Powel H. Brown, MD, PhD

2009-2010 BCRF Project:
Dr. Brown and his team of researchers have been testing novel targeted therapies for the prevention of estrogen receptor-negative (ER-negative) breast cancer.

In a new study, Dr. Brown will investigate the effect of combinations of cancer prevention agents on mammary tumor development and on cancer progenitor cells or "breast cancer stem cells". He will test whether the combination of two targeted drugs, a rexinoid that activates the RXR nuclear receptor and an inhibitor of the growth factor receptors EGFR and Her2, will prevent ER-negative tumor development and eliminate "breast cancer stem cells" in the mammary glands of two different strains that develop breast cancer.

Based on the results of the studies in laboratory models, he will develop a protocol to conduct an early phase cancer prevention trial. It is anticipated that over the next year the protocol will be developed and submitted for regulatory approval, with planned activation next year. Through these studies he will determine whether the combinations of molecularly targeted drugs eliminate cancer stem cells and prevent the development of ER-negative breast cancer.

Mid-Year Progress Report:
Dr. Brown and his team have been testing novel targeted therapies for the prevention of estrogen receptor-negative (ER-negative) breast cancer. His group has shown that several different molecularly targeted drugs can prevent ER-negative breast cancer in laboratory models, and he has tested several of these in human clinical trials. However, while these drugs do delay the development of ER-negative breast cancer in the models, they do not absolutely prevent breast cancer. This may be because they do not eliminate the precursor to cancer, the cancer stem cells. In this study Dr. Brown will investigate the effect of combinations of different classes of cancer prevention agents on mammary tumor formation and on breast cancer stem cell number and function.

In his first aim he will test combinations of agents in one model (MMTV-erbB2 model) to determine whether these cancer prevention drugs effectively eliminate the cancer stem cells that develop breast cancer. In the second aim he will test whether combinations of these agents effectively prevent both ER-positive and ER-negative breast cancer in another model of human breast cancer (MMTV-wnt1). In his third aim he will begin to develop a human clinical trial to test combinations of cancer preventive drugs. Through these studies he will identify which combinations of drugs are most effective at eliminating cancer stem cells and which will totally prevent the development of ER-negative breast cancer.

In an ongoing study also funded by BCRF, Dr. Brown and his team have investigated whether signal transduction inhibitors are useful for the treatment and prevention of breast cancer. The researchers are conducting studies of human breast tumors to identify novel targets for the treatment of estrogen receptor-negative breast cancer, and have previously identified several signaling molecules that are highly expressed in human ER-negative breast cancer which can serve as targets for the treatment of ER-negative breast cancer. Dr. Brown and his group have also shown that inhibition of these signaling molecules suppresses the growth of breast cancer.

Results from their studies in laboratory models demonstrated that the signaling inhibitor lapatinib prevents ER-negative breast cancer in mice. In addition, these studies have identified specific kinase molecules that are highly expressed in ER-negative breast cancer cells. These studies supported the development of a clinical trial to testing the kinase inhibitor lapatinib for the treatment of women with non-invasive breast cancer (ErbB2/Her2-positive DCIS breast cancer). This ongoing study, supported by funds from BCRF, is now open at Baylor College of Medicine, Dana-Farber Cancer Institute, Georgetown University, Walter Reed Army Hospital, MD Anderson Cancer Center, and the Mayo Clinic. Support from BCRF will allow completion of this important clinical trial which will determine whether the oral kinase inhibitor lapatinib will be useful for the treatment of ErbB2/Her2-positive DCIS breast cancer.

Bio:
Dr. Powel Brown is a medical oncologist and physician-scientist specializing in breast cancer treatment and prevention at the University of Texas, MD Anderson Cancer Center, where he serves as Professor and Chair of the Department of Clinical Cancer Prevention. Dr. Brown leads the Cancer Prevention program and his laboratory and clinical efforts are focused on developing more effective ways to prevent breast cancer.

In the laboratory, Dr. Brown is discovering how growth factors and hormones induce changes in gene expression that lead to the development of breast cancer. He has successfully identified several signaling pathways that are critical for breast cancer development, and has used novel designer drugs (signal transduction inhibitors) to prevent breast cancer in laboratory models. In the clinic he has translated these findings to human clinical trials. In his studies supported by BCRF he is testing promising cancer preventive agents for their ability to suppress the growth of normal and pre-invasive breast cancer cells. Those designer drugs that successfully suppress breast cell growth will in the future be used in large-scale clinical trials to prevent breast cancer. Through this work, Dr. Brown plans to develop new strategies to totally eliminate breast cancer.