ENPP1 as a therapeutic strategy for Osteosarcoma
Osteosarcoma (OS) is the most common bone cancer in children, yet treatments have not improved in decades, especially for patients whose disease spreads to the lungs. OS tumors are extremely unstable at the DNA level, which should activate the immune system, but instead these tumors evolve to create an immune-suppressive environment. Our work suggests that a molecule called ENPP1 plays a major role in this process. ENPP1 normally breaks down cGAMP, a signal that activates the STING pathway and alerts the immune system to danger. We found that OS tumors with high ENPP1 grow faster, spread more easily, and suppress anti-tumor immune cells. Surprisingly, ENPP1 also moves into the nucleus after DNA damage, suggesting a new role in helping tumors tolerate therapies that target DNA repair. Because ENPP1 can be blocked with an oral drug now in preclinical testing, this project will explore how ENPP1 promotes OS progression and whether combining ENPP1 inhibitors with DNA-damaging treatments can improve outcomes for children with metastatic OS.
Project Goals
The goal of my project is to develop a new treatment strategy for children with metastatic osteosarcoma (OS), a cancer for which survival has barely improved in decades. My work suggests that ENPP1, a molecule highly expressed in OS, helps tumors grow, spread, and evade the immune system. Importantly, ENPP1 can now be blocked with a new oral drug. In this project, I will determine how ENPP1 drives tumor progression, including a newly discovered role inside the nucleus during DNA-damage responses to promote genetic stability. I will also test whether blocking ENPP1 restores immune activation, slows tumor growth, and improves the effectiveness of drugs like PARP inhibitors that are already being evaluated in OS. Using detailed laboratory studies and innovative mouse models that mimic how OS spreads to the lungs, my aim is to generate the preclinical evidence needed to support a future clinical trial using ENPP1 inhibitors, alone or in combination with DNA-damaging therapies. Ultimately, my goal is to offer a new therapeutic option for children with high-risk, metastatic OS.
