Posted April 14, 2015
David Kleinberg, M.D., New York University School of Medicine
Numerous clinical trials have demonstrated the preventative effects of selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, in women at increased risk for estrogen receptor-positive (ER+) breast cancer. However, SERMs have a number of side effects linked to their anti-estrogenic properties, including hot flashes in premenopausal women, increased risk of blood clots, and endometrial hyperplasia and carcinoma, which contribute to reduced compliance among women treated with anti-estrogen therapy. Therefore, new anti-hormone therapies without negative side effects are a significant need in breast cancer clinical care.
To address this need, Dr. David Kleinberg of the New York University School of Medicine received a Fiscal Year 2006 (FY06) Breast Cancer Research Program (BCRP) Synergistic Idea Award to examine the efficacy of a somatostatin analog (pasireotide) that had been shown to inhibit the effects of insulin-like growth factor I (IGF-I) and estrogen in the mammary glands of rats despite the presence of estrogen. Together with Drs. Julia Smith, Deborah Axelrod, and Baljit Singh, Dr. Kleinberg enrolled 15 women volunteers with atypical hyperplasia (AH) of the breast to conduct the study in order to assess the effects of pasireotide on IGF-I and breast tissue in humans. The women were treated with the compound for 10 days in the study. By comparing tissue samples before and after the treatment phase, it was found that pasireotide inhibited cell proliferation and stimulated cell death in hyperplastic breast lesions by inhibiting IGF-I action and also reducing growth hormone secretion from the pituitary. Furthermore, the side effects of pasireotide were mild or moderate. The most notable was an increase in blood glucose during treatment.
Based on these promising results, Dr. Kleinberg proposed to further assess the potential clinical utility of pasireotide in a larger cohort of women with ductal carcinoma in situ (DCIS) through a FY09 BCRP Idea Expansion Award. Additionally, the treatment phase was extended to 20 days to both study the direct effects on DCIS over a longer time period and examine the persistence of altered blood sugar and growth hormone levels. The study is ongoing at this time. Preliminary imaging results have revealed that two patients with low nuclear grade DCIS experienced complete disappearance of DCIS at excision, two patients with high nuclear grade disease had apparent tumor shrinkage, and three with high nuclear grade disease had no apparent tumor shrinkage. Also, as with the pilot study, it appears that serum glucose levels return to normal following the treatment phase. The results from these two studies represent a major step toward the identification of a treatment that can prevent the development of breast cancer or reverse premalignant lesions of the breast, while maintaining intact circulating estrogen levels.
Publications:
Kleinberg DL, Ameri P, and Singh B. 2010. Pasireotide, an IGF-I action inhibitor, prevents growth hormone and estradiol-induced mammary hyperplasia. Pituitary 14(1):44-52.
Smith J, Axelrod D, Singh B, et al. 2011. Prevention of breast cancer: The case for studying inhibition of IGF-1 actions. Annals of Oncology 22 i50-i52.
Ameri P, Dannoff A, Kleinberg DL. 2012. Alternative approach to IGF-I inhibition for treating breast cancer. J Clin Oncol 30:1395-1396.
Singh B, Smith JA, Axelrod DM, et al. 2014. Insulin-like growth factor-I inhibition with pasireotide decreases cell proliferation and increases apoptosis in pre-malignant lesions of the breast: A phase 1 proof of principle trial. Breast Cancer Res 16(6):463.
Links:
Public and Technical Abstracts: Breast Cancer Chemoprevention by SOM230, an IGF-I Action Inhibitor