Rewiring cancer cells

Inhibition of oncogenic signalling in advanced cancers often results in secondary mutations that restore oncogenic signalling in the presence of drugs, indicating that we must consider fundamentally different approaches to treat cancer.

Insights gained over the past two decades have yielded a detailed knowledge of how cells are wired and how proliferation and survival signals are altered in cancer cells. Moreover, advances in synthetic biology, such as proximity-inducing molecules allows proteins that normally would not interact to come together, providing opportunities to change the wiring inside a cancer cell from a signal that promotes oncogenesis to one that has an opposite effect on cancer cells. Emerging approaches to overstimulate oncogenic signalling beyond a cell’s ‘goldilocks’ level, also provide opportunities to steer cells to less malignant phenotypes, as cancer cells may escape the drug-induced overactivation of oncogenic signalling through suppression of intrinsic oncogenic signalling.

This challenge aims to develop inventive ways to rewire cancer cells to a less malignant phenotype as a novel approach to therapy. 

Addressing this challenge will require methods to determine which cancers or cell types would be susceptible to a particular rewiring approach, and whether further cancer types can be made susceptible using innovative approaches.

Novel ways to target heterogenous tumour cell populations should also be considered, for instance affecting non-responsive cancer cells in a heterogeneous population, by making responding cells more immunogenic, by means of executing an immunogenic form of cell death or by driving cell populations into a more uniform state.

Note that applications should not focus on targeted protein degradation approaches.

An interdisciplinary team will be required, bringing together diverse areas of expertise, which could range from synthetic biology, artificial intelligence, medicinal chemistry and structure-based drug design to expertise in cancer biology, immunology and signalling. 

Cancer cells don’t behave like normal cells. Instead of stopping growth or dying when they should, they divide uncontrollably. This happens because their internal ‘signalling systems’, which normally regulate cell growth and death, become faulty, allowing them to survive, resist treatment, and keep growing. Even when therapies successfully block cancer’s growth signals, cancer cells often adapt, finding new ways to continue growing. This means that traditional treatments, which focus on stopping these signals, may not always be enough. However, new scientific advances suggest a different approach: instead of blocking cancer’s survival signals, can we rewire them, turning cancer’s own survival mechanisms against itself?

This Cancer Grand Challenge aims to develop innovative ways to rewire cancer cells forcing them to self-destruct. Using cutting-edge techniques, researchers could find ways to make cancer cells more vulnerable to treatments. They could also make cancer cells easier for the immune system to recognise and destroy. If successful, this approach could overcome the limitations of current therapies and lead to entirely new ways of treating cancer, offering new hope to patients.