Hi.
Just stumbled across this article. Published a while back but just recently made available online.
https://www.nature.com/articles/s41467-017-00984-9
I know it is still about saving mice ;), but it is indeed interesting given the preliminary results.
However I can´t really distill whether ABT263 is an existing drug developed for other purposes (http://www.selleckchem.com/products/ABT-263.html), if it is experimental but in human trials or if its experimental and to this point only applied to xenographs.
Any views/perspectives on the application of ABT-263?
The name given to this drug is navitoclax. It is in clinical trials for solid and liquid cancers (but no trials specifically for brain tumors).
ReplyDeletehttps://clinicaltrials.gov/ct2/results?cond=&term=navitoclax&cntry1=&state1=&recrs=
Another drug in this class, venetoclax, was FDA approved for chronic lymphocytic leukemia in 2016.
"Clinical development of the first BCL-2 inhibitor, navitoclax, was halted due to dose-limiting thrombocytopenia. The thrombocytopenia was determined to be secondary to inhibition by navitoclax of the antiapoptotic protein Bcl-xL, which is essential for controlling the fate and function of platelets. Venetoclax represents a chemical modification of the structure of navitoclax, in that it targets the BCL-2 overexpression characteristic of CLL while sparing Bcl-xL in circulating platelets.[5] The direct binding of venetoclax to the BCL-2 protein gives the drug a more favorable toxicity profile."
ReplyDeletehttp://www.cancernetwork.com/oncology-journal/novel-and-expanded-oncology-drug-approvals-2016-part-2
The study published in Nature Communications that is the subject of the original post in this thread (https://www.nature.com/articles/s41467-017-00984-9.pdf Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL), tested both navitoclax (ABT-263) and venetoclax (ABT-199) in IDH1-mut cells, and they found that the IDH1-mut cells were selectively sensitive to navitoclax, but not to venetoclax. The main difference between these two drugs is that navitoclax is a dual inhibitor of BCL-XL and BCL2, while venetoclax is a selective inhibitor of BCL2.
So unfortunately, the characteristic that caused navitoclax to be abandoned in favor of venetoclax for CLL treatment, is the same characteristic that makes navitoclax more useful for IDH1-mut gliomas according to the study in Nature Communications - the ability to inhibit BCL-XL.