The potential treatment for a wide range of cancers is now progressing into its first human clinical trial. If proven safe and effective, this innovative approach could revolutionize cancer therapy by targeting cancer cells while minimizing harm to healthy cells.
The RAS gene plays a crucial role in regulating how cells grow and divide. However, mutations in this gene are found in approximately one in five cancers, leading to an abnormal activation of RAS. When mutated, RAS becomes permanently active, sending continuous signals that stimulate cell growth and multiplication. This unregulated growth contributes to the development and progression of various cancers.
Within the cell, RAS is located on the membrane and initiates a series of growth processes. However, completely inhibiting RAS or the enzymes it regulates has proven challenging. This difficulty arises because these pathways are vital for normal cellular functions. One such enzyme linked to RAS is PI3K, which is also essential for regulating blood sugar levels through insulin. Blocking PI3K entirely can result in significant side effects, including hyperglycemia.
In a groundbreaking study published on October 9 in Science, researchers combined chemical screening with biological testing to identify compounds that effectively disrupt the interaction between RAS and PI3K while preserving normal cellular activities. The team at Vividion Therapeutics identified a series of small molecules that permanently bind to the surface of PI3K at the site where RAS typically attaches.
Using a specialized assay developed by the researchers at the Crick Institute, the team confirmed that these compounds successfully blocked the interaction between RAS and PI3K, all while allowing PI3K to continue its essential functions, including those involved in insulin signaling.
The collaborative team then tested one of these compounds in mice with RAS-mutated lung tumors. The results were promising: the treatment inhibited tumor growth without causing elevated blood sugar levels. Furthermore, the researchers explored combining this new compound with one or two additional drugs targeting enzymes within the same growth pathway. This combination therapy resulted in stronger and more prolonged tumor suppression compared to any individual drug.
Additionally, the scientists tested the compound on mice with tumors that had mutations in the HER2 gene, which is commonly overactive in breast cancer and also interacts with PI3K. Remarkably, tumor growth was halted even though the effect was independent of RAS, suggesting that this new compound might have the potential to combat a broader spectrum of cancers.
The promising drug has now entered its first human clinical trial, aimed at assessing safety and side effects in patients with both RAS and HER2 mutations. The trial will also evaluate whether this potential treatment is more effective when used in conjunction with other drugs targeting RAS.
Julian Downward, Principal Group Leader of the Oncogene Biology Laboratory at the Crick, stated, “Given the RAS gene is mutated across a wide range of cancers, we've been exploring how to stop it from interacting with cell growth pathways for many years. However, side effects have hindered the development of effective treatments. Our collaborative effort has overcome this challenge by specifically targeting the PI3K and RAS interaction, allowing PI3K to remain functional with its other targets.”
Matt Patricelli, Ph.D., Chief Scientific Officer of Vividion, expressed excitement about the clinical trials, emphasizing the importance of understanding chemistry and biology in creating potential cancer therapies. “By designing molecules that prevent RAS and PI3K from connecting while keeping healthy cell processes intact, we’ve discovered a way to selectively block a key cancer growth signal. It’s incredibly rewarding to see this scientific advancement progressing in the clinic, where it could significantly benefit patients,” he added.
