McMaster University researchers have identified a small molecule compound that can activate the Wnt pathway in non-Wnt subtypes of medulloblastoma, the most serious form of pediatric brain cancer, making these aggressive forms of the disease more susceptible to therapy. “Our work shows the Wnt pathway, which has historically been considered cancer-promoting, may function as a tumor suppressor in certain contexts,” said Branavan Manoranjan, MD, PhD, who carried out the research as part of his PhD thesis at McMaster’s Michael G. DeGroote School of Medicine MD/PhD program. “We also found all different subtypes do have a minority fraction of Wnt active cells, and this is promising,” he added. Manoranjan, now a neurosurgery resident at the University of Calgary, is first author of the team’s published paper in Nature Communications, which is titled, “Wnt activation as a therapeutic strategy in medulloblastoma.”
Medulloblastoma (MB) is the most common malignant childhood brain tumor, and has recently been categorized into four molecular subtypes. Group 1 tumors have excellent outcomes, rarely spread, and are rarely lethal. But Groups 2, 3, and 4 are aggressive, demonstrate metastatic spread, and are lethal in 20–30% of patients, despite full treatment. Group 1 MB is also called the Wnt subtype, because it is characterized by apparent activation of the Wnt signaling pathway, which is known to be important in multiple tissues and organs during normal development. “Wnt MB accounts for 10% of cases,” the authors noted. “Clinically, Wnt MBs have the most favorable prognosis with a >95% five-year survivorship. By contrast, non-Wnt MBs are characterized by metastatic disease, increased rates of recurrence, and intermediate-poor overall survivorship.”
Given that Wnt MBs represent the only subgroup in which metastasis is not indicative of a poor prognosis, it has been suggested that “ … Wnt signaling may contribute to their remarkable response to therapy,” the team noted. Their newly reported research, conducted in the lab of senior author, Sheila Singh, PhD, professor in surgery and biochemistry at McMaster University, was designed to investigate if activating Wnt in a Group 3 or 4 MB might make these tumors less aggressive, decrease the cancer stem cell fraction and self-renewal ability, and possibly reduce the ability of tumors to grow and spread.
Genetic sequencing of individual brain tumor stem cells indicated that a rare fraction of cells in Groups 2, 3, and 4 cancers were Wnt active, and when those cells were sorted, they generated smaller, more benign-looking tumors, whereas the Wnt inactive cells generated more aggressive, metastatic tumors.
The team then tested a small molecule that turned on the Wnt pathway, in mice with non-Wnt subtype medulloblastoma tumors. They found that the treated animals displayed reduced tumor growth and improved survival. “Given the few targeted treatment options for Group 3 and 4 MBs, our work highlights a rational therapeutic option in which the protective effects of Wnt-driven MBs may be augmented in Group 3 and 4 MBs through targeted Wnt activation,” the scientists concluded.
They acknowledged that before considering Wnt activation as a treatment for childhood MMB it will be important to identify the mechanisms by which Wnt signaling might target genes that could impede growth of the cancer. Nevertheless, they wrote, “As molecular oncology trials continue to develop, approaches to overcome the dependence of tumors on malignant pathways are warranted and as such we provide a therapeutic rationale with clinical appeal that may alter our approach to cancer by reactivating anti-oncogenic programs that have been developmentally silenced in a tissue-specific manner.” Singh noted that a drug currently in use for other conditions has been found to selectively and specifically activate Wnt signaling. “In the end, Wnt activation could present an innovative targeted therapeutic strategy for treatment-resistant medulloblastoma,” she said.
