Article

Therapeutic Target for Medulloblastoma Identified in Mice Models

Author(s):

The medulloblastoma subset has a poor prognosis, so investigators have been looking for new treatment options.

A subset of medulloblastoma tumors (MBs) are driven by the activation of Sonic Hedgehog (SHH) pathways, according to a new report. MBs are the most common malignant pediatric brain tumor, and there are at least 4 distinct subgroups.

Investigators from MD Anderson Cancer Center studied the RE1-silencing transcription factor (REST) in order to understand its role in gene repression. SHH is the best characterized group of the disease. The study authors wrote that those in the SHH group have intermediate prognoses. Surgical resection, radiation therapy, and chemotherapy are all therapeutic options, but metastasis remains a clinical challenge for 3 of the 4 subgroups.

“Increased activity of an oncogene called ‘Smoothened’ is widely believed to be the main driving event for SHH medulloblastoma development,” study author Vidya Gopalakrishnan, PhD, told Rare Disease Report®. “Therefore, the pediatric neuro-oncology community has been actively testing a class of drugs called ‘Smoothened Inhibitors’ for these patients. However, the responses have been unexpectedly variable.”

The investigators thought that Smoothened-independent mechanisms that would activate SHH signaling may exist and, if so, would be a viable therapeutic target.

In genetically engineered mice models, the investigators were able to show that the expression of the oncogene, REST, can amplify SHH pathway activity in a specific molecular subset of SHH-tumors (called SHH-alpha) in a Smoothened-independent manner.

The patients with SHH-alpha have a poor prognosis, Gopalakrishnan added.

“Given the limited response to Smoothened inhibitors seen in clinical trials, the field has been searching for new therapeutic approaches,” she continued. “Our data suggest that we should consider targeting the REST complex of proteins in combination with Smoothened inhibitors when treating this subgroup of patients.”

As an additional part of the research, the investigators analyzed 223 patients’ SHH MB samples. The samples were divided into 6 clusters based on REST mRNA amounts. Cluster 1 had the highest transcript abundance, and the investigators found that clusters 1 and 2 SHH-alpha tumors as well as cluster 5 showed a decreased expression of the gene that targets REST for degradation. This means, they thought, that there is potential for REST protein stabilization and increased activities in these samples.

Their further research indicated that increased REST tumor penetrance also caused a sharp decrease in tumor latency. The investigators believe REST expression in tumors was linked to a decrease of survival in a small subset of patients with desmoplastic MBs, which are SHH-driven tumors. In their human SHH tumor transcriptome, data showed the surprising result that increased REST expression and activity was linked to 2 clusters of SHH tumor samples with poor prognoses for patients.

“Growing evidence suggests that chromatin remodelers, such as REST, contribute to SHH-driven MBs,” the study authors concluded. “Their molecular dissection will provide a rationale for testing unique combinations of pharmacological agents against human SHH tumor subgroups, especially SHH-alpha and SHH-beta tumors, where prognosis continues to be grim.”

The paper, titled “Transcriptional repressor REST drives lineage stage—specific chromatin compaction at Ptch1 and increases AKT activation in a mouse model of medulloblastoma,” was published in the journal Science Signaling.

Related Videos
Signs and Symptoms of Connective Tissue Disease
How Gene and Cell Therapy Is Developing in Dermatology
Joyce Teng, MD, PhD, discusses how therapeutic advances in fields like epidermolysis bullosa should progress treatment discourse in other rare dermatoses.
The Prospect of Pz-cel in RDEB Treatment, with Peter Marinkovich, MD
Comparing New Therapies for Dystrophic Epidermolysis Bullosa
Reviewing 2023 with FDA Commissioner Robert M. Califf, MD
Dunia Hatabah, MD | Image Credit: HCPLive
Ricky Safer: What Clinicians Need to Know About PSC
Ryan T. Fischer, MD: Long-Term Odevixibat Benefit for Alagille Syndrome
© 2024 MJH Life Sciences

All rights reserved.