FOR THE CURE, TIME FOR PARADIGM SHIFT AND A REVOLUTION AGAINST SOME OF OUR LEADERS IN CANCER MEDICINE

Cancer is a disease involving the cell.  Our current understanding is that during the course of our lives, somewhere in our system, a cell's function will be altered enough to transform a normal cell into A CANCER CELL.   Our current understanding is that all cells want to stay alive and for cancer cell multiplication and dissemination it appears to be assurance of a type of cell preservation.  We know that to survive, the cancer cell will escape several mechanisms.  How to stimulate its growth, how to escape detection by the immune system and removal by the Macrophages and related natural measures, how to stay awake by lighting up certain pathways, how to resist against external chemical attacks, how to repair damages caused by attacks, how to survive on their own etc.?

We also know that cancer cells are not the same not only by tissue of origin, but also by pathways driving them.  We know that to escape death, the cancer cell uses redundancies and loopholes in its pathways, that is it may alter or multiply these pathways to overrun incoming inhibitions.  It may amplify measures to block our reach toward programmed death.  The cancer cell knows that once programmed death mechanisms are started, it has to die.  It builds things like Bcl-2 around the Caspase death path.  The cancer cell knows that there are inhibitory forces that need to be altered.  P53 is one of the Major forces. It needs to be altered or mutated.  Flow through a pathway is another force. And altering regulators may be one way to control the flow.  Or leaving a switch on to drive the pathways. etc...

We also know that every major target in pathways has effects downstream toward the nucleus and its DNA, and upstream toward the Membrane.  For some, we have found lateral connections serving as loophole escape.  More than one phenotype of an important Target is meant to provide Resistance to attacks of the main type.
 
With chemotherapy, we have had some success.  Our failures reside in the mechanisms of resistance, in the ability of the cancer cell to repair itself and escape death.  Escaping death appears to be also solely linked to protection against Necrosis and programmed death.

We also know about Driver pathways as well as forces we can use to stop cell migration, division and seeding. We have got to use this knowledge to plan our action for the cure.

The success of target therapy needs to tell us that leaders who continue to push chemotherapy as the only alternative, creating more combinations, need to be more and more left alone, while we switch to Targeting therapy and some combination therapies.

Targeting therapy tells us we got to get better at defining Driver pathways to be effective.  Particularly in solid tumors.  This is the major priority.  HOW DO YOU TELL THIS IS A DRIVER TARGET OR PATHWAY? IS IT BY DOSING REGULATORY MOLECULES, ENZYMES ALONG A PATHWAY, LEVEL OF TRANSCRIPTION GENES, STATUS OF SWITCH TO TARGET MOLECULES, PROMOTER EXPRESSION?  HOW DO YOU SAY THIS IS THE DRIVER PATHWAY?  WITH THIS KNOWLEDGE WE CAN AVOID STUDIES LIKE TAXOTERE & REVLIMID IN PROSTATE CANCER, WHEN TAXOTERE & VELCADE WOULD HAVE BEEN BETTER.

IF WE KNOW HOW TO DO THIS, OUR PATH TO CURE IS ASSURED.

The second question: HOW TO GET THIS CELL TO CASPASE, TO LYSOZOMAL HYDROLASES AND CATHEPSINS, AND OTHER NECROTIC AND AUTOPHAGIC PROCESSES? HOW TO PUSH IT TO PROGRAMMED DEATH?

TIME TO WAKE UP AND SMELL THE COFFEE BEFORE ANOTHER RUN FOR THE CURE! 

FLIPPASE, FLOPPASE, SCRAMBLASE

One of nature's secret and ability to hide it, is by being simple.  While we expect things to be complicated and full of contorsions,  we are startled when at the end what we find is simple to understand!  One of the things we had figured out to be simple is the role of flippase and floppase, and may be the role of scramblase.   If one looks at a battery we use to power small electric equipment, one side is positive, the other is negative.  So there is a positive pole and a negative pole.  We can conclude that the battery is polarized.  The limit of a cell or one way the cell keeps what is inside of it, is by having its membrane polarized like an electrical fence.  The cell has understood that to be electrically polarized you got to have molecules in the membranes full of electrons.   And these electron-filled-molecules need to be maintained in position no matter what !  So the cell figures we need some Flippases and floppases to put things in the order above.  Meaning if the molecules we need in position A is outside the cell in position B, flip it in the right position A no matter what.  While flippase go A to B bringing these molecule inside.  Floppase goes B to A, sending molecule outside.  The Scramblase does both functions to mix things up!

