Associate Professor Elgene Lim, Dr Heloisa Milioli, Dr Neil Portman
14 August 2020
In a proof-of-principle study, researchers at the Garvan Institute of Medical Research revealed a potential therapeutic approach for targeting oestrogen receptor positive (ER+) breast cancers resistant to current therapies.
By combining current gold-standard treatments with a drug that restores the activity of p53, a cancer suppressor protein, the researchers found they could sensitise breast cancer cells to therapy and slow cancer growth in laboratory models of ER+ breast cancer.
The findings are a promising step towards better treatments of breast cancer, which affects almost 20,000 individuals each year in Australia alone.
“This study has shown us a promising new path for advanced breast cancer, which we think may be applicable to as many as four in five patients with advanced ER+ breast cancers. We hope this new approach will help us stay one step ahead of breast cancer drug resistance,” says Dr Neil Portman, from Garvan’s Connie Johnson Breast Cancer Research Lab and co-first author of the study published in Breast Cancer Research.
Improving on standard therapy
While major advances have been made in the treatment of breast cancer, the development of treatment resistance remains a significant health issue.
To tackle resistance, a combination therapy of hormone therapy and CDK4/6 inhibitors became the new standard care for advanced disease in the clinic five years ago.
“However, advanced breast cancers will inevitably develop resistance even to this two-pronged approach,” says co-first author Dr Heloisa Milioli, from the Cancer Cell Plasticity Lab at Garvan.
“We’re anticipating the scenario that advanced breast cancer patients will eventually stop responding to CDK4/6 inhibitors and endocrine therapy. The main challenge now is to try and find an alternative for those patients that don’t respond,” she says.
In looking for new therapeutic targets, the team focused on MDM2, a regulatory protein that controls the tumour suppressor protein p53. Referred to as the ‘gatekeeper of the genome’, p53 helps protect DNA from the damage that leads to cancer. As all tumours have to inactivate p53 to grow and spread, the researchers investigated whether blocking MDM2, and thereby reactivating p53, could effectively target breast cancer.
Stopping the spread
Using an MDM2 inhibitor that is currently in clinical trials for the treatment of leukemia, the team assessed whether this approach could stop the growth of tumours in experimental models, when used in combination with currently used hormone therapies or CDK4/6 inhibitors.
The researchers discovered that the MDM2 inhibitor together with either hormone therapy or CDK4/6 inhibitors was able to significantly reduce the spread of cancer cells, in tissue culture and in mice.
Further, the researchers tested the treatment combinations in a breast cancer cell line that had already become resistant to hormone therapy or CDK4/6 inhibitors. The experiments showed that they could sensitise the resistant cancer cells by blocking MDM2.
Potential for patients
“This preclinical evidence gives us the promising indication that the new approach could be effective in patients with advanced breast cancers, and cancers resistant to current therapies” says senior author A/Prof Elgene Lim, who heads the Connie Johnson Breast Cancer Research Lab at the Garvan Institute.
The researchers are now developing clinical trials at the St Vincent Hospital to test the new approach in patients with advanced breast cancer.
“This study is another demonstration of how research underpins new cancer therapies. Our hope is to translate these findings into clinical trials, and ultimately make an impact on patient outcomes.”
This research was supported by Love Your Sister, the National Breast Cancer Foundation, The R T Hall Trust, the Cancer Institute of New South Wales, Breast Cancer Trials and Novartis A