Dr Randall on How Mouse Models Provide Valuable Insights in Preclinical Sarcoma Research

“Because sarcomas are so rare and it's hard to have robust clinical trials, because there's just not enough patients to be able to congregate into a specific disease type, [these] preclinical models hopefully will give us some better insights into vulnerabilities.”

R. Lor Randall, MD, FACS, the David Linn Endowed Chair for Orthopedic Surgery and chair of the Department of Orthopedic Surgery at the University of California, Davis, highlighted the utility of mouse models in advancing preclinical research in sarcoma. Given the rarity and biologic heterogeneity of sarcomas, particularly those defined by specific translocations or molecular signatures, there are inherent challenges in conducting large-scale clinical trials. As a result, the use of preclinical models has become increasingly important in elucidating disease mechanisms and identifying potential therapeutic vulnerabilities.

Randall emphasized that while genetically engineered mouse models (GEMMs) have been utilized in some studies, particularly for translocation-driven sarcomas, much of the ongoing work relies on immunodeficient (nude or SCID) mice. In these models, human sarcoma cells are transformed and implanted to evaluate tumor growth, progression, and therapeutic response in vivo. One notable limitation of these models is the absence of a functional immune system, which restricts their utility in studies focused on immunomodulatory therapies—an area of growing interest in sarcoma treatment. Despite this limitation, the models retain value due to their reproducibility and the ability to mechanistically investigate tumor biology with relative fidelity.

Importantly, Randall noted that the fidelity of these xenograft models has been increasingly validated. Tumor behavior in the murine host often recapitulates clinical characteristics observed in patients, supporting the relevance of these models in translational sarcoma research. This enables investigators to study oncogenic drivers, resistance pathways, and potential combinatorial approaches in a controlled environment, which can inform hypotheses for subsequent clinical evaluation.

Because the sarcoma field is limited by small patient populations and the inability to conduct subtype-specific randomized trials, robust preclinical data derived from such models are critical. They provide a platform to screen candidate therapies and uncover molecular vulnerabilities that might otherwise remain unexplored in conventional trial designs.

Randall underscored the need for continued development and refinement of these systems, including efforts to integrate humanized mouse models or co-clinical approaches that better account for immune interactions.