Preventing Metastatic Disease by Targeting Cells that Survive Chemotherapy

Researchers: Prof Ingunn Holen and Dr Lewis Quayle

Location: University of Sheffield

Dates:  Mar 2020 – Oct 2021     Status: In progress

Funding: £44,493

Research Theme: Therapies, Prevention

Aims

Dr Quayle and Professor Holen have been awarded further funding for a project that will study dormant breast cancer cells using advanced genetic methods. They hope to identify new strategies for the removal of dormant cancer cells, thereby preventing breast cancer from returning and improving the outcome for patients.

“This project will be the culmination of a 5-year body of work that has aimed to develop novel models to study tumour cell dormancy and drug resistance. It is my hope that the results from this project will generate a number of promising candidates that could form the basis for the first generation of truly curative treatments for metastatic breast cancer”.

Dr Lewis Quayle

Background

One characteristic of cancer cells is their uncontrolled rate of cell growth and division. Current chemotherapy treatment works by targeting actively growing/dividing cells and killing them. However, around 2 out of every 10 patients find that their breast cancer spreads (metastasises) and returns several years after they underwent treatment.

This is because some cancer cells escape from the primary breast tumour and settle in other parts of the body, usually the bone marrow, where they can survive for many years by becoming dormant (non-dividing) and remain undetected. In this dormant state, cancer cells are no longer sensitive to the chemotherapy that is designed to eliminate actively growing/dividing cancer cells.

At some point, these dormant cells can be triggered to start growing again and form new tumours, as well as spread further to other parts of the body such as the lungs, liver and brain.

We don’t yet understand the mechanisms that cancer cells rely on to enter this dormant state. Building on previously developed models from their initial project Professor Holen and Dr Quayle aim to understand this process in more detail by specifically isolating the dormant breast cancer cells that survive treatment. Using advanced genetic study methods along with computer-based analysis they will characterise the genetic machinery of the surviving cancer cells (dormant cells) and compare this to cells that are sensitive to chemotherapy (growing and dividing cells).

This will hopefully identify molecules that cancer cells “switch on or off” to become dormant and survive chemotherapy. The presence of any of these molecules in human breast tumours can then be checked using information readily available in clinical databases. This will ensure that the most promising molecular candidates can be identified for further study.

Potential benefit for patients

There are currently no specific treatments that can prevent breast cancer spread. The results from this project could establish whether altering particular molecules found on breast cancer cells can reduce their capacity to become dormant, thereby sensitising them to chemotherapy.

Ultimately this work will allow the development of new treatments to prevent breast cancer recurrence, thereby benefiting a large number of patients.

Project Results and Impact

• Development of a unique set of transcriptomic profiling data from quiescent cancer cells isolated from the four main sub-types of breast cancer that enable discovery of quiescence (dormancy) and chemoresistance-associated genes
• Identification of signalling networks and pathways associated with breast cancer dormancy and key signalling molecules within these that could be used in future as therapeutic targets to control / kill dormant cells
• Development of a novel signature of 22 quiescence-associated genes that reliably predicts slow tumour growth and dormant disease in clinical data sets
• On-going analyses that will:
  • Identify genes and pathways specifically associated with quiescence and chemoresistance in oestrogen-receptor negative (ER-) breast cancer
  • Determine whether pathways relating to DNA damage and repair can be used as a means of targeting dormant cancer cells
  • Establish whether our breast cancer quiescence-associated genes are more strongly associated with specific sites of metastasis
  • Indicate whether our quiescence-associated genes are relevant to other cancers that undergo metastatic dormancy

Q&A, discussing preventing metastatic disease by targeting breast cancer cells that survive chemotherapy.

As part of our regular Research Q&A series, Dr Quayle took the time to answer questions about his research which were posed by supporters of Against Breast Cancer.

You can find out more about the vital research being undertaken by Professor Holen and her team at the University of Sheffield’s Department of Oncology & Metabolism here.

Publications

Transcriptomic Profiling Reveals Novel Candidate Genes and Signalling Programs in Breast Cancer Quiescence and Dormancy. Lewis A. Quayle, Amy Spicer, Penelope D. Ottewell and Ingunn Holen. Cancers 2021, 13(16), 3922.