FUNDED INVESTIGATORS

Doris Germain, Ph.D. Samuel Waxman, M.D.
Mount Sinai School of Medicine Mount Sinai School of Medicine

Probing the Activatio of the Cyclin D1-STAT3 Network as a Biomarker of Response to Endocrine Therapy of Breast Cancer

Based on the work funded by the SWCRF, we currently have a clinical trial testing a new drug combination, fulvestrant and bortezomib, in post-menopausal women with estrogen receptor (ER) positive breast cancers. Our pre-clinical data suggest that Cyclin D1 can be used as a biomarker of response to this novel combination. Up to now 53 patients have been recruited. Our first objective is therefore to test our hypothesis that Cyclin D1 will identify the patients that will best respond to this combination using clinical samples.

Conversely, our previous work has shown that Cyclin D1 is a marker of poor response to the anti-estrogren drug Tamoxifen. The use of this drug is mainly limited to ER positive breast cancer in pre-and peri-menopausal women. However, several patients have less benefit from treatment with Tamoxifen and markers of resistance such as Cyclin D1 are not used clinically. This is due, in fact, to limited treatment options for young women with intact ovarian function. Thus for lack of a better option, a significant population of pre-and peri-menopausal women who are unlikely to benefit from Tamoxifen are being treated with it anyway. This has grave consequences since the breast cancers of these women will more frequently recur and most likely lead to increased morbidity. Younger women with ER positive breast cancer have lower 5-year survival rates than older women. Our second objective is to obtain additional pre-clinical data to expand our understanding of molecular mechanisms by which Cyclin D1 is linked to a poor response to Tamoxifen. We have obtained data indicating that Cyclin D1 is part of a genetic network involving other proteins such as erbB2 and STAT3. Drugs targeting these proteins are currently either already used clinically or being developed. Therefore, our third objective is to test novel and realistic combination therapies targeting the Cyclin D1 network.