Tuesday, February 26, 2013


Those of us who had treated metastatic colon cancer know that patients only dies when you have exhausted possible options. It is sobering moment to see a human being deteriorating before your eyes while you have nothing to offer!
So,  when something new comes along that appears effective, we embrace it in this disease.   We know our patients will be offered it at one given point.  Colon cancer seems to wait until you have finished all you can do!  This behavior is particular as opposed to lung cancer which appears to kill despite your doing!
The power of Regorafenib seems to reside in the number of kinases affected by this drug:VEGFR3, TIE2, PDGFR, FGFR, KIT and RET.
Through KIT, it has found its Approval for GIST.
A slew of Genes are affected by this drug (on top of those mentioned, DDR2, TrK2A, Eph2A, RAF-1,BRAF, BRAF v600E, SAPK2,PTK5, and Abl) have been included in its repertoire.

The CORRECT trial introduced us to this drug in Metastatic colon cancer.  Thumbs up!
Dose approved: 160 mg orally daily!

DDR2 has been commented on plenty here in various notes!
TrK2A seems to relate to transmembranes channel allowing survival in low K+ conditions
Eph2A is downstream the MAPK and is the feedback regulator. once activated it comes back on its membrane receptor and sens inhibitory influx to shut down the MAPK.  Cancer quickly desactivates this  to keep the signal transduction pathway on.  It kinds of remind me of the Sons of the Sevenless (my favorite).
(to be continued)

Regorafenib, the power of a good Multikinase,  the next generation Multikinase!

Remember RAS-RAF-MAPK, while  c-RAF is RAF-1, people are more talking about b-RAF or BRAF.

"-The phosphorylated form of RAF1 (on residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2-antagonist of cell death at 'Ser-75'.
- Phosphorylates adenylyl cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation. Phosphorylates PPP1R12A resulting in inhibition of the phosphatase activity.
- Phosphorylates TNNT2/cardiac muscle troponin T. Can promote NF-kB activation and inhibit signal transducers involved in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and angiogenesis (RB1).
-Can protect cells from apoptosis also by translocating to the mitochondria where it binds BCL2 and displaces BAD/Bcl2-antagonist of cell death.
-Regulates Rho signaling and migration, and is required for normal wound healing. Plays a role in the oncogenic transformation of epithelial cells via repression of the TJ protein, occludin (OCLN) by inducing the up-regulation of a transcriptional repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts caspase activation in response to selected stimuli, notably Fas stimulation, pathogen-mediated macrophage apoptosis, and erythroid differentiation."  (Reviewed, UniProtKB/Swiss-Prot)

Abnormality at RAF-1 causes the NOONAN and the LEOPARD syndromes,  "short stature" from genetic stand point, gives you the largest gift in genetic finding.  Again do not discriminate and round up short stature people!

It is the stress induced MAPK-8 or c-JUN, block ubiquitination of P53 and therefore up-regulates it.
By involving SAPK-1, Regorafenib is indeed one of the rare drug that can impact growth factors, cyclins, TNF in a more significant way in diseases where this pathway is very amplified (from cancer to inflammatory disease and infections!)
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