Close to 10% of women in the United States develop breast cancer at some point in their lives. Breast cancer can sometimes be prevented when early lesions are treated with an estrogen inhibitor, such as tamoxifen. However, not all tumors are sensitive to such therapy. Work from our group suggests that inhibiting a different hormone called insulin-like growth factor I (IGF-I) may offer a far more effective therapy than tamoxifen in preventing or reversing premalignant lesions. We believe that blocking IGF-I action will be more effective because in addition to blocking the actions of estrogen and progesterone, IGF-1 blockade may also have additional effects on factors that play important roles in the development of cancer, such as DNA repair, gene stability and cell division.

We have shown that a drug called pasireotide directly targets mammary gland proliferation by preventing IGF-I from acting. Pasireotide prevents hormone-induced typical and atypical mammary hyperplasia (an abnormal piling up of cells) in rats by inhibiting cell proliferation and increasing programmed cell death (apoptosis). Our studies showed that it was as or more effective than tamoxifen.

Hyperplasia is thought to be the first step in breast cancer development, after which the rapidly dividing cells are more susceptible to genetic alterations. With a Department of Defense-supported Synergistic Idea Award, we treated women with premalignant forms of hyperplasia for 10 days. Pasireotide inhibited cell proliferation and increased apoptosis in all 13 women tested. Thus, we now know that short-term treatment can be effective in women with premalignant disease. The next step is to determine whether longer term treatment will also be effective in preventing or reversing premalignant disease. For this we will turn to studies in mice.

We have developed an animal model of Brca1 deficiency in which we believe we will be able to demonstrate the effectiveness of pasireotide long term, while simultaneously shedding light on aspects of this inherited form of breast cancer. At this point the focus will be on preventing or reversing premalignant lesions. These animals have extreme mammary abnormalities including cysts and atypical (premalignant) large collections of mammary gland cells. Like some other models of Brca1 mutation, these animals have deficiency in a Brca1 protein, but they also develop premalignant disease much earlier and are much easier to breed than other models. Furthermore, treatment of the Brca1-deficient mice with pasireotide for 7 days dramatically prevented or reversed abnormal duct dilatation and premalignant hyperplastic lesions. Based on the studies in humans and the development of this animal model, we now wish to expand our work to see if longer term treatment with pasireotide will continue to keep the mammary gland relatively free of cystic and premalignant hyperplastic disease.

We further plan to determine whether pasireotide will stabilize the genome and mammary cell types to prevent formation of premalignant lesions that increase the risk for developing breast cancer. If blocking IGF-I action is found to stabilize the genome and mammary composition as well as to prevent hyperplasia, it will show that this type of treatment could be a more effective way to prevent breast cancer than currently available therapies. This could form the basis for further research in women with BRCA1 mutations. It might also apply to women without BRCA1 mutations that have an increased risk of developing breast cancer because of the presence of premalignant lesions.