Dr Luca Magnani
I received my PhD from Purdue University (US) before moving to the Department of Surgery and Cancer at Imperial in 2013 to take up a Junior Research Fellowship. I lead a team of researchers (funded from Wellcome Trust, Second Hope, Horizon 2020 and Cancer Research UK) focused on the causes of resistance to endocrine therapies and the epigenetic basis of breast cancer.
What is this project about?
Breast cancer is the leading cause of cancer related death for women globally and incidence has been steadily increasing in the last 40 years within the EU. Over 70% of breast cancers are oestrogen receptor alpha (ERα) positive and can be treated with endocrine therapies designed to block ERα signaling. Oestrogen receptor positive patients are treated with endocrine therapies for 5 years after initial surgery. These drugs are designed to block oestrogen receptor activation.
However, over 30% of patients do not respond or develop resistance to therapy. Resistance to endocrine therapies remains a major problem in the treatment of ERα positive breast cancer patients. Management of patients with recurrent and metastatic disease currently represents the major challenge in the clinic. Indeed, there are no biomarkers available to stratify ERα breast cancer patients towards specific adjuvant therapies (post-surgery) or monitor them at relapse. Furthermore, therapeutic options remain limited (chemotherapy). These problems are still unsolved and the mechanisms of invasiveness and tumour growth are still unknown.
Dr Ylenia Perone, supported through a CRUK Imperial Centre PhD Studentship, is conducting a research project to identify predictive and companion biomarkers to stratify ERα patients to the most appropriate form of endocrine therapy (Aromatase Inhibitor vs. Tamoxifen). Furthermore, they will test the feasibility of using novel and clinically available cholesterol inhibitors. Expected deliverables include the development of novel therapeutic strategies and companion biomarkers to stratify ERα patients at diagnosis and possibly extend the survival of metastatic patients.
The overarching aim of the project is to develop new therapeutics to prevent or treat Aromatase Inhibitor-resistant relapses and metastatic progression. Recent studies have linked hypercholesterolemia to increased breast cancer invasion and progression. Interestingly, structural data suggest that cholesterol metabolites including 27-hydroxycholesterol (27HC) can act as ERα ligands in endothelial and breast cancer cells.
How does this project align with the rest of our research?
In line with these findings, I've published exciting new research that links cholesterol and breast cancer. My group demonstrated also that adaptation to endocrine therapies is drug specific and resistance to aromatase inhibitors corresponds to increased metastatic potential. Resistance involved epigenetic reprogramming, meaning that cells adapted to each agent using extra-genetic (mutations etc.) mechanism. For example, cells that develop resistance to aromatase inhibitors strongly increase cholesterol production. Moreover, compounds such as 27HC can promote estrogen independent ERα binding to the chromatin.