Centre for Cancer Drug Discovery

Image: Triple negative breast cancer cells. Credit: Melina Beykou

Killing breast cancer cells in a way that trains the immune system to recognise and destroy residual cancer cells could offer longer lasting protection to people with the disease.

The early-stage discovery published in the journal Immunity, shows that by causing cancer cells to undergo a process called immunogenic cell death, the immune system is switched on and becomes alert to the disease in the body.

RIPK1

In order to bring about this type of cell death, scientists at The Institute of Cancer Research, London, targeted a protein called RIPK1, which plays a vital role in helping cancer cells survive and remain undetected in the body.

The team, based in the Breast Cancer Now Toby Robins Research Centre at The Institute of Cancer Research (ICR) collaborated with scientists at the ICR’s Centre for Cancer Drug Discovery and Centre for Protein Degradation. Funded by Breast Cancer Now and Cancer Research UK, they used a new and innovative technology called proteolysis targeting chimera (PROTAC) to successfully destroy RIPK1 in cancer cells.

Targeted protein degradation

Through a process known as targeted protein degradation, PROTAC eliminates specific unwanted proteins within cells that have previously been ‘undruggable’. While traditional inhibitor drugs merely block the function of the protein, this process destroys the problem protein entirely.

Getting rid of RIPK1 triggers immunogenic cell death and mobilises the immune system to destroy any remaining cancer cells that have evaded treatment or become resistant to drugs.

Longer lasting protection

Researchers demonstrated that targeting RIPK1 enhances immune system activation after radiotherapy and immunotherapy treatment in mice, boosting overall response to treatment and potentially offering longer lasting protection against the disease as the body learns to recognise and kill cancer cells.

These early findings suggest that this approach could be effective for a range of different cancers including triple negative breast cancer, which can be harder to treat and is also more likely than most other breast cancers to return or spread within five years following diagnosis.

Professor Pascal Meier, Professor of Cell Death and Immunity at The Institute of Cancer Research, London, said:

"While all therapies aim to kill cancer cells, doing so in a way that activates the immune system as well to detect and kill any remaining cancer cells could make treatment more effective and potentially offer individuals a longer lasting immune response against breast cancer.

“We know that RIPK1 plays a crucial role in helping cancer cells stay alive and avoid being detected by the immune system. By using this targeted protein degradation technology, known as a PROTAC, we have been able to use the cell’s own recycling system to specifically degrade and destroy the RIPK1 cancer protein.

"Our exciting findings suggest that targeting RIPK1 could improve the effectiveness of existing cancer treatments and protect people from recurrences of breast cancer, by training the immune system to recognise and destroy cancer cells.”

Professor Swen Hoelder, Professor of Medicinal Chemistry and Drug Design and Head of Chemistry within the Centre for Cancer Drug Discovery at The Institute of Cancer Research, London, said:

“We made this discovery through a fantastic collaboration between different scientists across the ICR. Drug discovery scientists within the ICR’s Division of Cancer Therapeutics worked with cancer biologists to see a concept through from fundamental discovery science to an active drug discovery project, resulting in the development of a PROTAC degrader which could keep people’s cancer at bay for longer.

“This study further demonstrates how targeted protein degradation can be used to attack cancer. The ICR has been pioneering this innovative technology for some time – and we continue to do so through our dedicated Centre for Protein Degradation. 

Dr Simon Vincent, Director of Research, Support and Influencing at Breast Cancer Now, which funded the research, said:

“There are many hallmarks of cancer, including the ability of cancer cells to evade detection by the immune system and resist being killed by common treatments such as chemotherapy.

"However, these exciting findings could pave the way for new, targeted breast cancer treatments which also have the potential to offer a longer lasting immune response against the disease.

"With one person dying from breast cancer every 45 minutes in the UK, research breakthroughs like these are urgently needed."

Paula’s story

Paula Glover, 45, from Surrey, was breastfeeding her 4-month-old baby in May 2012 when she found a lump. After having an ultrasound and a biopsy, Paula was given the devastating news on her son’s 6-month birthday that she had triple negative breast cancer.

In the following months, Paula had surgery to remove 3 lymph nodes, 6 cycles of chemotherapy and a double mastectomy with reconstruction with lymph node clearance.

Paula eventually finished treatment and started to rebuild her life. She had an extended maternity leave to help with her recovery and went back to her job as an occupational psychologist in April 2013.

Nearly ten years later, Paula found another lump and was diagnosed with breast cancer for the second time in December 2021.

'The anxiety about breast cancer coming back never goes away.'

Paula said: “After recovering from breast cancer, there is always a fear of recurrence. But after reaching nearly 10 years cancer free, I really thought I might be in the clear.”

Paula’s treatment started the following January with more surgery, chemotherapy, and radiotherapy.  She completed her treatment in September 2022.

Having experienced a local breast cancer recurrence, Paula is passionate about supporting any research that could offer long-term protection against the disease.

Paula added: “The anxiety about breast cancer coming back never goes away. Every ache and pain or rash is a worry. Knowing that there are new treatments being developed that could keep the cancer at bay for longer, gives me hope that there might be more options and less anxiety for people like me in the future.”