Innovative epigenetic therapy for optimising triple negative breast cancer outcomes

Project Description:

Chemotherapy is one of the standard-of-care therapies for triple negative breast cancer (TNBC) patients, however not all patients respond to treatment. Cancer cells are known to undergo chemical modifications to their DNA known as DNA methylation, which can disrupt the function of specific genes leading to the growth and survival of cancer cells. In this NBCF-funded research A/Prof Clare Stirzaker and her team will test a DNA demethylation agent decitabine in chemo-resistant TNBC tumours derived from patients. Decitabine, an epigenetic therapeutic agent, aims to reverse DNA methylation alterations associated with chemo-resistance and enhance the responsiveness of chemotherapy in TNBC.

Why is this work needed:

Triple-negative breast cancer (TNBC) is associated with a higher risk of disease recurrence and shorter overall survival compared to other breast cancer subtypes. Since TNBC lacks hormone receptors for targetable treatment, TNBC patients rely heavily on conventional combination chemotherapy. While 60% of TNBC patients respond to neoadjuvant chemotherapy, a standard-of care treatment given prior to surgery, leading to improved survival rates, the remaining 40% who do not fully or partially respond have a higher likelihood of advancing to metastatic disease. Therefore, there is a compelling need to develop novel therapeutic strategies to improve the survival outcomes of TNBC patients.

Expected outcomes:

The successful outcomes of this study aim to provide the first pre-clinical evidence that agents able to induce DNA demethylation, also known as epigenetic therapy, can reduce resistance to chemotherapy and suppress tumour growth in TNBC models.

Project description:

Triple negative breast cancer (TNBC) is an aggressive form of cancer with the lowest survival outcomes relative to other breast cancer subtypes and has a higher prevalence among younger women. Neoadjuvant chemotherapy, therapy prior to surgery, is the standard-of-care for TNBC patients, and while many women benefit from this treatment, the response is variable and treatment resistance is common.

Cancer cells are known to have unique chemical modifications in the DNA known as DNA methylation, which can disrupt the function of specific genes leading to the growth and survival of cancer cells.

Prior research led by A/Prof Clare Stirzaker and her team at the Garvan Institute of Medical Research showed that unique DNA methylation changes in cancer cells are associated with resistance to neoadjuvant chemotherapy in TNBC. This provides an opportunity to target chemo resistant TNBC with DNA demethylation agents, treatment known as epigenetic therapy.

In this NBCF-funded research A/Prof Clare Stirzaker aims to test a DNA demethylation agent, decitabine, in chemo-resistant patient derived TNBC models.

This innovative approach of combining decitabine with chemotherapy has the potential to significantly enhance outcomes for individuals with aggressive, treatment resistant TNBC. Moreover, using an agent, decitabine, already approved for the treatment of leukaemia, could accelerate its use for the treatment of TNBC patients in the clinic.