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!)
Showing posts with label regorafenib. Show all posts
Showing posts with label regorafenib. Show all posts
Tuesday, February 26, 2013
Monday, February 25, 2013
NEWS FROM THE FDA!
1.PEGINESATIDE A DRUG INDICATED FOR ANEMIA OF CHRONIC RENAL FAILURE HAS BEEN PULLED FROM THE MARKET BECAUSE OF 3 DEATHS FROM ANAPHYLACTIC SHOCK REPORTEDLY.
2.REGORAFENIB, APPROVED IN METASTATIC COLON CANCER, JUST GOT APPROVED BY THE FDA FOR REFRACTORY GIST TUMOR AFTER FAILURE OF GLEEVEC AND SUTENT.
"The most common adverse effects reported with regorafenib are weakness and fatigue, hand-foot syndrome, diarrhea, loss of appetite, high blood pressure, mouth sores, infection, changes in voice volume or quality, pain, weight loss, stomach pain, rash, fever, and nausea."
FROM MEDSCAPE:
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IN OTHER NEWS,
18 MONTHS ANDROGEN DEPRIVATION WAS COMPARBLE TO 36 MONTHS FOR SURVIVAL AFTER 77 MONTHS OF OBSERVATION WITH ABOUT 25% OF PATIENTS DYING FROM LOCALLY ADVANCED POOR PROGNOSIS PROSTATE CANCER. WITH POOR PROGNOSIS DEFINED AS PSA>20 AND GLEASON>7 ACCORDING TO CANADIAN RESEARCHERS!
1.PEGINESATIDE A DRUG INDICATED FOR ANEMIA OF CHRONIC RENAL FAILURE HAS BEEN PULLED FROM THE MARKET BECAUSE OF 3 DEATHS FROM ANAPHYLACTIC SHOCK REPORTEDLY.
2.REGORAFENIB, APPROVED IN METASTATIC COLON CANCER, JUST GOT APPROVED BY THE FDA FOR REFRACTORY GIST TUMOR AFTER FAILURE OF GLEEVEC AND SUTENT.
"The most common adverse effects reported with regorafenib are weakness and fatigue, hand-foot syndrome, diarrhea, loss of appetite, high blood pressure, mouth sores, infection, changes in voice volume or quality, pain, weight loss, stomach pain, rash, fever, and nausea."
FROM MEDSCAPE:
-----------------------------------------------------------------------------------------------
IN OTHER NEWS,
18 MONTHS ANDROGEN DEPRIVATION WAS COMPARBLE TO 36 MONTHS FOR SURVIVAL AFTER 77 MONTHS OF OBSERVATION WITH ABOUT 25% OF PATIENTS DYING FROM LOCALLY ADVANCED POOR PROGNOSIS PROSTATE CANCER. WITH POOR PROGNOSIS DEFINED AS PSA>20 AND GLEASON>7 ACCORDING TO CANADIAN RESEARCHERS!
Friday, December 21, 2012
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