Some cancer cells survive radiotherapy and immunotherapy by switching off their built-in suicide programme, apoptosis—and a new class of drug aims to kill those cells by triggering a different death pathway instead. This matters because when tumours become resistant to apoptosis, patients run out of treatment options. The researchers have identified a protein, RIPK1, that cancer cells use to block an alternative death process called necroptosis. Existing drugs that merely switch off RIPK1’s function fail because the protein still physically scaffolds other molecules to prevent cell death. The team has therefore designed “degraders”—molecules that force the cell’s own waste-disposal system, the proteasome, to destroy RIPK1 entirely. One prototype, R1-ICR-5, injected directly into breast tumours in mice, improved the effectiveness of radiotherapy. If this succeeds, the approach could turn treatment-resistant cancers into ones that respond to standard therapies. The researchers aim to develop a systemic drug—one that can be given by injection or pill, not just into a tumour—and test it in mouse models of breast, melanoma, and head-and-neck cancers. Ultimately, they hope to partner with a pharmaceutical company to move a clinical candidate into human trials, potentially giving NHS patients a new combination treatment with radiotherapy and immune checkpoint blockers.
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Context: Patients with various kinds of cancer receive treatment involving radiotherapy and immunotherapy drugs called immune checkpoint blockers (ICB). Some patients can be cured with these treatments; sadly, for many patients these treatments do not work or their cancer may initially respond but then return. At this point their cancer is said to be resistant. One of the reasons for this resistance is that cancer cells turn off one of the ways in which cells die, a process called apoptosis. When this happens, there are limited treatment options for these patients. Therefore, novel medical solutions are needed to overcome apoptosis-resistance. Approach: We believe that by triggering an alternative way for cells to die called necroptosis, we can overcome the resistance to apoptosis. Necroptosis is a different way for cells to die, it is how the body gets rid of cells infected by pathogens such as viruses. So, if we develop treatments that promote necroptosis, this could both kill tumour cells that are resistant to apoptosis and stimulate the patient's immune system to mount a strong response against cancer cells, as if they were infected by a pathogen. This would make radiotherapy and ICB treatment more effective. Aims: The goal of the project is to discover and develop prototype drugs which cause depletion of a protein called RIPK1. Our work shows that this will induce cell death by necroptosis. RIPK1 blocks necroptosis and so is used by cancer cells to evade cell death and allow them to hide from the immune system during radiotherapy and ICB treatment. RIPK1 blocks necroptosis by scaffolding - forming physical contacts with other proteins. Drugs that just switch off the function of RIPK1 are known, but these do not prevent this scaffolding and therefore do not work. We therefore needed to find a way to deplete RIPK1 in cells, which will induce a strong immune response like that of a viral infection in combination with radiotherapy or ICB. Degraders are drug molecules that induce destruction of a protein by the cell's own "waste-disposal system", the proteasome. We have discovered degraders that cause RIPK1 depletion in human and mouse cancer cells. Injecting our prototype molecule R1-ICR-5 directly into the tumour in a mouse model of breast cancer improved the effectiveness of radiotherapy. This is an exciting breakthrough, and our goal is to improve this molecule to discover a drug that can be tested in patients. In this project, we will design, make, and test new improved RIPK1 degraders that can be dosed systemically rather than injecting directly into tumour. We will test our improved degraders in proof-of-concept studies in mouse models of different cancer types including breast, melanoma and head and neck cancer, in combination with radiotherapy as well as ICB. These experiments will provide further confidence that this is a viable approach for effective cancer treatment. Potential applications: By designing new prototype drugs and showing they are effective in mice, we will be in an excellent position to partner the project with a pharmaceutical company, so that we can continue developing this into a drug that can be tested in patients (clinical candidate).?Our aim is to progress our RIPK1 degrader into clinical trials and ultimately see it used as a combination treatment with radiation and ICB for cancer patients on the NHS and internationally.
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