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. For patients with rhabdomyosarcoma, Ewing sarcoma and osteosarcoma, 5-year survival rates are between 20-40%. Dr. Kung’s team has developed a new approach to match available FDA approved drugs or to find novel drugs that can be used ultimately 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 not amenable to direct drug targeting. That is because many of the genes that drive pediatric sarcomas are transcription factors, proteins that activate gene expression. Transcription factors lack regions that can be easily used to tailor a specific drug (targeted therapy). There is therefore a pressing unmet need for new methods to identify vulnerable targets in childhood sarcomas.
Dr. Andrew Kung’s research team has developed a new 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 MRs. They have successfully used this method to identify critical MRs in a number of adult cancers. Using this approach, they will analyze single patient samples from children with high-risk sarcomas and identify MRs and then identify drugs that target the activity of the MRs.
Using a novel computational algorithm, Virtual Inference of Protein-activity by Enriched Regulon analysis (VIPER), the team will assess a panel of 100 pediatric sarcomas (rhabdomyosarcoma, osteosarcoma, Ewing sarcoma) to identify critical MRs. They will search for drugs that reverse the activity of the MRs. The drugs will then be tested in preclinical models. In adult studies using this approach, they have shown that several drugs previously not appreciated to be active actually possess anti-tumor activity in cell and animal 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 and further, the master regulators can be used in the clinic as biomarkers to predict patient response and prognosis and ultimately improve survival.