What This Project Does
Dr. Andrew Kung and his team of researchers at Memorial Sloan Kettering Cancer Center were awarded $1.26M to develop novel therapies for high-risk pediatric sarcomas that have low 5-year survival rates and a high risk of recurrence (likely to come back). For patients with rhabdomyosarcoma, Ewing sarcoma and osteosarcoma, 5-year survival rates are between 20 and 40 percent. Dr. Kung’s team has developed a new approach to match available FDA-approved drugs or to find novel drugs that can be used to treat sarcoma patients and improve the odds of survival.
Although outcomes for children with cancer steadily improve, survival of children with high-risk sarcoma has remained unchanged over the last 20 years. Advances in genomics have led to a much greater understanding about the genetic causes of childhood sarcomas, yet that knowledge has not translated to benefit children in the clinic. A major barrier to progress is that the genetic drivers of childhood sarcoma are often not amenable to direct drug targeting. That is because many of the pediatric sarcoma drivers are transcription factors, proteins that interact with the DNA to change gene expression. It is difficult to design drugs that target transcription factors as they lack regions that can be easily identified and modified by drugs. Therefore, there is a pressing unmet need for new methods to identify vulnerable targets in childhood sarcomas.
Dr. Andrew Kung’s research team has developed an original method to assess the entire signaling network within cancer cells and to identify the critical signaling nodes, or Master Regulators (MRs), that drive malignancy. The team is using a systems biology approach, where molecular profiling is paired with bioinformatics, to identify the key sarcoma MRs. They have successfully used this method, a computational algorithm called Virtual Inference of Protein-activity by Enriched Regulon analysis (VIPER), to identify critical MRs in a number of adult cancers. Using this approach, they will analyze 100 samples from children with high-risk sarcomas to determine pediatric sarcoma MRs. They will then determine drugs that target the activity of the MRs and test them in cell and animal sarcoma models.
Dr. Kung’s group, if successful, anticipates new treatment options for children with high-risk sarcoma to reach clinical translation within three to five years. Importantly, their approach in pediatric sarcoma can serve as a paradigm for other pediatric cancers where genetic alterations are hard to target. The master regulators can be used in the clinic as biomarkers to predict patient response and prognosis and ultimately improve survival.
18 Month Research Update
In order to apply and validate the analytical tool, VIPER, Dr. Kung’s lab must assess a large group of pediatric sarcoma patients. To date, 155 cases have been collected—including 51 from rare sarcomas—and VIPER analysis has been performed on 103 tumors. The analysis so far shows that sarcoma gene pathways feed into just a few MRs, regardless of sarcoma type. In order to test the susceptibility of these MRs to therapeutics, Dr. Kung has developed 78 novel patient-derived xenograft (PDX) models (models made by injecting patient tumor cells into mice) and 14 primary cell cultures from patient tissue. Dr. Kung’s group is generating the largest dataset of genetically characterized pediatric sarcomas as well as a matching portfolio of primary cell lines and mouse models. The data will be publicly available and can provide useful insight into exploring new drug options for sarcomas.