Advanced cancer treatment stops tumor growth without harming healthy cells

The potential treatment is now moving into the first human clinical trial. If proven safe and effective, it could become a way to treat a wide range of cancers while minimizing damage to healthy cells.

The RAS gene plays a central role in controlling how cells grow and divide, but mutations in this gene occur in approximately one in five types of cancer. When mutated, RAS becomes permanently active, constantly sending signals that prompt cells to continue growing and multiplying.

Inside the cell, RAS sits on the membrane and acts as the starting signal in a series of developmental processes. Completely shutting down RAS or the enzymes that control it has proven difficult, because these same pathways are essential for normal cell function. An enzyme associated with RAS, called PI3K, also helps regulate blood sugar through insulin. Completely blocking PI3K can cause side effects such as high blood sugar.

In their study, published October 9 in sciencesThe team combined chemical screening with biological tests to identify compounds that prevent RAS and PI3K from interacting, while leaving normal cell activity intact.

Researchers at Vividion Therapeutics have identified a group of small molecules that permanently attach to the surface of PI3K near where RAS normally binds. Using an assay created by the Crick researchers, they confirmed that these compounds successfully blocked the RAS-PI3K interaction, but allowed PI3K to perform its other roles, including those related to insulin signaling.

Crick’s team and their collaborators at Vividion then tested one of the compounds in mice with RAS-mutated lung tumors. The treatment stopped the tumor’s growth, and researchers found no signs of high blood sugar levels.

Next, they tried combining the new compound with one or two additional drugs that target enzymes in the same pathway. Together, the treatments produced stronger and longer-lasting tumor suppression than either drug used alone.

The scientists also tested the compound in mice with tumors carrying mutations in another cancer-related gene, HER2, which is often overactive in breast cancer and is also linked to PI3K. The tumor stopped growing again, although the effect was not dependent on RAS. This finding suggests that the new compound could help stop the growth of a wide range of cancers.

The drug has now entered its first human clinical trial to test safety and side effects in people with RAS and HER2 mutations. The trial will also evaluate whether the potential treatment is more effective with other drugs that target RAS.

“Given that the RAS gene is mutated across a wide range of cancers, we have been exploring how to turn off its interaction with cell growth pathways for many years, but side effects have hampered the development of treatments,” said Julian Downward, lead group leader of the Tumor Genomics Biology Laboratory at Crick.

“Our collaborative efforts have overcome this challenge by specifically targeting the interaction of PI3K and RAS, leaving PI3K free to bind to its other targets. It is exciting to see these clinical trials begin, highlighting the power of understanding basic chemistry and biology to arrive at something that has the potential to help people with cancer.”

“This discovery is a great example of how new discovery methods can open up completely new ways to treat cancer,” said Matt Patricelli, Ph.D., chief scientific officer of Vividion. “By designing molecules that prevent RAS and PI3K from communicating, while allowing healthy cell processes to continue, we have found a way to selectively block a key cancer growth signal. It is extremely rewarding to see this science now progressing into the clinic, where it has the potential to make a real difference for patients.”