65) This disorder is variably known as chronic eosinophilic leukemia or myeloproliferative HES, among other names, but is recognized in the 2008 WHO classification as myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB
, or FGFR1.
Identify the most promising approaches to kinase modulation in cancer and other diseases by examining drug targets including ABL1, EGFR, ERBB2, FLT3, KIT, PDGFRA, PDGFRB
, FLT1, FLT4, KDR, JAK2, MET, AKT1, CDC2, CDK2, AURKA, AURKB, PLK1, FRAP1 and PIK3CA.
Those changes included the fusion of a gene named EBF1 to the tyrosine kinase gene PDGFRB
In this "rational design approach," Cheresh and his co-workers used the supercomputer at the San Diego Supercomputer Center to custom-design molecules that stabilized the inactive forms of two similar kinases, PDGFRB
and B-RAF - both of which are found to be activated in tumours and in blood vessels that feed tumours.
These kinases included Raf kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFRB
, KIT, FLT-3 and RET.
In a phase II open-label trial--Study B2225, the largest study involving patients with DFSP)--imatinib mesylate, an inhibitor of PDGFRB
, was found to be safe and effective in the treatment of patients with locally advanced and metastatic DFSP tumors containing t(17;22) translocation.