Hsp90 & CML Protein (Bcr-ABL)

[Guest guest]

Something interesting I just discovered about CML treatment:

Hsp90 is a chaperone protein whose function is to stabilize client proteins such

as Bcr-Abl, HER2, AKT, and c-raf. Acetylation of hsp90 via inhibition of HDAC6

interferes with this function, thereby leading to the degradation of these

oncogenic client proteins.[2] Exploiting this activity against hsp90 has

exciting implications for the treatment of a number of different solid and

hematologic malignancies. For example, in the case of chronic myelogenous

leukemia (CML), mutations within the kinase region of Bcr-Abl confer resistance

to treatment with the available tyrosine kinase inhibitors (TKI) such as

imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna). Of particular

concern is the T315I mutation, which causes steric hindrance and insensitivity

to the standard therapeutic agents. In vitro studies have demonstrated that

treatment with HDAC inhibitors in combination with a TKI leads to enhanced

apoptosis and depletion of Bcr-Abl levels in imatinib-resistant CML cells,

including those harboring the T315I mutation.[3] Based on these data, a phase I

study is currently ongoing to evaluate the combination of vorinostat (Zolinza)

plus dasatinib in patients with CML in accelerated or blastic phase

(ClinicalTrials.gov Identifier: NCT00816283). "

Assistant Professor

Department of Medicine

UMDNJ – Wood Medical School

Cancer Institute of New Jersey

New Brunswick, New Jersey| February 9, 2010. Financial Disclosure: The authors

have no significant financial interest or other relationship with the

manufacturers of any products or providers of any service mentioned in this

article.

http://www.searchmedica.com/resource.html?rurl=http%3A%2F%2Fwww.cancernetwork.co\

m%2Fdisplay%2Farticle%2F10165%2F1521049 & q=February+2010+-+CML & c=on & ss=cancerNetw\

orkLink & p=Convera & fr=true & ds=0 & srid=1

FYI,

Lottie Duthu