Every year, tens of thousands of cancer patients carry tumours driven by fused genes created when chromosomes snap and rejoin incorrectly—but no drug exists to directly disable those hybrid proteins. Current cancer therapies mostly target enzymes, which are relatively easy to block with small molecules. Chromosomal translocation proteins are different: they sit inside cells, lack enzyme activity, and have no obvious pocket for a conventional drug to grab. This leaves a major gap in treatment options for cancers defined by these specific genetic markers, such as certain leukaemias and sarcomas. The researchers aim to fill that gap by developing two things at once: bespoke reagents that can bind to and neutralise these fusion proteins, and in vivo mouse models that accurately recreate human chromosomal translocations so the new reagents can be tested before reaching patients. If successful, this work could produce a new class of cancer therapeutics—one that targets tumour-specific proteins without harming healthy cells. The in vivo models would also allow researchers to study how these translocations drive cancer in the first place, potentially revealing additional vulnerabilities. The long-term goal is to combine these reagents with existing treatments and test them in patients.
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Cancer affects around a third of all adults during their life and as life expectancy increases, cancer incidence will increase in the following decades. The occurrence of mutations in cancer is indicative of specific changes that drive tumour development and which can be targets for new therapies that would not have the side effects as conventional treatments. One the most obvious changes seen in cancer cells is chromosomal translocation, which result from joining between two different chromosomes during cell division. These translocations usually have an effect on a gene or even fuse two genes together giving tumour-specific markers and new therapeutic targets. The problem is that these molecules are inside the cell and are not usually enzymes which can relatively easily be inactivated by drugs that are able to enter the cancer cells. We need new types of drugs to inactivate the chromosomal translocation-proteins and new ways of modelling chromosomal translocations to test out the novel drugs in an in vivo preclinical setting. The aim of the work proposed in the application is to develop new methods in both areas. We will develop ways to rapidly produce bespoke reagents that can interfere with chromosomal translocation-proteins to block cancer growth or, in some settings, to kill tumour cells whilst sparing normal counterparts. We will also develop methods to create in vivo models of human chromosomal translocations that can be used to assess the biological basis of cancer and as a setting for developing new therapeutic strategies. The aim is to evaluate the possible use of novel reagents for cancer patients in these models, either as single therapeutic entities or in combination with existing treatment modalities. Our long term aim is to treat patients with regimes shown to be effective in vivo.
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