Drug Detail

Information about Zolinza + Nexavar

Generic Name	Vorinostat + Sorafenib
IND	Vorinostat + BAY 43-9006
Brand Name (US)	Zolinza + Nexavar
Manufacturer	Merck + Bayer
Drug Type	Tyrosine Kinase Inhibitor
Delivery	Oral
Approval Status	Both are approved. This combination is not approved for GIST. It was evaluated in a phase 1 trial for non-GIST cancers.
Indications
Overall Strategy	GIST cell based
Strategy	Block KIT + Unblock cell death genes + Destroy KIT
Drug Category	HDAC inhibitor + KIT/PDGFRA inhibitor

Recent research has shown that histone deacetylase (HDAC) inhibitors were able to cause significant regression in a Gleevec-resistant xenografts model (mouse model) and GIST cell lines. HDAC inhibitors are a new class of drugs that have shown anti-cancer activity in three major 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 and none are in GIST specific trials.
Sorafenib has been shown to be a potent KIT inhibitor with activity against many of the secondary mutations that cause resistance to GIST, including the T670I gatekeeper mutation. It also reduces blood vessel formation by inhibiting the VEGF receptors and PDGFRB.
Sorafenib also appears to a cell survival protein, Mcl-1, but it is unknown if this protein is important in GIST.
In a 2007 study of CML cells (Dasmahapatra, et. al), the combination of sorafenib and vorinostat synergistically killed CML cells if given in the right sequence (vorinostat followed by sorafenib). See link.