Julian Downward, head of the Oncogene Biology Laboratory, has made it his mission to understand how mutations in key genes make cells multiply out of control, leading to cancer. His lab focuses on a major cancer-driving gene called RAS, which is mutated in around one in five cancers and was once referred to as ‘undruggable’. Mutated versions of the gene lock the RAS protein in an activated state, telling the cancer cell to keep growing bigger and keep dividing.  

His lab have now teamed up with partners in industry to publish new findings in Science, laying the foundations for a new clinical trial in people with RAS-mutated cancers. 

“For the last thirty years, we’ve been working on how to stop the mutated RAS protein from interacting with its targets, which are usually enzymes in growth pathways,” says Julian. “We turned our attention to a specific enzyme called PI3K, hoping there was a way to target it to stop uncontrolled cancer growth while maintaining its function in healthy cells.” 

Biology and chemistry unite to find better treatment options 

Diagram showing the interaction of a type of RAS protein (light blue surface in the background) with the active site of PIK3 (cyan molecule). One of the compounds developed in the research, VVD-442, is represented as the grey stick structure in between RAS and PIK3. 

A PI3K inhibitor, alpelisib, is already on the market for breast cancer. But because PI3K also interacts with insulin to control sugar levels, people given the drug often experience hyperglycaemia, which reduces their ability to take the medicine for long periods.   

To overcome this, San Diego-based biotechnology company Vividion Therapeutics used chemical screening to find a series of small compounds that might stop the RAS-PI3K interaction without blocking PI3K’s other functions.  

“Vividion reached out to us five years ago, as they had developed technology that could identify compounds that irreversibly stick to the surface of PI3K near the RAS binding site,” explains Julian. “If the compounds stopped PI3K and RAS binding, but still allowed PI3K to interact with other molecules, the team at Vividion thought that this might avoid the hyperglycaemia that people with breast cancer were experiencing.”  He continues, “We agreed to work together to test what such compounds might do to RAS mutant cancer cells and in mice with cancers carrying RAS mutations.” 

Julian’s team tested the compounds developed by Vividion in mice with RAS-mutated lung tumours, finding that thetreatment effectively halted tumour growth. Importantly, they also checked for and observed no evidence of hyperglycaemia, even at high treatment doses. 

They then tested the new drug candidate in combination with other drugs that also target enzymes in the RAS growth pathways. This combination resulted in stronger and longer-lasting tumour suppression compared to the individual treatments alone.  

Finally, the team also tested the drug candidate in mice with tumours containing mutations in another cancer-driving gene, HER2. This gene is often overexpressed in breast cancer, and the HER2 protein also interacts with PI3K. The researchers observed similar suppression of tumour growth, and surprisingly, this effect was independent of RAS, suggesting that the drug candidate may work to block the growth of even more types of tumours. 

Treatment potential

The drug has now entered the first clinical trial in humans to test for safety and side effects in people with both RAS and HER2 mutations. The trial will also assess if the potential treatment is more effective in combination with other drugs targeting RAS.    

The launch of the clinical trial marks a step forward for Julian. “We’ve been studying these pathways for thirty years but, until recently, the complexities of RAS meant getting somewhere that might benefit patients always felt just out of reach,” he says.  “It’s very exciting to see this work all the way through from the first scientific experiments to a clinical trial. I’m also hopeful that we can learn more about the underlying biology of how cancer cells hijack growth pathways through observing how these drugs work in people.” 

Matt Patricelli, Chief Scientific Officer of Vividion, share Julian’s hopeful outlook on the clinical trials, adding,

“This discovery is a great example of how new discovery approaches can open up completely novel ways to tackle cancer.”  He continues, “By designing molecules that stop RAS and PI3K from connecting, while still allowing healthy cell processes to continue, we’ve found a way to selectively block a key cancer growth signal. It’s incredibly rewarding to see this science now progressing in the clinic, where it has the potential to make a real difference for patients.”