STRATIFIN (IN OVARIAN CANCER)

LAM et al.

 " Stratifin, also known as 14-3-3 sigma protein, stimulates matrix metalloproteinase (MMP)-1 expression in dermal fibroblasts.  Treatment of dermal fibroblasts with stratifin resulted in rapid and transient upregulation of c-jun and c-fos mRNA levels.  Stratifin was demonstrated to increase MMP-1 protein levels. Microarray analysis of stratifin-treated fibroblasts shows an increase in Elk4/Sap1 mRNA expression and this finding was confirmed by northern blot analysis. Our results indicate that stratifin markedly increase Elk4/Sap1 mRNA expression in a time-dependent fashion. In conclusion, stratifin stimulates fibroblast MMP-1 levels through the activation of c-fos and MAPK pathway."

Our interpretation is that stratifin is part of an intergrin, its release in the Cytoplasm indeed stimulate MAPK C-JUN and c-fos.  This means it is interpretated by the cell as a chemical stressor. The NF-kB is not far away.  One of the most important hidden information here is the note by the authors that there is an increase of ELK4/Sap1.

ELK4 has been shown to interact with Serum response factor^[4][5] and BRCA1.^[6]

Serum response factor has been shown to interact with NFYA,^[10] Src,^[11] CREB-binding protein,^[12] GTF2I,^[13][14] ATF6,^[15] Nuclear receptor co-repressor 2,^[16] CEBPB,^[17][18] GATA4,^[19][20] Myogenin,^[21][22] GTF2F1,^[23][24] TEAD1,^[25] ELK4,^[15][26] Promyelocytic leukemia protein^[12] and ASCC3.^[27]

(wikipedia)

(PLEASE, WHEN A MOLECULE INTERACT WITH THIS MANY MOLECULE, IT IS A PERFECT, LEGITIMATE TARGET FOR THERAPY, AND SFR DOES)

ELK4 therefore control BRCA1 and serum response factor which control NFYA.  This uncover what the cancer cell has to do to start the neoplastic process.  It has to derail genetic repair by abrogating the action of BRAC1, but it also has to take controles of CBF complexes  and NFYA and ZHXY.  Remember CBF complexes control the direction of the metabolism, In essence, when it comes to function in the cell,  the role of Core Binding Factors (CBF) is indistinguishable from that of TRANSCRIPTION FACTORS.  They all impose the direction that the cell metabolism should take.

Remember also that because the Stratifin engages the MAPK mostly through the certain well selected CDK, it will tend to stop cell division.  In Breast cancer, Stratifin is one of the earliest methylated gene slated for silencing.

CDO1:
 Cysteine dioxygenase type I, IS A GENE CONTROLLING  CYSTEIN METABOLISM. DEEP ANALYSIS BRINGS THIS GENE TO ELECTRON EXCHANGE FOR THE FORMATION OF CYTOCHROME C, THE WAY TO APOPTOSIS.  THE CANCER CELL QUICKLY METHYLATES THIS GENE EARLY AND MUTATION HAS BEEN LINKED TO PROGNOSIS
 (WORK FROM CORNELL UNIVERSITY)

Nomenclature of 2 important genes in Ovarian cancer !

1.RASSF1A:  One of the thing cancer cell do is to Methylate some genes in order to block its path to death.
it appears this gene is a critical door to shut or disable.  It not only decrease the significance of RAS and MAPK in the pathogenesis of tumor that harbor this mutation.   It also remove blockage to proliferation by desensitizing the cell to the effect of P53, Cyclins.  Desensitize the cell to Death Receptor 6 and its Fas connection.  RASSF1a, demethylation is a valid target in ovarian cancer.

2.HNF1B:  " Hepatocyte Nuclear Factor 1α (HNF1α) is an atypical homeodomain-containing transcription factor that transactivates liver-specific genes including albumin, α-1-antitrypsin and α- and β-fibrinogen. Biallelic inactivating mutations of HNF1A have been frequently identified in hepatocellular adenomas (HCA), rare benign liver tumors usually developed in women under oral contraceptives, and in rare cases of hepatocellular carcinomas developed in non-cirrhotic liver. HNF1α-mutated HCA (H-HCA) are characterized by a marked steatosis and show activation of glycolysis, lipogenesis, translational machinery and mTOR pathway. We studied the consequences of HNF1α silencing in hepatic cell lines, HepG2 and Hep3B and we reproduced most of the deregulations identified in H-HCA."
 (Laura Pelletier et al)
This gene is the gene of differentiation for liver formation, it has the structure of a CBF (core binding Factor) therefore has a subunit binding the DNA, therefore silencing that portion, and another subunit having locations for enzymatic proteins or molecular structures that directly assume various functions intended by the cell (formation of Albumin, alpha Antitrypsine, and Beta Fibrinogen).
Interestingly enough, Steatosis is a prominent feature here.  This structure and gene may be of interest in LIPOSARCOMA?  
DOES ACTIVATION OF MTOR DEMONSTRATED HERE OPEN THE DOOR TO THE USE OF MTOR IN LIPOSARCOMA?

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!)

A PEEK INTO THE FUTURE!

The article published in the Lancet about Taxotere combined to Selumetinib in 2nd line treatment of lung cancer, opens the door to future therapy to come.  It marks the increasing trend of incorporating Target therapy to standard good old chemotherapy.  Selumetinib is a MEK inhibitor downstream from KRAS.
Already the results are impressive with the doubling of progression free survival and Overall survival.
Already, we have a peek to a new set of toxicity because these are new combinations and the outlook is grim now with almost half of the patients having Nausea, diarrhea, severe Neutropenia and stomatitis.
Not only is MEK down stream from RAS-RAF-MEK-ERK (MAPK) signaling pathway; it is the revolving door between epidermal presentation which should block Metastatic spread and Endodermal transformation that the Cancer chooses to metastasize.
Another question that will rise immediately is if we have a driver mutation, when should we stop inhibiting such target, when do we stop closing this revolving door? The rising need of maintenance therapy follows.  In lung cancer, Alimta, Tarceva and Taxotere have all shown to be beneficial in maintenance setting.  So the choice here would be Taxotere maintenance, or should we continue to push closed MEK with Selumetinib?
This article emphasized the fact that this was the first time that KRAS was used as a biomarker for  Target therapy.  Very true, but mesenchymal transformation and angiogenesis play a role in almost every cancer.
THE FIGHT IS ON.

(LAST POINT: WE HAVE NOT LEARNED ENOUGH ABOUT HOW TO PREVENT THESE SIDE EFFECTS, WE NEED TO STEP UP!)