First-in-class oral inhibitor of TGF-beta receptor in humanized mouse model of advanced osteosarcoma
Dr. Alex Huang – Case Western Reserve University School of Medicine, Cleveland, OH
Osteosarcoma (OS) is the most prevalent malignant bone cancer with a high propensity for lung metastasis in children and adolescent and young adults (AYA), with ~400-600 cases a year in the United States. Despite aggressive chemotherapy and surgery, the outcome for pulmonary metastatic OS (pOS) and recurrent/refractory OS (rOS) remains poor over the past 4 decades. Transforming growth factor-? (TGF-ß) is one of the most abundant cytokines in OS tumor microenvironment (TME), and correlates with high grade OS and lung metastases. Therefore, effectively targeting TGF-ß would be a desirable treatment approach. TEW-7197 (“Vactosertib”) is a first-in-class, non-toxic, orally available small molecule inhibitor of the TGF-ß type I Receptor (TßRI) kinase currently in adult Phase I clinical trial. Our preliminary data show that blocking TGF-ß signaling with oral TEW-7197 significantly reduced advanced late-stage preclinical OS models in vivo. We hypothesize that TEW-7197 will be an effective therapy against pOS and rOS by modifying tumor-intrinsic and extrinsic immune-related pathways to achieve clinical efficacy, and we will validate this hypothesis by validating TEW-7197 effect using a unique humanized mouse model consists of fully reconstituted human immune system. This research will establish a critical role of TGF-ß signaling in pOS progression and provide scientific rationale to develop a clinical trial targeting TGF-ß signaling with Vactosertib.
