Rexer, MD, PhD

2009-2010 BCRF Project:
ASCO Cancer Foundation Young Investigator Award

This project focuses on a particular type of breast cancer in which HER2, a protein on the surface of tumor cells, is expressed at abnormally high levels and drives the tumors cells to grow. There are two effective therapies for this type of cancer, one of which is an antibody that inhibits HER2 (trastuzumab, or Herceptin) and the other is an inhibitor of the function of HER2 that blocks its ability to send growth signals to the tumor cells on which it is expressed (lapatinib). Despite the effectiveness of these therapies, however, patients treated with these therapies eventually progress, suggesting that their tumors have developed mechanisms to overcome the inhibition of the HER2 protein achieved by these treatments.

This proposal will use laboratory models of this HER2-inhibitor resistant breast cancer to investigate the mechanisms by which these tumors are able to overcome HER2 inhibition. The goal is to identify the ‘escape pathways’ by which the tumors can continue to send growth signals despite treatment with HER2 inhibitors. This work will also test the ability of new drugs, currently in clinical development, to block these escape pathways, and whether combining these new drugs with existing HER2 inhibitors might prevent the development of resistance.

Mid-Year Progress Report:
Most of the work to date during the grant period has focused on confirming and extending results obtained through the experiments outlined in Aim 2 of the proposal. In this approach, Dr. Rexer used a technique known as mass spectrometry to generate a 'snapshot' of as many of the signaling pathways as possible that are active in the cancer cells based on a marker of activation referred to as tyrosine phosphorylation. This activation is directly what is blocked by the drug lapatinib.

One of the pathways that he identified using this approach involved the activity of a protein called Yes, which is in a family of protein kinases - molecules that can attach a phosphate chemical structure to other proteins - known as as Src family. In breast cancer cells that have become resistant to lapatinib, the activity of this Yes kinase is increased, and drugs that can block Src and related kinase activities (one of which is already FDA approved for use in Leukemia) can overcome lapatinib resistance in the cell line. In addition, he and his colleagues found that combining lapatinib with a Src inhibitor was more effective at inhibiting the growth of HER2-positive tumors in laboratory models than lapatinib alone. Future work will need to confirm whether this same mechanism occurs in patients whose tumors progress after lapatinib therapy to determine whether combining lapatinib with a Src inhibitor might be a potential therapy to be tested in this situation. This work was presented at two professional meetings.

Bio:
Dr. Rexer is currently an Instructor in Medicine at Vanderbilt University School of Medicine and the Vanderbilt-Ingram Cancer Center. He grew up in Texas and Arkansas and graduated with a B.S. in Chemistry from Baylor University. He came to Vanderbilt for medical school as part of the medical scientist training program and completed his MD and PhD degrees in 2003. He remained at Vanderbilt for residency training in Internal Medicine and a fellowship Hematology/Oncology which he completed this year.

In 2007 he joined the laboratory of Dr. Carlos Arteaga where his research interest has been understanding mechanisms of resistance to targeted therapies in breast cancer. Currently his focus is on discovering pathways of resistance to tyrosine kinase inhibitors targeting the HER2 oncogene, with the goal of identifying drug targets to overcome or prevent resistance to treatment of HER2-positive breast cancer.