- Combination of CDK 12 (cyclin dependent kinase 12) inhibitor and
PARP (poly ADP ribose polymerase) inhibitor shown
to be very effective in controlling Ewing Sarcoma
- Ewing sarcoma is the second most
common bone cancer in children and young adults but unfortunately is not
very responsive to conventional chemotherapy
Novel combination of CDK inhibitor and
PARP inhibitors have been found to be very effective in controlling growth of
Ewing sarcoma cells and could be potential game changer in treatment of this
"No one has previously considered
CDK12 inhibition as a way to combat Ewing sarcoma," says Kimberly
Stegmaier, MD, senior author of the new Cancer Cell
that describes the findings.
Drug Screen Results For
Ewing Sarcoma - The Initial Step
field of pediatric oncology has long
been challenged by the dearth of promising new drugs
and in addition, Ewing
sarcoma is not very responsive to conventional chemotherapy. These factors prompted the research team to do a wide ranging drug screen and found a
possible link between CDK 12 inhibition
and Ewing sarcoma.
‘CDK 12 inhibitors not only slow tumor growth and progression in Ewing sarcoma, but also make the cancer cells highly responsive to PARP inhibitors.’
abnormalities in genes that encode for transcription factors, shape-shifting
proteins that bind to DNA sequences to activate or repress gene
expression," says Stegmaier, who co-directs the pediatric hematologic
malignancy program at Dana-Farber/Boston Children's and is a member of the
Broad Institute's Cancer Program. "Due to their disordered physical structure, transcription factors have largely
eluded drug discovery
"CDK12 is known to be important for
gene regulation, so we wondered why the EWS/FLI fusion protein might engender sensitivity
to CDK12 inhibitors," Stegmaier says.
Testing the Role Of CDK
12 Inhibitors In Mice
- CDK12 inhibitors were found to
greatly retard tumor growth and progression and prolong survival rates of
mice models of Ewing sarcoma tumors.
Sifting through the scientific
literature, they also came across another interesting link between CDK
12 inhibitors and ovarian cancer.
According to earlier studies, ovarian
tumors with CDK-12 protein
inactivating gene mutation were found to be highly sensitive to FDA-approved
drugs called PARP (poly
ADP ribose polymerase) inhibitors
, which block the
activity of PARP proteins that play a role in DNA damage repair and other
cellular processes in cancer cells.
Following this piece of scientific
information, postdoctoral fellow Amanda Balboni Iniguez, PhD, who led the team
hypothesized that inhibition of CDK12 in Ewing sarcoma could serve a double-whammy clinical benefit
slowing down the growth of Ewing cells, as well as rendering
them susceptible to killing by PARP inhibitors.
- Testing the combination of CDK 12 inhibitors and PARP inhibitors in mouse
models of Ewing sarcoma and cultures of Ewing
sarcoma tumor cells in dishes, the team was pleasantly surprised to
note that there was a dramatic response and indeed some mice were even cured of the disease.
combination of CDK12 and PARP inhibitors showed no adverse effect on the
bone marrow of the mice. This was in
contrast to the earlier finding where PARP inhibitors were found to be
associated with serious bone marrow toxicity when given with conventional
Thus the findings of this study, namely that
Ewing sarcoma cells can be controlled by CDK 12 inhibitors and made them highly
sensitive to killing by PARP inhibitors with minimal or no toxicity.
In conclusion, the findings of this study
warrant further clinical trials to establish its safety and efficacy in humans.
"PARP inhibition is already
FDA-approved for use in certain cancers, and inhibitors of CDK12 and other CDK
proteins are in early-phase clinical testing," Stegmaier says. "If
they are proven to be safe in adults, I hope we can extend testing to children
with Ewing sarcoma."
Ewing sarcoma -
Molecular Pathology Involved
- In Ewing sarcoma there is a defect
(mutation) involving two genes resulting in an abnormal fusion transcription factor called EWS/FLI.
- The EWS/FLI transcription
factor totally disrupts normal cell division by activating normally
inactive regions of DNA, turning on genes that are supposed to be quiet,
at the same time turning off genes that should be active, thus creating disorderly multiplication of
cells leading to cancer.
"In Ewing sarcoma and other cancers
involving transcription factor fusion 'onco-proteins' like EWS/FLI, these mutated transcription factors drive
abnormal cell behavior and tumor growth
," Stegmaier explains.
- The emerging roles of CDK12 in tumorigenesis - (https://celldiv.biomedcentral.com/articles/10.1186/s13008-017-0033-x)
- PARP inhibitors - (http://www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/targeted-cancer-drugs/types/PARP-inhibitors)
- CDK inhibitor - (https://en.wikipedia.org/wiki/CDK_inhibitor#Approved)