Targeted Cancer Therapy Shows Promise by Disrupting RAS-PI3K Interaction
Researchers have developed a novel approach to cancer treatment focusing on selectively disrupting the interaction between the RAS and PI3K signaling pathways, potentially offering a more effective and less harmful choice to conventional methods. This strategy aims to halt cancer growth without interfering with the normal functioning of the body.
The RAS gene is frequently mutated in various cancers, driving uncontrolled cell growth.The PI3K enzyme plays a crucial role in this process, collaborating with insulin to regulate blood sugar and contributing to tumor progress when dysregulated. Completely blocking PI3K can lead to hyperglycemia, a significant side effect.
To overcome this challenge, a team from Vividion Therapeutics, in collaboration with the Francis Crick Institute, employed a combined chemical and biological approach. They identified small molecules that specifically bind to a region on the PI3K enzyme’s surface, preventing it’s interaction with RAS while preserving its ability to interact with other essential molecules, including those involved in insulin signaling.
Testing in mice with lung tumors driven by RAS mutations demonstrated that this treatment effectively stopped tumor growth without causing hyperglycemia. Moreover, combining the compound with other drugs targeting the same signaling pathway resulted in enhanced and prolonged tumor suppression.
Remarkably, similar positive results were observed in mice with tumors harboring HER2 gene mutations, commonly found in breast cancer. This suggests the potential for the new compound to be effective against a broader range of cancers beyond those solely driven by RAS mutations.
“For decades we have been trying to block RAS signaling without affecting normal cellular functions. now, through a precise chemical approach, we have succeeded in selectively disrupting the interaction with PI3K, a strategy that could transform the treatment of many types of cancer,” stated Julian Downward, coordinator of the Oncogenic Biology Laboratory at the Francis Crick Institute.
The investigational oral inhibitor, designated VVD-159642, has now entered Phase I clinical trials to assess its safety and side effects in patients with RAS and HER2 gene mutations. The trial (NCT06804824) will also evaluate the drug’s effectiveness when used in combination with existing targeted therapies like sotorasib and trametinib. The study will analyze safety, tolerability, how the drug is processed by the body (pharmacokinetics), its effects on the body (pharmacodynamics), and preliminary signs of tumor reduction.
Matt Patricelli, chief scientific officer at Vividion Therapeutics, a Bayer AG company, emphasized the meaning of the approach: “We have found a way to turn off the cancer growth signal while allowing healthy cells to function normally. This is an important step toward safer and more effective therapies.”
Vividion is also concurrently conducting Phase I trials for an oral KEAP1 gene activator and an oral STAT3 protein inhibitor, both targeting solid and hematologic cancers.
Reference:
1].Ian A. Prior et al “The Frequency of RAS Mutations in Cancer”.Cancer Res (2020) 80 (14): 2969-2974. ([https://aacrjournalsorg/cancerres/article/80/14/2969/640657[https://aacrjournalsorg/cancerres/article/80/14/2969/640657[https://aacrjournalsorg/cancerres/article/80/14/2969/640657[https://aacrjournalsorg/cancerres/article/80/14/2969/640657)
