“Hedgehog signaling has been reported to play an important role in medulloblastoma,” said Jun Long, a Ph.D. candidate in the Molecular Oncology Research Program in the DeWitt Daughtry Family Department of Surgery’s Division of Surgical Oncology. Long was the lead author of an article about the team’s research, “The BET bromodomain inhibitor I-BET151 acts downstream of Smoothened to abrogate the growth of Hedgehog driven cancers,” that has been published online by The Journal of Biological Chemistry.
“A pivotal upstream regulator of the pathway, known as Smoothened, has been targeted in clinical trials, and tumor shrinkage was achieved,” said Long. “The tumor, however, quickly regrew due to the mutation of Smoothened.”
Based on those prior findings, the researchers concluded that developing an effective therapeutic strategy would require targeting a location farther along the Hedgehog pathway.
“Epigenetic regulation occurs in several signaling modules, and these events act directly on the chromosome and modulate target gene transcription,” said Long. “Therefore, we initiated a small-scale epigenetic drug screening in a Hedgehog-dependent cell line to identify potential epigenetic modulation in Hedgehog signaling.
“After we had several positive hits, another cell line was utilized to verify if these compounds act downstream of Smoothened. Ultimately, one of them — I-BET151, a BET bromodomain inhibitor — was found to reduce Hedgehog target gene expression downstream of Smoothened. The compound also stopped the proliferation of medulloblastoma stem cells and tumor growth in the xenograft model.”
The study provides strong evidence that targeting epigenetic regulation in a way that bypasses Smoothened mutation may solve the problem of relapsing medulloblastoma. This treatment may also apply to other Hedgehog-induced solid tumors, such as basal cell carcinoma.
The investigators are already in the next phase of their research — conducting RNAi screening to identify novel methodologies for inhibiting gene expression related to tumor growth.
Additional authors of the journal article include corresponding authors David J. Robbins, Ph.D., professor of surgery, and Nagi G. Ayad, Ph.D., associate professor of psychiatry and behavioral sciences; Bin Li, Ph.D., and Jezabel Rodriguez-Blanco, Ph.D., post-doctoral fellows in Dr. Robbins’ laboratory; Claes Wahlestedt, M.D., Ph.D., Leonard M. Miller Professor, Associate Dean for Therapeutic Innovation, Vice Chair for Research in the Department of Psychiatry and Behavioral Sciences, and Director of the Center for Therapeutic Innovation; Chiari Pastori, Ph.D., a post-doctoral fellow in Dr. Wahlestedt’s laboratory; Claude-Henry Volmar, Ph.D., associate scientist, Department of Molecular and Cellular Pharmacology; Anthony Capobianco, Ph.D., Director of the Molecular Oncology Research Program; Xin-Hai Pei, M.D., Ph.D., assistant professor of surgery; and Feng Bai, Ph.D., associate scientist, DeWitt Daughtry Family Department of Surgery.