Making brain cancers in children respond better to treatment
Small molecule compound that can activate the Wnt pathway in non-Wnt
subtypes of medulloblastoma identified

Date:
August 28, 2020
Source:
McMaster University
Summary:
Research has identified a small molecule compound that can activate
the Wnt pathway in non-Wnt subtypes of medulloblastoma, making these
aggressive forms of cancer more responsive to therapies. The work
also found the Wnt pathway, which has historically been considered
cancer- promoting, to function as a cancer inhibitor in certain
contexts.



FULL STORY ========================================================================== Brain cancer in children is always a devastating diagnosis, but McMaster University researchers may have found a way to have the most serious
types of pediatric brain cancer respond better to therapies.


========================================================================== Medulloblastoma (MB) is the most common malignant childhood brain tumour
and it 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 still aggressive, have 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, a signaling pathway important in multiple tissues and organs during normal development.

Research conducted in Dr. Sheila Singh's laboratory at McMaster University published today in the journal Nature Communications, has identified a
small molecule compound that can activate the Wnt pathway in non-Wnt
subtypes of medulloblastoma, making these aggressive forms of cancer
more responsive to therapies.

The work also found the Wnt pathway, which has historically been
considered cancer-promoting, to function as a cancer inhibitor in
certain contexts.

Branavan Manoranjan did the research as part of his PhD thesis in
McMaster's Michael G. DeGroote School of Medicine MD/PhD program.



==========================================================================
He investigated several different ways to see if activating Wnt in a
Group 3 or 4 MB made the tumour less aggressive, decreased the cancer
stem cell fraction and self-renewal ability, and decreased the ability
of the tumour to grow and spread.

Through performing genetic sequencing of individual brain tumour stem
cells, he found that a rare fraction of cells in the Group 2, 3 and 4
cancers were Wnt active and when those cells were sorted, they generated smaller, more benign- looking tumours, while the Wnt inactive cells
generate the aggressive, metastatic tumours.

The team then tested a small molecule that turned on the Wnt pathway in
mice with non-Wnt medulloblastoma subtype tumors, which resulted in a
reduction in tumor growth and improved survival.

"Our work shows the Wnt pathway, which has historically been
considered cancer- promoting, may function as a tumour suppressor in
certain contexts," said Manoranjan, now a neurosurgery resident at the University of Calgary. "We also found all different subtypes do have a
minority fraction of Wnt active cells, and this is promising." Singh,
the senior author for the study, added 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.

The research was funded by several agencies, notably Canadian Institutes
of Health Research, Cancer Research Society, and Brain Tumour Foundation
of Canada.


========================================================================== Story Source: Materials provided by McMaster_University. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Branavan Manoranjan, Chitra Venugopal, David Bakhshinyan, Ashley A.

Adile, Laura Richards, Michelle M. Kameda-Smith, Owen Whitley,
Anna Dvorkin-Gheva, Minomi Subapanditha, Neil Savage, Nazanin
Tatari, Dillon McKenna, Blessing Bassey-Archibong, Neil Winegarden,
Robin Hallett, John P. Provias, Blake Yarascavitch, Olufemi Ajani,
Adam Fleming, Gary D.

Bader, Trevor J. Pugh, Bradley W. Doble, Sheila K. Singh. Wnt
activation as a therapeutic strategy in medulloblastoma. Nature
Communications, 2020; 11 (1) DOI: 10.1038/s41467-020-17953-4 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200828081024.htm

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