Lead 8A analog can treat osteosarcoma in children

Jiayuh Lin, PhD, and colleagues at Nationwide Children's Hospital have developed a drug to target the most common cancerous bone tumor in children, osteosarcoma, using a version of the FDA-approved drug, Celebrex. The team will soon begin testing the drug using human and canine tumor cell lines thanks to a two-year, $200,000 grant from Alex's Lemonade Stand Foundation for Childhood Cancer.

Osteosarcoma is an aggressive bone tumor that usually develops during the period of rapid growth that occurs in adolescence. A signaling pathway known as the STAT3 pathway is common in osteosarcoma and is crucial to tumor formation and cancer progression. Blocking STAT3 signaling is considered a potential approach for treating osteosarcoma; however, few drugs are available that can inhibit STAT3 and be clinically relevant.

"One of the main barriers to developing a clinical drug to inhibit STAT3 is finding lead compounds that exhibit desirable drug properties," says Dr. Lin, who is a principal investigator in the Center for Childhood Cancer at The Research Institute at Nationwide Children's Hospital.

Dr. Lin and associate professor at The Ohio State University College of Pharmacy, Chenglong Li, PhD, have found that developing STAT3-selective inhibitors can be accelerated by pairing a novel STAT3 drug discovery method with drug repositioning techniques to create inhibitors with desirable drug properties. Using this method, Dr. Lin's team has developed a STAT3-selective inhibitor, 8A, using the FDA-approved drug, celecoxib (brand name: Celebrex-, Pfizer, New York ). Celecoxib is typically prescribed to relieve pain, tenderness, swelling and symptoms of inflammatory conditions like osteoarthritis. 8A is more potent and selective than celecoxib against STAT3 signaling in osteosarcoma cells.

The new funding will allow Dr. Lin's team to develop two additional 8A analogs that would further increase STAT3 binding, while retaining the drug properties of celecoxib. The team will then test all three versions in human and canine osteosarcoma cell lines and in a mouse tumor model. Future research will include collaboration with Cheryl London, DVM, PhD, at The Ohio State University College of Veterinary Medicine to initiate clinical trials of a lead 8A analog in dogs with spontaneous osteosarcoma. Osteosarcoma in dogs is very similar to osteosarcoma in humans. Trials will provide valuable data for human trials as well as help determine the feasibility of using lead 8A analog to treat these tumors in canines.

"This is a unique approach in osteosarcoma targeted therapy," says Dr. Lin. "We feel confident that our findings will advance the field of childhood osteosarcoma treatments."

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