Saturday, March 16, 2013

GENES MUTATED AT CHROMOSOME 8q IN PANCREATIC CANCER

1.CDH 17
The change in expression of this gene in advance pancreatic cancer does not come as a surprise
because by now we have become familiar with the fact that advance cancer is on the move and should metastasize, CDH belong to the Cadherin family, the family of adhesion molecule, cells need to detach and go. Takamura M et al. have shown that the Liver-intestine Cadherins reduction correlated with Colon cancer metastatic to lymph nodes.
CDH17 appears to be a gene of differentiation and could help determine the origin of of tissue in those ambivalent cases where we are dealing with an cancer of unknown primary.  It is a proton pump dependent cellular membrane structure.   What is fascinating is the fact that how quickly these structures are internalized or their stimulation effect is transmitted to the Nucleus at splicing center to be expressed as differentiation agents.
Zhu at al. have suggested that the hepatic Nuclear factor 1 and CDX2 participate in the regulation of CDH17 expression. (larger speculation Where is the p molecule counterpart? since this cadherin is on 8q) 

2. PSCA:  PROSTATE stem cell Antigen
When the prostate lends a hand to the pancreas you know this is bad news.  This antigen does not exist in the normal pancreas.  But when it appears in the Pancreas you know the disease is advanced.  Even in the Prostate the amplification of this antigen marks very high Gleason at presentation or bone Metastatasis.  It is not PSA we should be looking for, but PCR overexpression of PSCA.   By its name it says it all "Stem cell" meaning the cancer is now OMNIPOTENT and Incredibly resistant.  The presence of this antigen is not only predictive but also prognosis. The makers of SIPULEUCEL-T should be incubating patient dendritic cells  with with this antigen rather than PAP to be active in pancreatic cancers.

One interesting observation was made by Moore et al. while they were knocking down rats to further study this gene, they noted an over-expression of the AURORA kinases, these genes that regulate mitosis by controlling events at the Centrosomes.  It is interesting because it raises the possibility of using the PSCA as an indicator for use of Aurora inhibitors (Hesperadin, ZM447439,Tozasertib,VX680).  Also recent evidence of activity of Abraxane in Pancreatic cancer would open up the opportunity to use Abraxane in combination with Aurora kinase inhibitor in this disease.   Clearly if P53 is dysregulated, we can safely assume the Aurora kinase may have a role since they are more likely over-expressed.

SO: new target Therapy in Pancreatic cancer  ABRAXANE with an Aurora MutiKinase Inhibitor would be the next step if we want to introduce target therapy in Pancreatic cancers.

A recent TV documentary showed that a chemical compound that the EPA is investigating because it has contaminated the drinking waters in the USA caused cells to have Multiple Centrosomes in exposed cells, clearly is it affecting the AURORA and most likely AURORA A.  It raised the possibility that Metallic based chemical compound toxicity may have a larger weight on this pathways.  I wonder what Arsenic Trioxyde would add to this!   remember the anti-Aurora have a secondary anti-Histone (3) activity contributing to their effect in CML.

3. MYC:
*a GLOBAL AMPLIFIER OF ALL GENES INCLUDING PROLIFERATIVE GENES.
 *RECRUITER OF HISTONES DEACETYLASE PROTEIN
*OVERACTION OF CBF LIKE MOLECULES
*IT HAS IRES THE INTERNAL RIBOSOME ENTRY SITES WHICH IS THE KEY TO THE DOOR TO RIBOSOME FOR PROTEIN FORMATION (REGULATOR FOR MATION) AND HAS A THE ZIPPER TO ATTACH AND OPEN WIDE DNA FOR TRANSLATION.  OVER-EXPRESSION OF MYC DRIVES PROLIFERATION AT HIGH PACE!

WIKIPEDIA SAYS IT ALL
Myc protein is a transcription factor that activates expression of many genes through binding on consensus sequences (Enhancer Box sequences (E-boxes)) and recruiting histone acetyltransferases (HATs). It can also act as a transcriptional repressor. By binding Miz-1 transcription factor and displacing the p300 co-activator, it inhibits expression of Miz-1 target genes. In addition, myc has a direct role in the control of DNA replication.[4]
Myc is activated upon various mitogenic signals such as Wnt, Shh and EGF (via the MAPK/ERK pathway). By modifying the expression of its target genes, Myc activation results in numerous biological effects. The first to be discovered was its capability to drive cell proliferation (upregulates cyclins, downregulates p21), but it also plays a very important role in regulating cell growth (upregulates ribosomal RNA and proteins), apoptosis (downregulates Bcl-2), differentiation and stem cell self-renewal. Myc is a very strong proto-oncogene and it is very often found to be upregulated in many types of cancers. Myc overexpression stimulates gene amplification,[5] presumably through DNA over-replication."
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