Published in the Journal of Experimental Medicine, researchers co-led by St. Jude Children’s Research Hospital have identified a preclinical therapeutic combination that targets EP300 and inhibits AKT, successfully slowing pediatric bone cancer tumor growth and prolonging survival in laboratory models by exploiting specific genetic vulnerabilities.
PROTAC Therapy Destroys EP300 to Slow Tumor Growth
- Targeted Destruction: The therapy uses a specialized molecule known as a PROTAC to mark and destroy EP300, a protein that is co-opted to express oncogenes in many cancers.
- Synergistic Pairing: By combining EP300 degradation with an existing Food and Drug Administration (FDA)–approved drug that blocks the AKT pathway, researchers slowed tumor growth and increased survival.
- Personalized Potential: Genetic sequencing could help clinicians identify which osteosarcoma patients harbor these specific mutations, opening doors for precision medicine in hard-to-treat metastatic cases.
Identifying Vulnerabilities in Osteosarcoma Preclinical Models
Osteosarcoma remains a pediatric bone cancer characterized by lower survival compared to many other cancers, particularly in relapsed and metastatic cases. According to findings published in the Journal of Experimental Medicine, no new treatments have gained regulatory approval for this disease over the last forty years. Co-led by investigators at St. Jude Children’s Research Hospital and reported by News-Medical, a team of scientists set out to find actionable biological weaknesses by exploring protein degradation.
The research builds upon earlier scientific success using proteolysis-targeting chimeras—commonly called PROTACs—to mark proteins for destruction. While evaluating this technique in various settings, including neuroblastoma models, the team discovered that a small but meaningful subset of osteosarcoma tumor samples exhibited sensitivity to EP300 degradation. Further genetic profiling revealed that most of these susceptible tumors shared a common biological denominator: mutations that hyperactivated the AKT signaling pathway.
“We found a compound combination that looks promising for a disease that is exceptionally challenging to treat and has not had a major therapeutic improvement for a long time. It’s especially exciting because the approach may have potential in patients who are metastatic and are least responsive to current therapies.”
— Adam Durbin, MD, PhD, co-corresponding author, St. Jude Department of Oncology
Combining EP300 Degradation with AKT Inhibitors
Because AKT is a central regulator of many cellular processes that is frequently dysregulated in cancers, clinicians already possess FDA-approved pharmaceutical inhibitors designed to suppress it. Capitalizing on this pharmacological availability, the research team administered both the EP300 protein degrader and an AKT inhibitor simultaneously to mouse xenograft models carrying patient-derived tumors.
The combined administration yielded a synergistic effect across the preclinical models. Tumor progression slowed, and overall survival duration increased. According to UA.News, these specific AKT mutations could eventually serve as a biomarker to pinpoint which patients will respond best to this dual-drug regimen.
| Biological Mechanism | Intervention Strategy | Preclinical Observation |
|---|---|---|
| EP300 Protein | PROTAC-mediated protein degradation | Destroys proteins in sensitive tumor subsets. |
| AKT Pathway Hyperactivation | FDA-approved AKT pathway inhibition | Slows tumor growth and increases survival in mouse models. |
| Protein Synthesis Rates | Genomic and biochemical screening | Identifies tumors unable to “outrun” degradation via rapid protein production. |
Fast Protein Synthesis Causes Resistance to Therapy
To understand why certain tumors resisted the therapy while others responded, the research team conducted biochemical analyses comparing the two groups. They determined that resistant osteosarcoma cells maintained a faster rate of global protein synthesis. Essentially, these cells managed to “outrun” the degrader by manufacturing more proteins overall than the cell can destroy.
This discovery carries implications that extend beyond pediatric bone cancer. As pharmaceutical companies develop PROTACs for many diseases, understanding cellular protein production levels will prove critical to preventing treatment resistance. Co-corresponding author Brian Abraham, PhD, of the St. Jude Department of Computational Biology, noted that the results offer a strategic way to connect a tumor’s unique genotype to a potential rational therapy.
Combination Therapy Remains Unavailable for Clinical Practice
Because these findings stem entirely from preclinical models and patient-derived xenografts, this combination therapy is not currently available in standard clinical practice or open for general patient administration.
Next Steps in Translational Oncology
References
- Delahunty, I. M., et al. (2026). Dysregulated AKT signaling reprograms osteosarcoma to drive selective reliance on EP300. Journal of Experimental Medicine, 223(11), e20251898. DOI: 10.1084/jem.20251898
- St. Jude Children’s Research Hospital. (2026). Combination approach slows osteosarcoma growth and prolongs survival in preclinical models. News-Medical.
- UA.News. (2026). EP300 and AKT combination slowed osteosarcoma growth.
