1 min readTargeting a Transporter to Treat SHH Medulloblastoma

Memphis, TN — Investigators at St. Jude Children’s Research Hospital have found that the ABCC4 transporter is critical to the SHH signalling pathway in the brain tumour medulloblastoma. This work provides a rationale for development of small molecule inhibitors that target ABCC4. The findings appeared in Cancer Research.

Medulloblastoma is the most common malignant paediatric brain tumour. There are four genomic subgroups of the disease: WNT, SHH, Group 3 and Group 4. The SHH subgroup accounts for about 25% of all paediatric medulloblastoma cases. The five-year survival rate for SHH medulloblastoma is approximately 75%.

Transporters are proteins found on the cell membrane. They help substances enter and exit cells. The researchers found that the ABCC4 transporter is highly expressed in SHH medulloblastoma.

“We have studied the ABCC4 transporter for many years, and wanted to better understand how it interacts with critical pathways that drive tumour growth, like SHH,” said senior author Dr. John Schuetz, of the St. Jude Department of Pharmaceutical Sciences. “By teasing apart the relationship between ABCC4 and the SHH pathway, we’ve identified a novel strategy for potentially treating these tumours.”

The researchers built a medulloblastoma “interactome” to determine which proteins interact with and are essential to the SHH pathway. The findings showed that ABCC4 is highly expressed in the SHH subgroup and is required for optimal activation of the pathway.

The researchers found that increased expression of ABCC4 correlates with poor overall survival in SHH medulloblastoma. Targeting ABCC4 using genomic methods reduced the size of medulloblastoma tumors and extended the lifespan of mouse models.

“By following the web of interactions between different parts of key tumor pathways, we can take a more targeted approach to cancer therapy,” said first author Dr. Juwina Wijaya, formerly a postdoctoral fellow in Schuetz’s laboratory. “We now know another one of SHH medulloblastoma’s weaknesses.”

Article adapted from a St. Jude Children’s Research Hospital news release.

Publication: An ABC transporter drives medulloblastoma pathogenesis by regulating Sonic Hedgehog signaling. Juwina Wijaya et al. Cancer Research (2020): Click here to view.

ABCC4, ABCC4 transporter, Malignant paediatric brain tumour, medulloblastoma, Paediatric medulloblastoma, SHH Medulloblastoma, SHH signalling, Wnt

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