UCLA Study Reveals Genetic Weakness in Aggressive Cancers, Offering New Treatment Hope
Key Takeaways:
- Genetic Dependency Identified: Researchers discovered that small cell neuroendocrine cancers, including those in the lung and prostate, exhibit a heightened reliance on the E2F3 protein after losing the RB gene.
- Tumor Growth Inhibition: Laboratory studies demonstrated that reducing E2F3 levels in RB-deficient cancer cells effectively halted tumor growth and induced cell death.
- Potential for Drug Repurposing: Inhibiting the DHODH enzyme with existing FDA-approved medications lowered E2F3 levels, suggesting a potentially faster path to clinical application for these aggressive cancers.
UCLA researchers have identified a critical genetic vulnerability in small cell neuroendocrine cancers, potentially opening new avenues for treating these aggressive tumors that arise in the lung, prostate, and ovary, according to a study published in Proceedings of the National Academy of Sciences.
Small cell neuroendocrine cancers are characterized by rapid growth, early metastasis, and a notable resistance to many standard therapies. A key feature of these cancers is the loss of the RB gene, which normally acts as a tumor suppressor, controlling cell growth. Without a functional RB gene, cancer cells proliferate unchecked. However, the research indicates that this genetic loss creates an unexpected dependency on a protein called E2F3.
“Discovering a vulnerability like this opens the door to thinking about entirely new treatment strategies,” said Dr. Owen N. Witte, Presidential Chair in Developmental Immunology and member of the UCLA Health Jonsson Cancer Center, in a news release. “That’s especially important because there has not been a major change in how we treat these cancers for decades.”
To pinpoint these vulnerabilities, the UCLA team developed laboratory models of small cell prostate cancer by genetically modifying normal human prostate cells to mimic the genetic alterations found in the disease, including the loss of RB and TP53. Using genome-wide CRISPR screens, they systematically tested thousands of genes to determine which were essential for cancer cell survival. Their findings revealed a strong dependence on E2F3 across small cell cancers originating from various organs.
In laboratory experiments, reducing E2F3 levels in cancer cells lacking the RB gene caused the tumors to cease dividing and, in some instances, undergo cell death. This phenomenon, known as “synthetic lethality,” occurs when the simultaneous loss of two genes leads to cell death, while the loss of either gene alone does not.
Recognizing that no existing drugs directly target E2F3, the researchers investigated inhibiting the DHODH enzyme, which plays a role in the metabolic pathway responsible for producing DNA building blocks. They discovered that blocking DHODH lowered E2F3 levels and slowed tumor growth. Importantly, DHODH inhibitors, such as leflunomide and teriflunomide, are already approved by the Food and Drug Administration (FDA) for the treatment of autoimmune diseases.
“What’s exciting is that our findings open the door to applying existing drugs in a new way,” said Evan Abt, assistant professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA, in a news release. “By understanding how these cancers depend on E2F3, we can start to think about strategies that might work much more quickly in patients.”
This research offers a promising new direction for the treatment of small cell neuroendocrine cancers, potentially leveraging existing medications to target a newly discovered genetic vulnerability. Further studies are needed to confirm these findings and translate them into effective clinical therapies.