ANAHEIM, CA (UroToday.com) - Dr. Angela Brodie, University of Maryland presented “Aromatase Inhibition for Cancer Prevention and Treatment” as the SBUR Donald S. Coffey Lecture.

Dr. Brodie received her PHD from Manchester University and followed with a post-doctoral fellowship at the NIH. She is a professor at the University of Maryland. Her work focuses on aromatase inhibitors as regulators of estrogen biosynthesis for breast cancer treatment. She has also developed compounds that inhibit androgen synthesis.

Both estrogens and androgens stimulate breast and prostate cancer, respectively. Surgical approaches including gonadectomy, adrenalectomy and hypophysectomy were the initial hormonal treatments for cancer. Aromatase converts testosterone to estradiol and this observation initiated her interest in the field while at the Worcester Institute for Experimental Biology. Concentrations of estrogen are higher in breast tissue than serum and equivalent to pre-menopausal levels. Systemic approaches to inhibit estrogen include blocking estrogen binding to ER using tamoxifen or inhibit estrogen biosynthesis using aromatase inhibitors. Her work focused on the latter approach. A concern was that antagonist/agonist effect on the tumor might not be optimal and the increased risk of estrogenic side effects. Aromatase is the last step in steroid synthesis from cholesterol to testosterone and estrogen. Cortisol and aldosterone synthesis would not be affected by inhibiting aromatase, thus limiting side effects.

A ompound identified in the lav had high target affinity and specificity. It bound as a competitive inhibitor and in a non-competitive time dependent fashion inducing loss of activity by binding directly to the enzyme and inactivating it. In animal models, use of the inhibitor 4-OHA on mammary tumors was significant. Estradiol levels were suppressed as well. Dr. Brodie sought to develop 4-OHA on large scale synthesis, but there was a lack of interest by pharmaceutical companies in becoming involved in development. This was due to their conviction that chemotherapy was the future of breast cancer therapy. Collaboration with the Royal Marsden Hospital in London resulted in a patent for a method for inhibiting estrogen biosynthesis. Ultimately, the University of Maryland performed the large scale synthesis and toxicity studies were performed and confirmed low toxicity. Clinical trials showed good results and tolerability. Nonsteroidal aromatase inhibitors bind to a different region of the P-450 site of aromatase and were put into trials. In her lab, it was discovered that breast cancer tumors are sensitive to both tamoxifen and the aromatase inhibitor Letrozole. Combination therapy resulted in longer and better tumor inhibition. Sequential use of chemotherapy and Letrozole demonstrated that Letrozole following tamoxifen was better than either drug alone, but was not as effective as starting Letrozole from the onset. Tamoxifen beyond 5 years of therapy has not shown benefit, so Letrozole beginning at that point in time for 2.4 years was studied and published. Overall survival was increased and complications of the cancer decreased.

She then sought to identify the mechanisms of resistance to Letrozole at different time points in an animal model of breast cancer. Her-2 was upregulated, as was p-MAPK and Grb2 in the resistant tumors. Estrogen receptor alpha expression was decreased. MAPK signaling was critical to driving ER transcription and gene activation of genes promoting disease progression. Inhibitors of pMEK1/2 did not have a growth inhibitory effect on parental breast cancer cells but did inhibit the resistant cells. Combination of Herceptin and Letrozole blocked the Her-2 pathway and was more effective in the resistant cells than monotherapies.

She concluded that breast cancer may soon be viewed as a chronic disease as opposed to a fatal disease.

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Written by Christopher P. Evans, MD, a Contributing Editor with UroToday.

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