REGORAFENIB, A DEFINITIVE ADVANCEMENT IN CANCER MEDICINE!

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!
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RAF-1 OR c-RAF

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

RAF-1
"-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!

SAPK-1
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!)

Managing the loopholes in the cell cycle

Cure to cancer is within reach and is within the management of LOOPHOLES. Cancer cells have within their pathways, redundancy that protects these pathways to maintain life of the malignant cell. You close one door, just to see another one open up to ensure that the life of the cancer cell is maintained. So, unless you hit a critical pathway with no escape routes, the treatment result will be partial and temporary. To succeed we need to hit several targets in total and and sometimes sequentially to impose on the cell to choose the path to its natural death (apoptosis). So most treatments which are limited to one or only a few targets prove partially and temporary effective. This is why building an electronic Cell and being able to put in all the pathways and observe where they lead to, what doors open and which ones are closed or closing, which are critical and which lead to apoptosis (natural cell death) is crucial. Which sequence of shut down leads to sure cell death? Right now we are at the step where we are learning about shutting or opening one door and evaluating the sequence of events that follow. But with our model in hand, we can be more comprehensive in our approach. The model will help determine effects on cancer cells by shutting several doors at once, "closing Loopholes" as Tax people would love to say. This approach with target therapy has led to breaking resistance to certain types of cancers that were notoriously resistant. Today, we are starting to have response rates in Melanoma. We have double or triple longevity in Chronic Myeloid Leukemia, GIST, Myeloma etc...Just wait to see what we will get once we manage to give Multistage Multitarget Therapies (MMT). Cure is within the management of Loopholes!