(L to R) Co-corresponding author Adam Durbin, MD, PhD, St. Jude Department of Oncology; co-first authors Yang Zhang, PhD, St. Jude Department of Computational Biology, and Stephanie Nance, PhD, St. Jude Department of Oncology; and co-corresponding author Brian Abraham, PhD, St. Jude Department of Computational Biology.
Scientists co-led by St. Jude Children’s Research Hospital have identified a potential therapeutic vulnerability in some forms of osteosarcoma. Published today in the Journal of Experimental Medicine, a combination approach slowed tumor growth and prolonged survival in preclinical models of this pediatric bone cancer. The therapies degraded EP300 (a protein that is co-opted to express oncogenes in many cancers) and inhibited AKT (a well-known cancer drug target), highlighting the combination’s clinical potential.
Osteosarcoma has lower survival compared to many other cancers, with relapsed and metastatic disease showing especially poor outcomes. As no new treatments have been approved for the disease in the last 40 years, the findings provide a much-needed new therapeutic avenue to explore.
“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,” said co-corresponding author Adam Durbin, MD, PhD, St. Jude Department of Oncology. “It’s especially exciting because the approach may have potential in patients who are metastatic and are least responsive to current therapies.”
Discovering the combination
The study builds on previous work showing that EP300 can be targeted by a PROTAC, a type of compound that marks a protein for destruction. That approach had shown benefit in models of neuroblastoma, so researchers explored whether EP300 degradation could work in another setting. In osteosarcoma, they found that a small but meaningful subset of samples was disproportionately sensitive. sensitive.
To find what made those tumors vulnerable to EP300 degradation, the scientists looked at the tumor genetics. Most osteosarcoma samples responsive to EP300 degradation had mutations that hyperactivated the AKT pathway. AKT is a central regulator of many cellular processes and is commonly dysregulated in cancers. There are already Food and Drug Administration (FDA)–approved inhibitors for AKT. That connection led the researchers to combine EP300 degradation with AKT inhibition. The paired drugs had a synergistic effect in mouse model xenografts of patient tumors, slowing tumor growth and increasing survival. The findings suggest that these mutations may serve as a biomarker for sensitivity to the combination approach.
“We’ve seen interventions that were selected using a particular tumor’s genotype to be effective in other diseases, such as leukemias,” said co-corresponding author Brian Abraham, PhD, St. Jude Department of Computational Biology. “Our results provide a strategic way to connect an osteosarcoma’s genotype to a potential rational therapy.”
Protein degradation efficacy depends on protein production levels
To understand why AKT hyperactivation and EP300 degradation synergized in specific tumor models, the scientists compared sensitive and resistant tumors biochemically. They found that sensitive cancers had a slower rate of global protein production than their resistant counterparts.
“One way to make a degrader less effective is to make more proteins than the cell can degrade,” Abraham said. “We found that resistant osteosarcomas seem to be able to ‘outrun’ EP300 degradation by making more proteins overall.”
The finding has implications beyond osteosarcoma. Pharmaceutical companies are developing PROTACs for many diseases. If diseased cells increase protein production enough to overcome degradation, that mechanism could cause protein degrader therapies to fail in certain cases. This study provides an early example of how predicting such protein production levels could instead be exploited for therapeutic benefit.
“Our data would suggest that, in the future, we may be able to identify a patient whose osteosarcoma is likely to be sensitive to this combination therapy approach through genome sequencing,” Durbin said. “If we can personalize their treatment with that information, we might have found a foothold to improve outcomes for some of the toughest osteosarcoma cases.”
Authors and funding
The study’s co-first authors are Ian Delahunty, Stephanie Nance and Yang Zhang, St. Jude; Francois Lamoureux, Nantes Université; and Qi Liu, Dana-Farber Cancer Institute. The study’s other co-corresponding authors are Benjamin Ory, Nantes Université; and Jun Qi, Dana-Farber Cancer Institute. The study’s other authors are Bénédicte Brounais, Nantes Université; Barbara De Kegel, Matthew Rees, Mustafa Kocak, Ashish George, Melissa Ronan and Jennifer Roth, Broad Institute of MIT and Harvard; Alejandro Sweet-Cordero, University of California San Francisco; William Wright, Elaine Ritter, Noha Shendy, Sandra Kietlinska, Mohammad Mohammad Nezhady, Yuan Feng, Meifen Lu, Anoop Kavirayani, Bo Wang, Yanling Liu, Paris Prinsen, Yousef Khashana, Vernon Ebegboni, Lillian Guenther, Paul Geeleher and Xiaotu Ma, St. Jude.
The study was supported by grants from the National Institutes of Health (K08CA245251, R37CA286444, R01CA296556 and P30CA021765); the St. Jude Children’s Research Hospital Transcription Collaborative; the Pediatric Cancer Dependencies Accelerator of the Broad Institute, Dana-Farber Cancer Institute, and St. Jude; Alex’s Lemonade Stand Foundation; the Rally Foundation for Childhood Cancer Research; the Curing Kids Cancer Foundation; CureSearch for Children’s Cancer; the V Foundation for Cancer Research; Hyundai Hope on Wheels; the American Association for Cancer Research, and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.
St. Jude Children's Research Hospital
St. Jude Children’s Research Hospital is leading the way the world understands, treats, and cures childhood catastrophic diseases. As the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children, St. Jude advances groundbreaking research and shares its discoveries worldwide to accelerate progress in pediatric medicine. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to more than 80% since the hospital opened more than 60 years ago. Through collaboration and innovation, St. Jude is working to ensure that children everywhere have access to the best possible care. To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.