Kristen VanHeyst, DO

Their recent work shows that the TGFB inhibitor TEW-7197 not only slows tumor growth, but also disrupts key cancer-driving signals involving c-Myc, a gene whose overactivity is linked to especially poor outcomes in osteosarcoma. The team has uncovered that tumors with high c-Myc levels may resist TEW-7197 because the c-Myc protein remains unusually stable, and they are now investigating ways to overcome this resistance and exploring potential drug combinations. In parallel, they are working to refine a humanized mouse model that better mimics how a child’s immune system response to therapy, allowing them to evaluate whether TEW-7197 can work together with immune checkpoint inhibitors to boost anti-tumor immunity.

Recently, they developed a more advanced mouse model with a human-like immune system, allowing them to better study how the TGF-β inhibitor TEW-7197 might work alone or in combination with other immunotherapies. While results from these new experiments are still in progress, earlier findings showed that TEW-7197 can significantly slow tumor growth and block signals that help the cancer thrive. This work is helping to lay the foundation for future clinical trials that could bring new hope to patients with limited treatment options.

Furthermore, her comparisons with other known TGF-β inhibitors have shown that TEW-7197 is more effective in reducing TGF-β signaling. She is currently working with collaborators to develop a mouse model with a humanized immune system to evaluate the efficacy of TEW-7197 in combination with immune checkpoint blockade (ICB) therapy. The preclinical findings from this work could support the integration of TEW-7197 with ICB therapy as an additional arm in an ongoing Phase I/II clinical trial for relapsed or refractory osteosarcoma at UH Rainbow Babies & Children’s Hospital, or they may provide the scientific basis for a stand-alone trial of this therapeutic approach.

At the time of diagnosis, some patients have osteosarcoma not only in their bone, but also in their lung(s). Osteosarcoma is typically treated with a combination of surgical resection and chemotherapy. Despite this treatment, the prognosis for patients with osteosarcoma in both their bone and lung(s), or who have the disease that does not respond to this treatment or recurs, is very poor. Treatment of patients with metastatic, progressive or relapsed disease, therefore, remains a significant challenge and novel therapeutic approaches are desperately needed.

Transforming Growth Factor Beta (TGF-beta) is produced by osteosarcoma cells and cells that exist within the tumor’s environment. The presence of TGF-beta makes it more difficult for a patient’s own immune system to eradicate this tumor. Dr. VanHeyst’s prior data supports the use of an inhibitor of TGF-beta as a therapeutic option for patients with recurrent/refractory osteosarcoma and led to the developmental of a clinical trial using a TGF-beta inhibitor.

Dr. VanHeyst and her team want to further examine the effects of this TGF-beta inhibitor on the environment in which osteosarcoma cells live in addition to combining it with other forms of therapy that stimulate the patient’s immune system to fight the osteosarcoma. They are actively working toward these goals and plan to repeat their most recent experiments with modifications to strengthen the validity of the results they obtained. The outcome of this project may improve therapeutic options and potential survival for children, adolescents and young adults with osteosarcoma.