Columbia University Medical Center Heroes and Heroes Archives

2018

Quantum Collaboration Grant

Julia Glade Bender

New York, NY

Targeting Master Regulator Dependencies in High Risk Osteosarcoma (OS)

Despite decades of well-conceived clinical trials for pediatric osteosarcoma (OS), there has been no improvement in overall survival over the last 30 years, and no systemic therapy proven to prolong survival in the setting of recurrent or refractory disease. It is intriguing that despite the complex and heterogeneous genetic landscape of OS, the “molecular phenotype” is highly conserved. In this proposal, we suggest that the aberrant activity of a limited number of “master regulator” proteins (MR), induced by upstream mutations, can act as a network “switch” that can induce and maintain the OS cancer cell state; that the activity of these MR can be inferred from their transcriptional program and that computational biology can be used to predict clinically relevant drugs that can collapse this tumor-specific MR-driven architecture using a CLIA certified test called Oncotreat. Patients with OS require a paradigm shift in our thinking and approach to therapy. We present a rigorous experimental program where we will characterize the OS-specific regulatory proteins, discover agents that will target them, provide preclinical in vivo validation and a clear pathway forward to deploy OncoTreat in the clinic.

• Patients with OS have not benefited from recent cancer breakthroughs.
• Patients with OS require a paradigm shift in our thinking and approach to therapy.
• We will use computer-based reverse engineering to characterize a handful of “master regulator” proteins which act as a switch, turning “on” a program that induces and maintains the cancer state in pediatric OS.
• The same computational methods, called OncoTreat, can predict drugs capable of turning the patient-specific cancer program “”off.””
• We will use these methods to prioritize a pipeline of drugs and drug combinations that can be rapidly tested in patient -derived osteosarcoma mouse models and then test the feasibility of using OncoTreat to identify novel therapies for patients with drug resistant OS.