A team of researchers from the Gustave Roussy Cancer Campus and Inserm in Paris, MRC Molecular Hematology Unit and the MRC Weatherall Institute of Molecular Medicine at the University of Oxford in UK, Memorial Sloan Kettering Cancer Center in USA and Celgene in USA have mapped the family trees of cancer cells in AML to cognize how this blood cancer responds to enasidenib, a new drug.
Enasidenib
is an Isocitrate Dehydrogenase 2 Inhibitor. Upon administration,
enasidenib specifically inhibits various mutant forms of IDH2, including
the IDH2 variants R140Q, R172S, and R172K, which inhibits the formation
of 2-hydroxyglutarate (2HG). This may lead to both an induction of
cellular differentiation and an inhibition of cellular proliferation in
IDH2-expressing tumor cells.
Acute myeloid leukemia
(AML) is a type of cancer in which the bone marrow makes abnormal
myeloblasts (a type of white blood cell), red blood cells, or platelets.
About 12-15% of AML patients have a mutation in the IDH2 gene that
stops bone marrow cells from differentiating or maturing into blood
cells that are required for life and the immature cells accumulate in
the bone marrow and blood. Previous research done by the same team
showed that enasidenib elicit blood cell differentiation and restores
normal blood cell production.
A phase I/II clinical trial showed that the drug was effective in 40% of AML patients with an IDH2
mutation who had failed other treatments which led the US FDA to
approve enasidenib in 2017. However, after an average of nearly nine
months, the cancer has returned in these patients.
Using
samples from 37 patients in the trial who had responded to enasidenib,
the researchers looked at the markers on the surface of the bone marrow
cells to identify the different populations of bone marrow cells, from
the immature, undifferentiated cells, through to mature, differentiated
cells. Using specialized techniques,
the researches have studied how the bone marrow fails to do its duty
and how enasidenib helps in promoting differentiation to make bone
marrow function properly. As AML is caused due to errors in DNA sequence
or mutations in blood cells, the team studied the genetic make-up of
AML cells. They found that AML cells from the same patient can be
grouped into families which share genetic mutations called clones. Cells
belonging to the same clone or family, come from the same ancestor
cell. Understanding how clones relate to each other will provide
information as to how the AML started first.
“When
an AML patient has a bone marrow test, we are taking a snapshot of the
family tree of leukemia cells,” said Dr Quek. “As we treat the AML,
there are shifts in the family dynamics as some clones will die and
others will grow. In every cancer there are several families or clones
of cancer cells. In AML we were able to see how these responded to
enasidenib. We used techniques to study genetic mutations on a
cell-by-cell basis, and re-constructed the family tree of a patient’s
AML. We then tracked changes in the family of AML cells as they
responded to enasidenib and as patients lost response to the drug. This
is the first time that anyone has done such a detailed study at a single
cell level. As enasidenib is a new anti-leukemic drug, it was vital to
understand the effects of the drug on leukemic cells.”
Dr
Virginie Penard-Lacronique, research director and team leader at the
Inserm unit at Gustave Roussy, said: “We have provided genetic proof
that enasidenib was able to differentiate cancer cells so that some of
their normal functions were restored, even though they still contained
the IDH2 mutation. This is important because unless we can track these
clones, we don’t know whether the mature cells in a patient are coming
from normal cells after all the cancer cells have been killed or from
leukemic cells that are now able to mature.”
The
Cancer returned in almost all the patients in the clinical trial, and
the team showed that the leukemic cells stop responding to enasidenib
when some of the clones develop additional mutations. These new
sub-clones were resistant to enasidenib, providing clues about the
mechanism of drug resistance. This may help in designing future therapy
trials to overcome therapy resistance. It may also mean that enasidenib
needs to be combined with other anti-cancer drugs to prevent relapse.
For more details, PS: https://hematology.cmesociety.com/ | https://worldhematology.wordpress.com/ | https://hematology.cmesociety.com/conference-brochureSource: https://www.news-medical.net/news/20180717/Researchers-map-family-trees-of-cancer-cells-to-understand-how-AML-responds-to-new-drug.aspx | https://pubchem.ncbi.nlm.nih.gov/compound/Enasidenib#section=Top | https://www.cancer.gov/types/leukemia/patient/adult-aml-treatment-pdq
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