Sunday, December 9, 2012


As I am listening to DRS Irene Ghobrial and Paul Richardson discussing about a difficult case of refractory Myeloma, a blood cell cancer involving plasma cells, I am increasingly struck by the fact that blood cell disorders seems to respond to treatment aimed at steps in the signaling cascade starting at the membrane, deep into the cell at the nuclear level.  In Myeloma, signal pathways and interaction with the stromal milieu of cancer cells, seems to be the Trend. Here our 5th law seems to predominate.  Everything is added to Velcade to work.  Proteasome inhibition is king.   But as soon as you enter leukemia and lymphoma, we are back to the 1st and 2nd law where destruction of DNA and microtubules appears to be the current predominant approach.  Whether this emphasis on attack of Signal transduction versus DNA destruction is imposed by research or driven by what works in the clinic, is clearly not sure.  It could also be due to the type of abnormality happening within the cell.
The first impression is that in Myeloma, signal transduction is the major disturbance area, where in Myelodyspasia and leukemia, transcription factors (TF) (ACTIVITY OF VIDAZA/DECITABINE SUPPORTS THIS) and nuclear DNA disturbances appear to be major causal forces .  In solid tumor, because of the need for  mass creation,  epidermal/ membranous phenomena (events and composition of receptors at the membrane) and nuclear and perinuclear (TF) events appear to be the main areas of disturbance.  Signal transduction, globally secondary to membrane receptor stimulation, seem less important, although genetic heterogeneity in various individual make them  more or less signal transduction interruption susceptible.

As we move forward, drugs are being develop to hit hundreds of targets in chain of reactions steps which follows a circuitry in cascade.  We are plugging here while unplugging there. sometime we are applying multiple plugs at the same time (ie Muti-kinase inhibitors). Computer models will help here.  What we don't know yet is whether the sequence of plugging is important to stop (full language of the cell) major escape mechanisms for the survival of cancerous cells.  Already major trends are being discovered as covered by our proposed various laws.  The fight is on, let's keep working.

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