Michael B. Sporn, MD

2012-2013 BCRF Project(s):
(made possible with generous support from Nestlé Waters North America, Inc.)
Co-Investigator: Karen Liby, PhD, Dartmouth Medical School

Drs. Sporn and Liby have established two new laboratory models of estrogen receptor negative (ER-) breast cancer. These include one in which the human breast cancer gene has been deleted, and another in which the process of inflammation drives the development of breast cancer. In these new models, Drs. Sporn and Liby are testing new drugs for their action as chemopreventive agents. In the past year, they have published new results that show that a new synthetic triterpenoid, bardoxolone methyl (CDDO methyl ester), can suppress the development of breast cancer in the laboratory setting. These results are particularly important because this drug is currently in worldwide phase 3 clinical trial for treatment of severe chronic kidney disease, and if this trial is successful and the drug is approved by Food and Drug Administration, this should open the possibility of testing it for prevention of breast cancer in women at exceptionally high risk.

In 2012-2013, Drs. Sporn and Liby's major efforts will be to continue their overall efforts in chemoprevention with special emphasis on using combinations of new drugs. Most notably, they will give particular emphasis to the use of agents that have anti-inflammatory activity, whether by suppressing the activity of macrophages or by other mechanisms. The role of inflammatory cytokines in enhancement of carcinogenesis is receiving increasing attention, and development of protocols of use of anti-inflammatory agents in combination with anti-proliferative agents is an important approach to chemoprevention. They will continue to give emphasis to develop the concept of "intermittent chemoprevention," which this team pioneered several years ago. This enables one to give pulsed high doses of chemoprevention, followed by rest periods. This may be more effective for inducing apoptosis of premalignant breast cells. Drs. Sporn and Liby will also continue all of their studies on the basic molecular and cell biology of their drugs.

Mid-year Progress: There is a continuing need to devise new approaches to prevent breast cancer. This need is particularly compelling for the clinical management of women who have been newly diagnosed as carriers of BRCA mutations and are, therefore, at exceptionally high risk for development of estrogen receptor (ER)-negative breast cancer. At present, there are no ideal choices for these women. Bilateral prophylactic mastectomy, which can reduce risk by 90%, is one option, but it is certainly not an acceptable one from a personal perspective. Chemoprevention that would be highly effective and acceptable for use for prevention of aggressive, ER- breast cancer in pre-menopausal women has yet to be developed. Thus, the immediate goal of this project is to investigate promising new agents for preventing ER- breast cancer and to study their molecular and cellular mechanisms of action in this regard. The long-term goal of this project is to improve quality of life for women at exceptionally high risk for developing breast cancer by finding an effective and safe preventive drug regimen that would eliminate the need for bilateral prophylactic mastectomy. A similar strategy for chemoprevention of heart attacks and strokes in people at high risk, using cholesterol-lowering drugs (statins) and anti-platelet agents (aspirin), is widely accepted and effective.

During the past year, Drs. Sporn and Liby have completed and published new studies that show that a new drug, Vorinostat, (SAHA), which is now in accepted clinical use for treatment of cancer, can suppress the development of ER- breast cancer in laboratory models. Moreover, SAHA will also enhance the potency of other drugs for prevention of breast cancer in experimental mdoels. In studies of mechanism of action, Drs. Sporn and Liby have shown that SAHA has important anti-inflammatory actions. Hopefully their work will eventually lead to the actual use of such preventive drugs in women at high risk.

Bio:
Michael B. Sporn received his MD degree at the University of Rochester, and then started a 35-year career at the National Institutes of Health, where he became the Chief of the Laboratory of Chemoprevention in the National Cancer Institute in 1978. In the 1980's his laboratory in Bethesda played a key role in the original discovery of the multifunctional cytokine known transforming growth factor-beta (TGF-beta). In 1995 he moved to Dartmouth Medical School, where he has held an endowed chair as Professor of Pharmacology and Medicine.

He has been a strong advocate for prevention of cancer for many years, and much of his own research has dealt with the development of new drugs to be used as chemopreventive agents. These drugs have included synthetic retinoids and rexinoids (analogs of vitamin A), synthetic deltanoids (analogs of vitamin D), as well as selective estrogen response modulators (SERMs). Most recently he has been focusing on the use of new synthetic triterpenoids as agents for preventing breast and lung cancer and for suppressing inflammation and oxidative stress.