Joyce Slingerland, MD, PhD, FRCP(C)

About two-thirds of breast cancers express the estrogen receptor(ER). These ER positive breast cancers can be treated with anti-estrogen drugs like tamoxifen or aromatase inhibitors. Unfortunately, most breast cancers that are treated with anti-estrogen therapy develop resistance to these drugs. BCRF support is allowing Dr. Slingerland and her team to investigate if a new molecular targeted drug that blocks the oncogene Src can be used to overcome resistance to conventional anti-estrogens used for ER positive breast cancer. They found that ER positive breast cancers often have high levels of Src, a molecule that turns off the brakes and powerfully activates breast cancer growth. This could promote resistance to antiestrogens, such as ER blockers like tamoxifen and fulvestrant, or aromatase inhibitors, such as anastrazole.

In the last year, the scientists found that conventional anti-estrogens, anastrozole and fulvestrant, both activate Src. Their tissue culture studies and laboratory models show that Src inhibitor drugs can restore responsiveness to anti-estrogen therapy in breast cancer cells that have become resistant to conventional therapies. Theses exciting results provide strong support to start clinical trials of these new drug combinations in women with metastatic breast cancers that have become resistant to tamoxifen or aromatase inhibitors.

The researchers have also discovered other growth-promoting pathways that get inadvertently activated by conventional anti-estrogens. Their data provides a rationale for combining Src inhibitors with inhibitors of another growth stimulator, the MEK pathway, to increase the efficacy of anti-estrogens. They propose to test these drug combinations during the next year to bring new, more effective molecular targeted treatments to bear on the problem of anti-estrogen resistant breast cancer.

Mid-Year Progress Report:
The Slingerland lab has shown that estrogen promotes breast cancer growth by causing the degradation of a key cell cycle inhibitor, p27. The researchers also showed that estrogen deprivation and drugs that block the ER, including tamoxifen and Faslodex (fulvestrant), depend on p27 to cause breast cancer cells to stop growing. p27 levels are often reduced in human breast cancers. Their recent work showed that the Src oncogene acts on p27 to change its shape and function to promote p27 degradation in breast cancer cells. Based on these basic science observations, the researchers have tested a new strategy to combine Src inhibitor with anti-estrogens drugs to restore levels and growth inhibitory action of p27 to better inhibit breast cancer growth.

In the last few years with BCRF support, the Slingerland team has studied whether new Src inhibitor drugs could delay or prevent the development of resistance to anti-estrogens including aromatase inhibitors (AI) and ER- blockers such as fulvestrant. They now have very strong data showing that a new Src inhibitor drug can synergize with anastrozole (Arimidex, an AI commonly used for breast cancer) to block the growth of these tumors. They also have early data showing that the Src inhibitor can also enhance breast cancer response to the ER-blocking drugs, tamoxifen and fulvestrant. Work in the next year will expand these findings to get enough data to move this work into new clinical trials using anti-estrogen and Src inhibitors to treat women with ER positive cancers.

Bio:
Dr. Slingerland received her MD from the University of Toronto in 1983. She is certified in Internal Medicine by the American Board in Internal Medicine and in Canada, and in Medical Oncology by the Royal College of Physicians and Surgeons. In 2002, Dr. Slingerland came to the University of Miami Miller School of Medicine as the Director of the Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center where she is working to expand and coordinate multidisciplinary breast cancer research. She has published over 60 articles and reviews in addition to several book chapters and has received numerous awards. Dr. Slingerland continues her medical practice devoted entirely to breast cancer patients at the Sylvester Comprehensive Cancer Center and the Jackson Memorial Hospital.

Dr Slingerland's lab research has provided insights into how cancers escape negative growth controls. Following her discovery of a key cell cycle inhibitor, p27, she found that p27 levels are reduced in up to 60% of common human cancers (breast, prostate, lung, ovarian and others) in association with poor patient prognosis. She also showed that cell cycle inhibitors p15 and p27 cooperate to cause G1 arrest by transforming growth factor¡Vbeta (TGF-ƒÒ) and that cancer cells lose responsiveness to TGF-ƒÒ through loss or deregulation of p27.

Current work addresses how p27 function is impaired in human breast and other cancers. Functional inactivation of p27 in human cancers can either occur through accelerated p27 degradation or through altered p27 phosphorylation leading to p27 mislocalization. Slingerland's group demonstrated that anti-estrogen drugs require the cdk inhibitors p21 and p27 to arrest breast cancer growth. She showed that oncogenic signaling via the Src and MEK pathways deregulate p27 function causing tamoxifen resistance in breast cancer. Efforts to prevent or reverse hormone independent, ant-iestrogen resistant breast cancer growth using EGFR, MEK and Src inhibitors are under investigation in pre-clinical studies and clinical trials.