Drug Detail

Information about Gleevec

Generic Name	Imatinib + Panobinostat
IND	STI571 + LBH589
Brand Name (US)	Gleevec
Manufacturer	Novartis + Novartis
Drug Type	Tyrosine Kinase Inhibitor
Delivery	Oral
Approval Status	Gleevec is approved for GIST. This combination is in a phase 1/2 trial for GIST.
Indications
Overall Strategy	KIT Protein + GIST cell based
Strategy	Block KIT + Unblock cell death genes + Destroy KIT
Drug Category	HDAC inhibitor + KIT/PDGFRA inhibitor

Work presented at the Life Fest meeting in Dallas, showed that a histone deacetylase (HDAC) inhibitor was able to cause significant regression in a Gleevec-resistant xenografts model (mouse model). HDAC inhibitors are a new class of drugs that have shown anti-cancer activity in several ways:

* Inducing apoptosis
* Arresting the cell cycle

By destabilizing certain cancer-causing proteins such as bcr-abl (and possibly KIT). This may occur because HDAC inhibitors cause hsp90 to become inactive, possibly resulting in the destruction of the KIT protein.

Another way that HDAC inhibitors might accomplish their effects is by “turning on” some tumor suppressor genes that have been silenced.
HDAC inhibitors are in various stages of development. Panobinostat is the only HDAC inhibitor that is in a GIST-specific trial (in a combination with imatinib).

Deibec-Rychter et al, have shown that HDAC inhibitors are able to cause significant regression in a Gleevec-resistant xenograft model. Bauer et al have shown that LBH589 has antiproliferative and proapoptotic effects in IM-sensitive and IM-resistant KIT+ GIST. In this study, the antiproliferative effects of LBH589 were 22-38x stronger that SAHA (vorinostat/Zolinza).