# c-Myc regulation by TGF-beta signaling as a therapeutic target in Osteosarcoma > **NIH NIH R03** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $80,500 ## Abstract PROJECT SUMMARY Osteosarcoma (OS) is an aggressive malignant primary bone cancer with a high propensity for lung metastasis. Since the development of aggressive chemotherapy and surgery, the 5-year event-free survival rate for non- metastatic patients has attained 70%. In contrast, the outcome for pulmonary metastatic osteosarcoma (pOS) remains poor and the 5-year event-free survival has not improved significantly over the past 3 decades (20%). Therefore, treating pOS effectively remains a challenge. Transforming growth factor-β (TGF-β) is one of the most potent immune suppressive cytokines in tumor microenvironment (TME) and can promote metastasis in solid tumors. TGF-β production is increased in the sera of OS patients. This increase in TGF-β production is correlated with high grade OS and associated with the presence of lung metastases. Therefore, target TGF-β is the new therapeutic approach for the treatment of OS. In this proposal, we will demonstrate the therapeutic effects of a novel inhibitor of TGF-β signaling, TEW-7197, on OS growth in vitro and in vivo and associated immune responses in the OS TME. TEW-7197 (“Vactosertib”) is the first-in-class small molecule inhibitor of the TGF-β type I Receptor (TβRI) kinase and currently in Phase I clinical trial at UH Seidman Cancer Center for Multiple Myeloma, another disease with high TGF-β (#NCT03143985). TEW-7197 is orally available (taken qD or BID) and well tolerated with minimal side effects. Our preliminary data show that blocking TGF-β signaling with TEW- 7197 inhibited OS proliferation in vitro and oral administration of TEW-7197 to OS-bearing mice significantly reduced established pOS in vivo. Our preliminary observation has resulted in an Orphan Drug Designation authorization by the FDA in August 2021 as well as Fast-track IND issuance in January 2023 for the use of TEW- 7197 in OS. More recently, a multi-center phase I/II clinical trial using Vactosertib as monotherapy for the treatment of advanced osteosarcoma in patients age 14 and up been organized and planned for accrual in spring 2023 (#NCT05588648) at 21 sites across US, Europe and Asia. Recently, we have made the additional observation that TGF-β induced c-Myc expression in OS cells and those inductions were completely inhibited by TEW-7197 in OS cells. c-Myc is a major proto-oncogene which is highly amplified in OS. c-Myc overexpression in human OS correlates with aggressive tumor cell invasion and metastasis and worsens overall patient clinical prognosis. Therefore, these new results suggest that c-Myc regulation by TGF-β may be an important therapeutic target in OS. We hypothesize that TGF-β signaling inhibition may be an effective therapeutic strategy against metastatic pOS by modifying tumor-intrinsic signaling (c-Myc regulation) and extrinsic immune-related TME to achieve optimal immune-effector function and maximal clinical response in pOS. To confirm this hypothesis, we will utilize various mouse and human OS cell lines... ## Key facts - **NIH application ID:** 10793802 - **Project number:** 1R03CA273468-01A1 - **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY - **Principal Investigator:** Sung Hee Choi - **Activity code:** R03 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $80,500 - **Award type:** 1 - **Project period:** 2023-12-01 → 2025-11-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10793802 ## Citation > US National Institutes of Health, RePORTER application 10793802, c-Myc regulation by TGF-beta signaling as a therapeutic target in Osteosarcoma (1R03CA273468-01A1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10793802. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*