Kappa Delta Ann Doner Vaughan Award recognizes efforts to develop novel treatments

Osteosarcoma is an aggressive disease that has a high propensity for local invasion and early distant metastasis (Fig. 1). Aggressive treatment protocols, including chemotherapy and wide surgical resection, can achieve cure in approximately 60 percent to 70 percent of patients, primarily adolescents and young adults. Yet the 5-year survival rate for patients with relapse is only 20 percent, and this number has not changed significantly over the last two decades.

A type of anticancer agent that targets the Wnt pathway is a potentially useful agent to limit tumor growth and metastasis in cancers such as osteosarcoma. For the past 7 years, Bang H. Hoang, MD, a clinician scientist, has been studying the mechanisms by which Wnt signaling and Wnt antagonists influence tumor progression and metastasis.

“By elucidating the underlying mechanisms for tumor progression, we hope to capitalize on these data to ultimately benefit patients with untreatable sarcomas in the future,” said Dr. Hoang. For these efforts, Dr. Hoang and colleagues were awarded the 2011 Kappa Delta Ann Doner Vaughan Award.

A career’s work
Early in his career, while completing a fellowship at the National Institutes of Health, Dr. Hoang was given the opportunity to isolate and clone a gene encoding the first secreted Wnt antagonist protein. He later demonstrated that Wnt antagonists are suppressors of human cancers, including bone and soft tissue sarcomas and carcinomas.

Involvement of the Wnt pathway in human osteosarcoma, however, was only recently defined. Dr. Hoang and his colleagues were first to identify the Wnt receptor LRP5 as a biomarker for disease progression in human osteosarcoma. Using human tissues, they found a significant correlation between LRP5 mRNA expression and a lower metastasis-free survival in osteosarcoma patients, suggesting that Wnt signaling would be a clinically relevant target to pursue.

Subsequent studies identified Wnt target genes that participate in the progression of osteosarcoma and showed how blocking Wnt signaling could reverse a key process in cell migration, invasion, and metastasis. By re-expressing Wnt antagonists in cancer cells, the researchers were able to induce a morphologic and phenotypic change associated with less invasive behavior.

Additionally, a strategy that could reverse the epithelial-to-mesenchymal transition (EMT) might have clinical utility as a therapeutic intervention against tumor metastasis. EMT is a biologic process that allows cancer cells to undergo complex biochemical changes, making them more invasive. Dr. Hoang and his colleagues were able to demonstrate that blocking Wnt signaling using secreted antagonists can reverse EMT, suggesting that blocking the Wnt pathway may decrease the metastatic potential of osteosarcoma.

The team went on to test several of their theories in animal (mouse) models and is continuing its efforts to identify other therapeutic targets. According to Dr. Hoang, “Although an abundance of data has been presented on Wnt-induced mechanisms of tumor progression, many burning questions still remain, and these questions will drive future investigations in our laboratory.

“Our objective is to understand how Wnt signaling and secreted Wnt inhibitors contribute to the pathobiology of human osteosarcoma,” he continued, “with the hope that this pathway may be targeted for therapy to prevent tumor progression and metastasis. Ultimately, the success of our program belongs to the orthopaedic community and to thousands of patients who face these difficult diseases.”

The coauthors of “Toward Novel Therapeutic Intervention for Osteosarcoma: Clinical Implications of the Wnt Pathway” are Yi Guo, MD; Randall F. Holcombe, MD; and Xiaolin Zi, MD.

Disclosure information: The authors report no conflicts. Research funding was provided by the National Cancer Institute (NIH-K08), the Aircast Foundation, the Orthopaedic Research and Education Foundation, the American Cancer Society, and the Department of Orthopaedic Surgery and the Chao Family Comprehensive Cancer Center, University of California, Irvine.