UCLA study finds possible drug target in aggressive small cell cancers
Researchers found RB-deficient small cell tumors rely on E2F3, a dependency that existing autoimmune drugs may help exploit.
By Lucas Ferreira · Science & Environment Writer
3 min read
UCLA researchers have identified a genetic dependency in aggressive small cell cancers that may give drug developers a new target. The finding matters because these tumors often grow quickly, spread early and have seen limited treatment progress, according to UCLA Health Sciences.
The study, published in Proceedings of the National Academy of Sciences, focuses on cancers that have lost a gene called RB. UCLA Health Sciences said small cell neuroendocrine cancers can arise in the lung, prostate and ovary, and loss of RB is a common feature of these difficult cancers.
RB loss creates a dependency
RB normally helps restrain cell growth. When the gene is missing, cancer cells can multiply rapidly and resist many targeted treatments, UCLA Health Sciences said.
The UCLA team found that cells lacking RB become reliant on a protein called E2F3. In laboratory models, reducing or blocking E2F3 stopped tumor growth through synthetic lethality, a situation in which cancer cells can tolerate one defect but fail when a second linked function is disrupted.
Dr. Owen N. Witte, the study’s senior author and a member of the UCLA Health Jonsson Comprehensive Cancer Center, said the discovery points to treatment strategies for tumors whose standard care has changed little over many years. UCLA Health Sciences said Witte has studied these cancers for decades.
New models helped reveal the target
UCLA Health Sciences said progress has been slowed by the lack of laboratory models that closely reflect small cell neuroendocrine cancers, including those that develop in the prostate. To address that problem, the researchers engineered normal human prostate cells with five major cancer-driving changes, including loss of RB and TP53.
The cells were grown as organoids and then used to form tumors in mice. According to UCLA Health Sciences, those models resembled human small cell prostate cancer and built on more than 10 years of work in Witte’s lab.
The researchers then ran genome-wide CRISPR screens to test which genes the cancer cells needed to survive. UCLA Health Sciences said the screens identified nearly 1,400 genes involved in cancer cell survival, with E2F3 emerging as a shared weakness across small cell cancers from different organs.
When the team lowered E2F3 levels in RB-deficient cells, the cancer cells stopped dividing, lost their ability to form clusters and in some cases died, according to UCLA Health Sciences. First author Dr. Evan Abt, an assistant professor at the David Geffen School of Medicine at UCLA, said the models made it possible to find a vulnerability that would have been hard to detect otherwise.
Existing drugs may offer a route
No approved drugs directly target E2F3, UCLA Health Sciences said. The researchers instead tested whether they could affect E2F3 indirectly by blocking DHODH, an enzyme involved in producing the building blocks cells need to make DNA.
Inhibiting DHODH lowered E2F3 levels and slowed tumor growth in the laboratory models, according to UCLA Health Sciences. The finding drew attention because DHODH inhibitors such as leflunomide and teriflunomide already have FDA approval for autoimmune diseases.
UCLA Health Sciences described the work as early-stage research. The study suggests that repurposing existing drugs could be explored as a faster path toward therapies for patients with RB-deficient small cell cancers, but the findings still need further testing before they can be considered a clinical treatment.
This story draws on original reporting from ScienceDaily.