Osteosarcoma is a rare and aggressive bone cancer that primarily strikes children and adolescents, with an average age at diagnosis of 15. Standard treatment—MAP chemotherapy with surgery—has not changed in over 40 years and sadly fails a third of patients. Outcomes are particularly poor when the disease spreads, most often to the lungs.

Despite major advances in precision medicine for other cancers, osteosarcoma remains largely untouched. Progress has been held back by a combination of biological and logistical barriers: the tumor arises in dense bone tissue and carries a highly unstable genome; obtaining and analyzing high-quality samples is challenging; the disease is rare affecting about 1,000 U.S. patients annually; and research efforts have been fragmented.

The Defying Osteosarcoma TeamLab aims to change that. By bringing together more than 20 researchers across 8 institutions, the project is building a cross-institutional research engine to replace outdated, one-size-fits-all therapy with targeted, subtype-specific strategies. The Defying Osteosarcoma TeamLab’s vision begins with rapid tumor profiling at diagnosis, followed by the development of biology-matched therapeutic hypotheses. Clinical trials then test these hypotheses, connecting bench and bedside in real-time, allowing continuous feedback and learning. Discovery is accelerated through integration of human, canine, and murine models—each contributing unique biological insights.

A new trial platform will test multiple molecularly guided interventions, including antibody-drug conjugates that target the tumor cell surface and DNA damage response agents that disrupt genomic repair pathways. The design includes longitudinal collection of tissue and blood samples to enable biomarker discovery and molecular assays that track residual disease to uncover mechanisms of relapse.

Canine osteosarcoma—which is nearly identical to the human form and occurs in over 10,000 dogs annually—will be incorporated through trials in fully immunocompetent dogs. This model offers a faster, lower-regulation path to test promising therapies while generating real-world biological insights. Smart science that allows man’s best friend to help lead the way to new treatments.

Trial samples will be analyzed using a suite of advanced techniques to build a molecular atlas of osteosarcoma. These include whole-genome and transcriptome sequencing to identify genetic alterations and active pathways, single-cell “nuc-seq” to resolve tumor heterogeneity, and spatial profiling to understand how tumor cells are organized and interact with each other and their environment. Researchers will also study the surfaceome and investigate chromothripsis—a phenomenon where chromosomes shatter and reassemble in chaotic patterns. Found in up to 75% of osteosarcomas, chromothripsis is believed to be a major driver of the disease’s genomic instability. These data will help define subtypes, identify therapeutic targets, and uncover mechanisms of resistance and progression.

Break Through Cancer is enabling this ambitious effort by providing the operational infrastructure, shared data science platform, and coordination across teams and institutions. All data from trials, models, and molecular analyses will flow into DASH, our centralized cloud-based hub, for real-time analysis and discovery.