Wang Lab Receives Chordoma Foundation Grant to Develop Novel RNA-Targeted Therapy for Bone Cancer

Yaqiang Wang, PhD, assistant professor in the Department of Biophysics, has been awarded a one-year, $100,000 pilot grant from the Chordoma Foundation, titled Targeting the TBXT Exon6 Skipping Stem-Loop with RNA-Targeted Small Molecules. The purpose of this grant is to develop a new therapeutic approach for chordoma, a rare, locally aggressive bone cancer with no approved systemic treatment and a median overall survival of about seven years.

Chordoma is driven by a protein called TBXT (Brachyury), which is overexpressed in nearly all chordoma cases and acts as the key driver of the disease. Directly drugging TBXT has proven difficult, because the protein lacks the well-defined pockets that small molecules typically bind. Dr. Wang's laboratory will take a different approach: instead of targeting the TBXT protein, the team will target a structured region of the TBXT messenger RNA, the molecular blueprint the cell uses to make the protein. This region acts as a natural switch that determines which version of TBXT a cell makes: a full-length form that drives tumor growth, or a shorter form thought to be far less active. Using structural biology and a binding-first approach, a core strength of the Wang laboratory, the team aims to find small molecules that lock the switch toward the shorter, less active form, dialing down TBXT's cancer-driving activity without ever touching the protein itself. Curiously, the same shift toward this shorter form of TBXT is thought to have helped apes and humans lose their tails, an unexpected legacy of our evolutionary past that Dr. Wang's lab now hopes to turn against chordoma.

"This pilot study brings together RNA structural biology and drug discovery in a way we believe could open a completely new therapeutic avenue for chordoma patients," said Dr. Wang. "We hope it will lay the groundwork for a larger research program at MCW."

The Chordoma Foundation is a nonprofit dedicated to accelerating effective treatments for chordoma patients worldwide.