Potential new approach against fatal childhood brain cancer
In mouse models of DIPG, simultaneously attacking two metabolic pathways
led to significant improvements in survival

Date:
August 13, 2020
Source:
Michigan Medicine - University of Michigan
Summary:
In mouse models of DIPG, a fatal childhood brain cancer,
simultaneously attacking two metabolic pathways led to significant
improvements in survival.



FULL STORY ========================================================================== Progress against DIPG, a fatal childhood brain tumor, is usually a game of inches. Studies that hint at even small gains are cause for celebration.


========================================================================== That's why researchers at the University of Michigan and their
collaborators are excited about discoveries that point toward a new
potential treatment approach -- one that significantly lengthened survival times in two mouse models of DIPG.

The team's findings, which appear in the journal Cancer Cell, suggest
that simultaneously targeting two energy-production pathways within the
cancer cells could help overcome the effects of a cancer-causing mutation
that is one of the hallmarks of DIPG, or diffuse intrinsic pontine glioma,
and similar tumors.

"DIPGs have a characteristic, epigenetic histone mutation -- that is,
a mutation in the spool that DNA wraps around, and which can affect
gene expression," says the study's senior author Sriram Venneti, M.D.,
Ph.D., a neuropathologist and researcher at the U-M Rogel Cancer Center
and Chad Carr Pediatric Brain Tumor Center. "It's not clear exactly how
this mutation causes cancer, but it's associated with poor outcomes,
which implies these mutations are aggressively driving the biology of
these tumors." An epigenetic change is one that affects how a gene gets
used without changing the underlying DNA sequence -- similar to the way
a playlist of songs can be altered without changing the songs themselves.

"What we discovered, unexpectedly, is that this mutation specifically
increases activity in two metabolic pathways in the cell, and that
these pathways also directly influence the epigenetic changes within the
cell," Venneti says. "So the question was: Can we use metabolic drugs
to interrupt these energy production pathways within the cancer cells
and at the same time modify the cells' epigenome in a productive way?"
The result in two different mouse models of DIPG was a resounding yes.



========================================================================== Inhibiting each of the two metabolic pathways individually provided
a small increase in how long the mice survived, while targeting both
pathways at the same time caused the mice to live much longer.

In one model used in the study, DIPG is always fatal. When the two
experimental compounds were given, however, 60% of the mice were still
alive, when the experiments were ended.

"Treatments for DIPG are desperately needed. So, while these are still
early stage, pre-clinical results, we are excited about continuing to
develop this new strategy toward human clinical trials," Venneti says.

DIPG is usually diagnosed in children between the ages of 5 and 10, though
it can develop at any age, including rare cases in adults. These tumors
start in the brainstem, which makes them nearly impossible to remove surgically. In 2015, Chad Carr, the grandson of former U-M football
coach Lloyd Carr, died at age 5 after being diagnosed with the disease
14 months earlier.

"The Chad Carr Pediatric Brain Tumor Center was started in 2018 and has
placed the University of Michigan as one of the leading centers for DIPG research and patient care. We could not have performed this research
without their strong support and critical funding from the Chad Tough Foundation," Venneti says.



==========================================================================
Both of the compounds used in the study -- one of which was developed
by the pharmaceutical company AbbVie and the other by Johns Hopkins
University -- are able to penetrate the blood-brain barrier, which is
critical for treating brain tumors, Venneti adds.

"The barrier is there for a reason," he says. "You don't want toxins to
be able to reach your brain. The challenge in developing drugs against
brain cancer is that you need the drugs to be able to cross through this barrier and attack the tumor cells. We were fortunate that both of the
study compounds can do so." The study also uncovered new information
about the biology of DIPGs and related tumors through the analysis of
cancer cells and imaging scans from DIPG patients. Along with shedding new light on the energy cycles of the cancer cells, researchers discovered
why two different types of mutations -- one seen in children with DIPG
and the other observed in adult brain tumors -- are mutually exclusive.

"We found that these two mutations use the same pathways, but in opposite
ways, which explains why they can't occur at the same time," Venneti says.

Continuing to develop a better understanding of the underlying tumor
biology will help researchers to develop and refine new treatment
strategies, he notes.


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


========================================================================== Journal Reference:
1. Chan Chung, Stefan R. Sweha, Drew Pratt, Benita Tamrazi, Pooja
Panwalkar,
Adam Banda, Jill Bayliss, Debra Hawes, Fusheng Yang, Ho-Joon Lee,
Mengrou Shan, Marcin Cieslik, Tingting Qin, Christian K. Werner,
Daniel R. Wahl, Costas A. Lyssiotis, Zhiguo Bian, J. Brad Shotwell,
Viveka Nand Yadav, Carl Koschmann, Arul M. Chinnaiyan, Stefan
Blu"ml, Alexander R. Judkins, Sriram Venneti. Integrated Metabolic
and Epigenomic Reprograming by H3K27M Mutations in Diffuse Intrinsic
Pontine Gliomas. Cancer Cell, 2020; DOI: 10.1016/j.ccell.2020.07.008 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200813134556.htm

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