Saturday, March 30, 2013

Esophageal Cancer (continued)

We have discussed that chemical, traumatic and sometimes burns from caustic solutions that people ingest unfortunately, that will stimulate the cellular membrane receptors which in turn will stimulate RAS, which in turn will amplify PI3K, MAP Kinase and RAL/CDC42.   But remember these are stressful stimulations, so instead of the standard MAPK, the stimulation is imposing on RAS to awake the NFkB pathway, the c_JUN and at nuclear level the FOS which results in inflammatory proteins stimulation including cyclin production or liberation from membranes with extracellular release of Metalloproteases. Cyclins combining to CDCs will exacerbate cell divisions and proliferation, growth factors will promote cell growth, there is an associated ligase proliferation that will impact P53 (through MDM2) and  c-MYC, NOTCH, and even c_JUN itself through FBW7/hCDC4.  This is how the proteasomes come into play!

By now you now
1. that amplification of c-MYC exacerbate proliferation by allowing progression of cells int S-phase and bolster DNA replication, imparting bad prognosis to cancer cells.
(nature is kind and gies you a chance to affect here by freeing RB1 and increasing FBW7.  Oh! also find MYCN and the p isoform to q for answers!)

2 Rb1 does sequester E2F.   you can look at it both ways.  that E2F stabilize Rb1 instead,  whichever way one stop the other for acting!   Remember E2F activates CPP32 which increase APOPTOSIS!  (DRUM UP THOSE TARGET THERAPY!)

3.REMEMBER RAS NEEDS A FATTY ACID MOIETY TO STAY AT THE MEMBRANE FOR ITS ACTIVITY (THIS IS ITS SO CALLED POST-TRANSLATIONAL MODIFICATION) BY THIS PHRENYLATION IS IMPAIRED BY THE FARNESYL TRANSFERASE INHIBITOR
(ie. TIPIFARNIB) THAT WE DO NOT USE ENOUGH I FEEL!  ALTHOUGH I AGREE THAT SIDE EFFECTS MAY BE PROHIBITIVE GIVEN THE EXTENT OF WHICH NORMAL CELLS WILL ALSO BE COMPROMISED.  BUT IT GOES TO THE FACT THAT WE NEED TO FURTHER TWEAK THIS MODALITY TO MAKE IT USABLE IN CANCERS!
ANTI-MEK HAVE DEMONSTRATED USE IN KRAS MUTATION CANCERS!  MAY BE ESOPHAGEAL CANCERS WILL BENEFIT HERE!

4Role of combining Velcade and Carfilzomib in Esophageal cancer to see if c-Myc can be affected?   Will it increase the right Ligand (FBW7)?
Post a Comment