Powel H. Brown, MD, PhD

2012-2013 BCRF Project:
Estrogen receptor positive (ER+) breast cancers are typically treated with anti-estrogen drugs, which have significantly improved the success of treating and preventing many cases of invasive breast cancer. However, ER-negative breast cancers, and particularly the aggressive triple negative breast cancers, which represent about 20% of cases, are unresponsive to anti-estrogen drugs and do not effectively respond to current chemotherapeutic strategies, which themselves subject the patient to significant toxicity. Thus, there is an urgent need to identify molecules critical for cellular growth and tumor formation (tumorigenesis) in order to develop effective, non-toxic, targeted therapies for treatment of women with ER-negative breast cancers.

Dr. Brown's team has performed a screen across both ER-negative (triple negative) and ER-positive (luminal) cells in vitro to identify genes that regulate cell growth. Among their results, three genes-- MAP3K3, MAP3K12, and MAP3K17-- were identified as critical for the proliferation of triple negative cells. In this BCRF project, Dr. Brown and colleagues seek to define the mechanism by which these MAP3Ks mediate tumorigenesis. Toward this end, they will perform in vitro and in vivo experiments to determine which growth pathways are dependent upon the activity of MAP3K signaling. They will identify proteins that are altered in response to MAP3K-knockdown using protein/messenger-RNA microarrays.

This study will provide the scientific rationale necessary for the development of molecularly targeted therapeutic strategies allowing for personalized treatment regimens for women with ER-negative breast cancer. In this way, Dr. Brown's research will significantly improve future prognoses of women suffering with this aggressive form of breast cancer.

Mid-year Progress: Dr. Brown's team has investigated whether the novel kinase MELK is a promising target for the treatment of triple negative breast cancer. They have determined this kinase to be associated with poor prognosis in women with breast cancer, and that suppression of its expression causes suppression of the in vitro growth of triple negative breast cancers. However, they have not been able to demonstrate that MELK inhibition suppresses in vivo tumor growth of triple-negative breast cancers. The researchers are continuing their in vivo studies of MELK inhibition to determine whether MELK suppression inhibits other characteristics of breast tumors such as invasion and metastasis. If MELK inhibition does prevent invasion or metastasis, these studies will lay the foundation to target this kinase for the treatment of this very aggressive form of breast cancer.

Separately, Dr. Brown and his team of collaborators have investigated whether signal transduction inhibitors are useful for the treatment and prevention of breast cancer. They are conducting studies of human breast tumors to identify novel targets for the treatment of estrogen receptor (ER)-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 treatment. Dr. Brown and his group have 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. This award supported a clinical trial testing the kinase inhibitor lapatinib for the treatment of women with non-invasive breast cancer (ErbB2/Her2-positive DCIS breast cancer). This ongoing clinical trial, supported by additional funds from BCRF, is currently open at Dana Farber Cancer Institute, the Mayo Clinic, MD Anderson Cancer Center, and the University of Alabama. Funding from BCRF supports 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.

In a related, ongoing project, Dr. Brown's group has been testing novel targeted therapies for the treatment and prevention of estrogen receptor-negative (ER-) breast cancer, the majority of which is also referred to as triple negative breast cancer. Clinical trials have shown that anti-estrogen medications are useful for the treatment and prevention of breast cancer; however, anti-estrogen drugs do not effectively treat or prevent all breast cancers. Specifically, anti-estrogens are not effective for the treatment or prevention of ER- breast cancers. Thus, there is an urgent need for more effective strategies for the treatment and prevention of ER-negative breast cancer. In this project, Dr. Brown's team is conducting a clinical trial testing the therapeutic effectiveness of the signal transduction inhibitor lapatinib in women with HER2-positive or EGFR-positive DCIS breast cancer. The goal of this clinical trial is to show that lapatinib stops the growth of the DCIS breast cancer cells and to determine any potential suppression of growth in the surrounding normal breast cells. This year, the researchers have continued to accrue to this trial. They will perform the biomarker studies once accrual is complete. The results of this clinical trial will lay the foundation for future trials using this new signal transduction inhibitor for the treatment and prevention of 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. Dr. Brown is leading a multicenter neoadjuvant trial of lapatinib for the treatment of women with DCIS breast cancer. The results from this study will demonstrate whether lapatinib suppresses breast cell proliferation in women with DCIS. These results will be used to plan future breast cancer prevention clinical trials in which lapatinib will be given to women in an attempt to prevent breast cancer (as opposed to just suppress breast cell growth). The lapatinib trial will provide essential information to develop future breast cancer prevention drugs. Such an advance will potentially have a major impact on the public health of women world-wide.

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.