is one of the
most devastating and highly aggressive cancers that result in the development
seizures and vomiting due to rapid pressure build-up in the brain. Treatment
options are few, which include chemotherapy, radiotherapy, and surgery.
Moreover, glioblastoma exhibits the highest mortality in both children and
glioblastoma cells share the same genes responsible for brain development
during infancy and early childhood. The study, published in Cell Reports
, has demonstrated that 'reverse engineering'
brain cancer stem cells, gene-by-gene, is capable of elucidating many potential
drug targets for developing targeted therapies against this cancer.
The study was
jointly led by Dr. Peter Dirks, MD, PhD and Dr. Stéphane Angers, PhD,
with active collaboration from Dr. Samuel Weiss, PhD.
Dr. Dirks is a
Staff Neurosurgeon and Senior Scientist at the Hospital for Sick Children
(SickKids) in Toronto, Ontario, Canada. He is also a Professor of Neurosurgery
at the University of Toronto, Canada. Dr. Dirks is credited for discovering
cancer stem cells in brain tumors, way back in 2003.
Angers is an Associate Professor at the Leslie Dan Faculty of Pharmacy,
University of Toronto, Ontario, Canada.
collaborator was Dr. Samuel Weiss, PhD, who is a Professor in the Cumming
School of Medicine's Departments of Cell Biology, Anatomy, Physiology, and
Pharmacology at the University of Calgary, Alberta, Canada.
"We think that, in one big experiment, we have
uncovered many new targets for glioblastoma, some of which were surprising,"
says Dirks. "These glioblastoma stem cells are also
resistant to treatment, which is one reason that these tumors are so hard to
cure. We need new ways to disrupt these cells specifically if we are going to
give people a better chance of survival."
Exploitation of CRISPR-Cas9 Technology for
is a robust technique for studying cancer biology by means of genome-wide
Dr. Anger's lab focuses on CRISPR-Cas9 technology for investigating
cancer. Researchers at his lab used 10 patient-derived glioblastoma stem cell
cultures from Dirk's lab, and carried out what is termed as CRISPR 'cell
fitness screens'. This technique enabled the researchers to look for genes in
the cancer stem cells that are essential for cell growth and survival, which
therefore facilitate the progression of cancer.
"Cancer stem cells fuel the growth of tumors and
progression of the disease,"
says Angers. "In
order to effectively target these cells, having a comprehensive view of the
genes controlling the
growth programs is critical. If you know which genes are necessary for these
cells to survive and proliferate, you can then look at ways to attack or block
these genes and stop tumor growth in its tracks."
Findings of the CRISPR-Cas9 Experiments
the researchers at Anger's lab systematically knocked out each of the 20,000
genes - one gene at a time - in the glioblastoma cells from the 10 patients. They found that
multiple genetic vulnerabilities can lead to cancer
Of note is the fact
that the study is one of the first instances where CRISPR screens were
performed directly in parallel on multiple patient cells that had been freshly
isolated. Moreover, the study generated a huge amount of new data that could be
mined to identify novel drug targets for glioblastoma.
A gene, termed as DOT1L
, was crucial for persistence of the tumors
in 7 of the 10 glioblastoma patient cell cultures. The collaborators, led by
Dr. Weiss, tested the efficacy of a drug (Temozolomide
) that is used for treating
leukemia, in preclinical models for inhibiting the DOT1L
gene product in
glioblastoma stem cells.
"We found that blocking this specific protein in this
particular form of brain cancer reduced tumor growth and resulted in longer
survival in the preclinical model,"
says Angers. "This is promising because it uncovered a
biological process, not previously suspected to be implicated in glioblastoma,
for which a small molecule drug already exists."
substantial amount of time, effort and money have been spent in recent years
for sequencing the genome of cancer cells. While this has provided insights
into the mutations in glioblastoma cells, it has not resulted in advancements
in the development of treatments for this cancer. This indicates that
information about genetic mutations is not sufficient as this provides a static
picture of cancer.
study, therefore, highlights the fact that a better understanding of the
functioning of cancer cells as well as specific genes responsible for tumor
growth is essential, so that the tumor cells can be effectively targeted and
- Genome-Wide CRISPR-Cas9 Screens Expose Genetic Vulnerabilities and Mechanisms of Temozolomide Sensitivity in Glioblastoma Stem Cells - (https://doi.org/10.1016/j.celrep.2019.03.047)