This seems simple enough but wait!
This is how the cell tells the other cell "I am a dead cell, get rid of me"
Indeed, dead cells move Phosphatidyl serine, a normally internal surface molecule, to the outside of the cell, making it one of the most powerful signals to the Macrophage that this cell needs to be attacked and removed.
This disruption in lipid molecules is also linked to Bleb formation in the membrane, another powerful sign of cell death.   It is related to Caspase activity as an inducer of death, and therefore it is related to our 2nd law of nature which induces Caspases.  YOU CAN SEE HOW SIMPLE THINGS GET COMPLICATED FAST!  (This is also linked to protein Kinase activation, by the way!)
QUESTION NOW: ARE FLIPPASE AND SCRAMBLASE TARGET FOR THERAPY?  You better believe it.

We are working hard at CRBCM, but CPRIT is resisting with the help!  Please help us!

NOTE   A is inside the cell
              B is outside the Cell, in our example.

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...

Sons of the Sevenless

SONS OF THE SEVENLESS/Hypothesis for cancer Research

As we move forward here at CRBCM, we are increasingy  fond of one line of molecules;
first because of their name, and because we believe that their inhibitors could be the answer to the resistance
to some of the medications already in our armamentarium, namely Avastin,  Imatinib and Herceptin.  We believe that the Sons of The Sevenless which are regulator molecules switching on RAS would break resistance to Tyrosine Kinase resistance.  Sons of the Sevenless, what a name!  But don't you remember they say: "KILL THE SWITCH" AND DARK WILL COME.   THE SWITCH IS THE SONS OF THE SEVENLESS...BASAL CELL CANCER OF THE BREAST, THE CRBCM IS AFTER YOU...SINCE THE SUGGESTION THAT BASAL CELL CANCER OF THE BREAST IS LIKE OVARIAN CANCER BY ITS GENOME.  MARK MY WORD: KILLING THE SONS OF THE SEVENLESS OR KILLING THE SWITCH IS THE KEY TO TREATMENT.

ADDING TAXANE (or better yet an Anti-Kinesin) AFTER KILLING THE SWITCH (SONS OF THE SEVENLESS) WILL TURN ON THE MITOCHONDRIAL CASPASE BY AN INHERENT REFLEX MECHANISM WHICH WILL BYPASS BCL-2.  THAT'S HOW YOU LEAD TO CANCER CURE!

OH BY THE WAY,  ADDING STELAZINE TO AVASTIN MAY JUST DO THE TRICK FOR RECURRENT BRAIN TUMORS TOO. IT IS AN ANTI-CALMODULIN AFTER ALL!

RESEARCH IS ON AT CRBCM.  

We believe in the cure for Cancer:

People talk about a cure and skeptics balk!
But the cure is possible and actually exists already in every survivor who had a remote history of cancer.
Remember this, a cancer cell is full of messages encrypted in chemical messages when to grow, when to start aging and when to die.  Yes cancer cells have an internal message when to start apoptosis (self destruction).
It means you could tell it to start apoptosis and kill itself.  Our challenge is to know how to speak to a cell.
Research are starting to learn that language in what is now known as Target Therapy.  Cancer treatment is now becoming a Piano tune.  if you hit the right keys in a song and the cancer cell get it, it will find its way to self destruction.  We are at the early stage of this music, still learning it.  Hitting this key here and seeing what happens.  We are finding out that even tough cancers such as Melanoma, if you hit the BRAF key, things start happening.  In some lung cancers, if you hit the EGFR key, you start getting somewhere.  It is just a matter of time before we start asking to a cell, now time for an increase in BAX or Caspases, and self destruct.  The cell has some redundancy and networking to complicate the road to self destruction, but we still believe that with the right tune, cancer cells will dance to self destruction, and yes cure is within our reach!