Preventing breast cancer recurrence by targeting the cells that resist chemotherapy

Professor Steven Stacker is a Cancer Biologist and Group Leader at the Peter MacCallum Cancer Centre.

The challenge:

Breast cancer remains the most commonly diagnosed cancer in women and a leading cause of cancer-related deaths. One of the biggest challenges in cancer treatment is the development of resistance to chemotherapy. This occurs when some cancer cells adapt and evolve to survive chemotherapy, which may later cause the cancer to return.

In some tumours, a small group of ‘stem-like’ cancer cells are thought to exist from the beginning of tumour development. These stem-like cells may be particularly resistant to chemotherapy and could be capable of regenerating the tumour, contributing to treatment resistance and recurrence. Current treatments try to eliminate all cancer cells, but do not focus on this potentially important group of stem-like cancer cells.

Project description:

Professor Steven Stacker’s Pink Sky Grant project, funded by the National Breast Cancer Foundation (NBCF), aims to better understand how breast cancer cells adapt to survive chemotherapy over time, and how to disrupt this process to prevent recurrence. He and his team, including leading postdoctoral scientist Dr Aadya Nagpal, propose that a small population of ‘stem-like’ cells exist within tumours from the outset, uniquely capable of regenerating all other cancer cells, withstanding chemotherapy and driving recurrence. They have created a preclinical model that closely mirrors how resistance develops in Triple Negative Breast Cancer (TNBC), one of the most aggressive and difficult-to-treat forms of the disease. Using this model, their early findings show that resistant stem-like cells produce high levels of a protein called RYK, which is involved in cell growth and renewal. They have also developed entirely new cellular and molecular tools that can target RYK and slow the growth of chemotherapy-resistant cancer cells.

The research team will build on these early discoveries by using advanced molecular ‘tags’ to track these stem-like cells as they adapt and survive during chemotherapy, offering unique visibility of the dynamic changes that occur during treatment resistance. Additionally, this project will determine whether RYK-targeting therapies can effectively prevent chemotherapy resistance by specifically targeting this potentially lethal stem-like subset of cells. These strategies could enable the identification of new weaknesses in ‘stem-like’ cancer cells that could be targeted to precisely disrupt chemotherapy resistance.

Potential impact:

If successful, Professor Stacker’s Pink Sky Grant project could support the development of new therapeutic strategies and treatment combinations for aggressive breast cancers, delivered at the right time to prevent resistance and recurrence. He and his team would also produce the critical data needed to support the advancement of these new RYK-targeting therapies towards early-phase clinical trials.

This project could create a fundamental shift in breast cancer care from a reactive to a proactive management of treatment resistance, leading to reduced deaths, prolonged survival, and reduced recurrence rates for people diagnosed with TNBC and other aggressive breast cancers.

Grant code: 2025/PS0078
Active years: 2026-2029
Scientific project title: Sending Breast Cancer Down an Evolutionary Dead End: Exploiting Cancer Cells Hostile Upbringing