Cinzia Allegrucci - Overcoming secondary breast cancer with combination epigenetic therapy

Lay abstract

Background: Secondary breast cancer is the main reason people die from breast cancer. After treatment, cancer cells can still spread to other parts of the body over many years, especially in patients with estrogen receptor (ER)-positive breast cancer. One of the main problems is that cancer cells can become resistant to treatment over time, leading to the cancer coming back. So, we need new treatments that can stop this resistance and prevent the cancer from returning.
Techniques and methodology: Our project aims to test new drugs, called epigenetic inhibitors, along with other drugs used to treat ER-positive breast cancer (like endocrine therapy and CDK inhibitors) to treat resistant breast cancer and stop it from spreading to other parts of the body.
Impact on breast cancer research: This project could give us new ways to stop secondary breast cancer from happening. Our goal is to find new treatments that can stop the cancer from coming back. If successful, this could lead to better patients’ survival. We hope our work will lead to new clinical trials to test these therapies further so that patients can benefit from more effective treatments in the near future.

Scientific Abstract

Background: Secondary breast cancer represents a leading cause of cancer-related deaths. Metastatic spread can start after the initial treatment and occur over decades in patients with estrogen receptor (ER)-positive breast cancer, thus representing a significant clinical challenge. The development of resistance to long-term therapy is a critical factor for cancer recurrence. Therefore, new therapeutic approaches that can overcome resistance to therapy and minimal residual disease are needed to prevent secondary cancer and improve patient outcome. We have evidence that stable cancer reversion is dependent on re-establishment of the chromatin repressive mark H4K20me3, which ensures stable exist of cell from the cell cycle and inhibition of cell growth. Therefore, this project will test the new hypothesis that this epigenetic landscape is also required for overcoming cancer resistance to therapy and prevent secondary cancer.
Aims: The aim of this project is to investigate a new therapeutic strategy by using inhibitors of the histone demethylase PHF8 in combination with endocrine and CDK inhibitors for the treatment of resistant ER-positive breast cancer and prevention of secondary cancer.
Techniques and methodology: We will use PHF8 inhibitors to overcome cancer resistance. The inhibitors will be tested alone or in combination to endocrine therapy and cell cycle inhibitors using resistant cancer cell lines. The effect on cell proliferation and invasion will then be tested, and gene networks involved in the inhibition of cancer resistance identified. Novel gene targets will be validated using patients’ tumour samples and clinical data to determine their prognostic value.
Impact on breast cancer research: This project will provide new strategies to prevent secondary breast cancer. Our vision is to discover novel therapies for the inhibition of residual disease and cancer recurrence. The impact of this project is to inform new clinical trials based on combination epigenetic therapy for the improvement of patients’ survival.