LBK1, A CONFUSING MARKER OF CANCER
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In lung cancer, Harvard researchers have pushed us now to request a lengthy list of Markers in order to direct our treatment.  The many options of therapeutic interventions have to be selected more sharply as new Driver mutations are discovered and new Target therapy drugs are made available.  We made a summary of drugs and their relevant Driver Mutations in our previous blog. (KRAS, EGFR, ALK, HER-2, BRAF, ROS-1,RET, MEK-1,NRAS, MET etc. for Driver Mutations.....Medications included Erlotinib, Gefitinib, Herceptin, Lapatinib, Veramufenib, Cabozantinib, Crizotinib etc. - SEE OUR BLOG)

But for a while, 5 Mutations were mostly adopted: KRAS, BRAF, EGFR, ALK and LBK1.
The surprise choice of LBK1 has remained somewhat of a confusion. Because no one knows what to do with the information despite the fact that we know a bit about the gene.  In these days, any Mutation or suppressed gene is suspect and prognosis conclusions are down. Presence of Mutation at LBK1 is considered of poor prognosis.  But wait a second! Let me shake a bit this notion:

Where do we find LBK1 alteration?

In DCIS
and In Polyps
and in Hamartomas ( Peutz Jeggers) : These do not sound like invasive cancers to me!

The DCIS case: Clinicians have maintained that DCIS do not invade, and Lymph node biopsy is generally not performed in case of DCIS.  Malignant transformation occurs here at 1% a year.  So we need additional Mutations for DCIS to adopt a cancerous profile.

In Peuts Jeggers, despite the presence of LBK1 (STK-1), polyps take their time to transform.  There the patient could develop pancreatic cancers for sure, but only after additional mutated genes come to bear! And the likelihood of this is high since a number of known substrates have been recognized to interact with LBK1.

Through Wikipedia:

SUBSTRATES OF LBK1 INCLUDE:

1.   BRSK 1&2 --------Through these substrate, it insure Neuronal Polarity.  And control length of neurons.
                       I should come to cellular polarity in a bit!  But here also comes its power to organize Microtubules and could have implications on resistance vs sensitivity to Taxanes!

2.  MARK 1&2--------This is where it controls Apico-basal cell Polarity, it may be controlling the      popular topic of Flippase, Floppase and Scramblase.

3.  SIK 1,2 : Through this substrate and its co-activator TORC2, LBK1 finds its inhibitory effect on Gluconeogesis.

4. AMPK signal pathways which favor proteins formation and translation while blocking lipogenesis.  Metabolically, it favors Catalysis with generation of ATP while blocking reactions requiring consumption of ATP.  At the cellular membrane the exchange of phosphorylated groups drive GTPase.  Putting LBK1 center to pathways activation.  At the Mitochondrial Membrane this has even more of an impact.

5.  NUAK  1,&2  which regulate Apoptosis through P53.  It is speculated that the overall effect of LBK1 is naturally anti-tumor.  Its alteration stops Apoptosis.

6. In the Embryo, LBK1 has demonstrated a role in Angiogenesis.   MEK or VEGF interaction is assumed.

One speculated that chronic exposure to Insulin like growth factor stimulation, or Estrogenic stimulation or inflammation or chronic mechanical stimulation forces desensitization through SPRADD or other genes altering LBK1 leading to loss of polarity and linear arrangement of cells by dysfunctional adhesion leading to "benign tumorous formations called polyps.  Further alterations happen as abnormal genetic evolution occurs and progresses into a full blown Malignancy.

It is also believed that once malignant transformation happens, LBK1 functions could "amplify" then the transformation favoring cell migration.

Many questions remain to be solved when it comes to LBK1...

