Treatment and Prevention of Breast Cancer Using Multifunctional Inhibitors of Cholesterol Biosynthesis
Final rept. 1 Jun 2012-31 May 2015
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Most human breast cancers are hormone responsive, with proliferation of tumor cells dependent on estrogens and progestins. Hormone-responsive tumors respond initially to endocrine therapy, though most human breast tumors develop resistance to currently used endocrine therapeutic protocols. It is therefore essential that we identify additional molecular targets in the signaling pathways that lead to tumor growth if we are to effectively treat and prevent cancers of the breast. Our goal was to identify alternative targets in the pathway leading to the production of cholesterol, which might be regulated with less toxic inhibitors to control the progression of breast disease. Inhibitors of oxidosqualene cyclase OSC, an enzyme down-stream of HMG CoA-reductase in the cholesterol biosynthetic pathway, effectively arrested breast cancer cell proliferation. In the 2014-2015 Annual Reports we discussed a number of findings establishing that an OSC inhibitor, RO 48-8071 RO possesses potent anti-cancer properties. These results have been published in Breast Cancer Research and Treatment, a highly reputable journal, and are appended in this report. A second report was also published in the journal Oncology and is also appended. During the no-cost extension period we concentrated on finalizing the immunohistochemical studies to determine mechanism of action of RO. We show that therapy involving a combination of RO and an estrogen receptor-beta agonist is an extremely effective means of treating breast cancer. Our studies show that estrogen receptor beta is induced by RO or in some cases levels are not affected. Importantly, the pro-proliferative estrogen receptor-alpha is destroyed by RO.
- Medicine and Medical Research