Promising Drug Target Identified in Medulloblastoma
March 26, 2015
Scientists at Dana-Farber/Boston Children’s Cancer and
Blood Disorders Center have identified a protein critical to both
the normal development of the brain and, in many cases, the development of medulloblastoma, a
fast-growing brain tumor that usually strikes children under 10 years of age.
As reported in the journal Developmental Cell, when the researchers
cut the level of the protein, called Eya1, in half in mice prone to develop
medulloblastoma, the animals’ risk of dying from the disease dropped
dramatically. The findings point to Eya1 as a prime target for new drugs for
this type of medulloblastoma, and for other cancers that share the same path of
“Medulloblastomas account for about 18
percent of all brain tumors in children,” said the study’s senior author, Rosalind
Segal, MD, PhD, of Dana-Farber/Boston Children’s. “Today, 60 to 70 percent of
patients can be cured, but the major therapies – surgery, radiation, and
chemotherapy – have significant downsides. There is great interest in
developing more targeted therapies that can attack the cancer while producing
milder side effects.”
Medulloblastomas are divided into four
molecular subtypes. The current study focused on one in which tumor growth is
driven by a cell-signaling pathway initiated by the Sonic Hedgehog (Shh)
“The Sonic Hedgehog subtype accounts for
about 30 percent of all medulloblastomas,” Segal remarked. “And, in fact, the
Shh pathway is activated in as many as one-third of all human cancers. While
Shh signaling clearly plays a key role in many medulloblastomas, the basic
mechanism by which it is controlled hasn’t been clear.”
The new study looked at one of the
less-explored aspects of that mechanism. While much research has centered on
the role of enzymes known as kinases in cancer, less attention has been given
to kinases’ biological counterparts – enzymes known as phosphatases. Kinases
attach compounds known as phosphate groups to proteins; phosphatases remove
phosphate groups. Together, kinases and phosphatases act as a red light/green
light mechanism for protein activity: kinases generally switching a protein on,
phosphatases switching it off.
To learn which phosphatases are most
important for the Sonic Hedgehog pathway to function, first author Adriana
Eisner, PhD, of Segal’s lab measured the amounts of all 380 types of
phosphatases in medulloblastoma cells driven by Shh signaling. Eya1 stood out
because it was very highly expressed – produced in large amounts – in the
Follow-up experiments in mice confirmed
Eya1’s key role in the Shh pathway, both in normal brain development and in
medulloblastoma. In embryonic mice, the development of the rear portion of the
brain – a process dependent on Shh signaling – faltered in the absence of Eya1.
In young mice genetically predisposed to develop medulloblastoma, reducing the
levels of Eya1 by half (by canceling one of the two copies of the gene
responsible for the protein) caused death rates from the disease to plunge.
Normally, 35 percent of such at-risk animals die of medulloblastoma. By
contrast, only 10 percent of those with lowered Eya1 levels succumbed to the disease.
One of the potential advantages of Eya1 as a
drug target in medulloblastoma is that it belongs to a subfamily of
phosphatases with only four members in it. As a result, drugs that target Eya1
are likely to interfere with only a few other phosphatases, potentially
reducing the severity of side effects, the researchers say.
Funding for the study was provided by the
National Institutes of Health and the Pediatric
Low-Grade Astrocytoma Foundation.
The co-authors of the study are Maria
Pazyra-Murphy, Pengcheng Zhou, PhD, Xuesong Zhao, PhD, and Emily Chadwick of
Dana-Farber; Ershela Durresi, MD, PhD, and Michael Greenberg, PhD, of Harvard
Medical School; Pin-Xian Xu, PhD, of the Icahn School of Medicine at Mount
Sinai in New York; and R. Tyler Hillman and Matthew Scott, PhD, of Stanford
University School of Medicine.