COMBINATION OF XELODA, AND ANTICALMODULIN AND AN ANTI-P35 ANTIBODY FOR TRIPLE NEGATIVE BREAST CANCER.,

OR TAXOTERE-XELODA-VELCADE-ANTI-P35

If the fighting cancer strategy is to disrupt the cell where it hurts the most, the above combinations make the most sense.  These combinations achieve the following:

1.  Disruption of Microfilaments/Microtubules which in turn disrupt Anaphases in dividing cancer cells.  This also disrupts membrane attachment of  Cytochromes in Mitochondria by disrupting the Cytoskeleton, and leads to Caspase release.
2. Xeloda leads to an increase of intracellular 5-FU and to DNA breakage which triggers activation of P53 induced stoppage of cell division.
3. The Anti-Calmodulin will add and increase an intracellular release of Calcium leading to stimulation of Endonucleases which will further damage the DNA.
4. The Anti-P35 decreases resistance to Caspases since P35 is an inhibitor of  Caspases.
5. To lead to growth advantage, most cancers get a mutation of the MDM2 which leads to increased ubiquitination proteins/cyclins  favorable to apoptosis, making Velcade a powerful drug as it disrupts the proteasomes!

With these combinations, we are trying to harvest the strongest destructive forces in a cell!

Following-up on the 2nd Law discussed previously

Follow-up on the 2nd law discussed yesterday.
It is not by mistake that the 2 new drugs active in breast cancer, triple negative, target microtubules.
Indeed, both Erubilin and Ixabepilone target Microtubules.
I just took the test on Hope S. Rugo's presentation following the logic, passed the test without problem. So:
SHOULD WE USE CASPASE RELEASE IN LABORATORY AS PROOF OF CHEMOTHERAPY EFFECTIVENESS ON A STANDARD BASE (ROUTINELY), ON FRESHLY OBTAINED TISSUE, THAT IS!

Nature seems to tell us that when there is an error in the gene, we can repair this, but when the Microfilaments are destroyed, Mitosis is compromised and the cells' destiny is to die!  This is where the power of Vinorelbine comes from...Vinorelbine-Cisplatin is used as standard therapy for lung cancer, particularly in other parts of the world! 

DISCUSSION ON PARP INHIBITOR TO FOLLOW...

SEARCHING FOR A CANCER CURE

At CRBCM we believe that CPRIT is our necessary path to Victory over Cancer.
We also know we will not get its help this time around, not because we do not deserve the help but frankly because it is distracted.  Science is an objective thing.  It is a race.  You have the right move, the right stuff, you win, no matter where you come from.  It is the Olympics without steroids.

We at CRBCM have understood one thing, in the race for the cure, harnessing the force and laws of nature has an unparalleled advantage.  Forcing a cell to die can be done by telling and convincing it to die. Or blasting it and crossing our fingers and hoping it will die.  Chemotherapy did this mostly the second way but its success was partial.  Chemotherapy only works when it manages to finally talk the language.  Indeed, some chemotherapy manages to reach the syllables of the cellular language of death.

Sorting through the maze of messages, 2 powerful set of syllables come out:

1.  That if it fails to repair broken DNA and therefore does not perform GENE REPAIR, this fact will automatically activate your P53 leading to an automatic stop of the cell into its cycle division.  There is no loophole to this principle unless the P53 is abnormal.   Knowing this is powerful.  Now we understand why Cisplatin (and to some extent Gemcitabine)  is a powerful drug because it disrupts the DNA structure.  We also understand that cells with rapid repair of DNA, will brush it off, literally.

2.with further proof of principle, we believe that there is a second automatic message or syllables.
Destruction of Microfilaments (and therefore secondarily Microtubules in general) during cell division, leads to an automatic release of Caspase from the Mitochondria no matter what (and this is what includes the BCL-2 protection). It is in this law that resides the strength of Taxanes.  Medication that works even in resistant diseases such as Melanoma where Abraxane has a role.  Taxanes' limitations appear to be in the type of microtubules attacked. Medication that attacks Microfilament of the type involved in cell divison, where the Centromere is attached, appears to send a more determinant trigger to Caspase release.  This is where our interest comes in the Anti-kinesin.  We believe and predict that an effective anti-kinesin drug in combination with Taxane and Cisplatin/gemzar based combination, will harness best this law.  They will prove to be effective in cure because they will be effective in both treatment and maintenance settings.  This is also why the combination of Gemzar and Taxol has proven to be the strongest non platinum combination.

Following this principle, we believe now at CRBCM, that target therapy not following the laws of nature will have only 20-30% response rate, meaning effective in only the cells that lack loophole mechanisms.  (this also means because of phenotype heterogeneity, 70-85% of cells have potentially intrinsic loophole to any signal transduction target stimulation or blockage).

Lets keep our eyes on the ball, do not invest in stuff they are throwing at you!  More to come...