About 70 % of breast cancers (BCs) are estrogen receptor (ER) positive. In post-menopausal women estrogens, synthesized primarily by human aromatase (HA) enzyme, exert a pro-oncogenic effect by binding and activating ERalfa. Endocrine therapies against BC rely on modulation of ERalfa via selective estrogen receptor modulators (SERMs) and down-regulators (SERD), or on estrogen deprivation via HA inhibitors. Despite their beneficial effects, all drugs in clinical use have severe side-effects and resistance issues, some appearing after few years of treatment under the evolutionary pressure of the therapies.
In this project we have characterized the mechanism of the HA enzyme and the impact of mutations conferring resistance to SERM. We are currently developing and characterizing small molecules allosteric modulators of HA and dual-acting compounds targeting HA and ERalfa. The project has been financed by a MyFirst AIRC grant. The project is in collaboration with Dr. N. Zaffaroni, IRCSS Istituto dei Tumori, Milan, Italy, and Prof. S. Gobbi, University of Bologna, and Prof A. Casini, TUM, Muenich, Germany.
Key publications
Caciolla, J. et al. Balanced dual acting compounds targeting aromatase and estrogen receptor α as an emerging therapeutic opportunity to counteract estrogen responsive breast cancer. Eur. J. Med. Chem. 224, (2021).
Pavlin, M. et al. A Computational Assay of Estrogen Receptor α Antagonists Reveals the Key Common Structural Traits of Drugs Effectively Fighting Refractory Breast Cancers. Sci. Rep. 8, (2018).
Magistrato Lab 