Hello all,
I've not fully understood how mIDH1-inhibitors work? I know they reduce 2-HG levels but does that lead to tumour regression, or is there some other mechanism simultaneously?
I've been looking into different mIDH1-inhibitor trials, but have doubts if they work as monotherapy?
Br,
Juha
In leukemia trials, IDH inhibitors are found to cause cell differentiation. The simple definition of cell differentiation is "The normal process by which a less specialized cell develops or matures to possess a more distinct form and function." In cancer therapy, cell differentiation is a good thing.
ReplyDeletehttp://www.bloodjournal.org/content/early/2017/06/05/blood-2017-04-779447?sso-checked=true
Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response
[Enasidenib was previously known as AG-221, and is an inhibitor of mutant IDH2]
The accumulation of 2-hydroxyglutarate has many different effects, including a blocking of cell differentiation.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465106/
In fact the very first paper on a small molecule mutant IDH inhibitor for glioma was entitled "An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells"
https://www.ncbi.nlm.nih.gov/pubmed/23558169
Differentiation therapy can be very effective for some types of cancer, and is the standard treatment for acute promyelocytic leukemia, which is treated with all trans retinoic acid, a differentiating agent.