Esophageal Cancer (continued)

We have discussed that chemical, traumatic and sometimes burns from caustic solutions that people ingest unfortunately, that will stimulate the cellular membrane receptors which in turn will stimulate RAS, which in turn will amplify PI3K, MAP Kinase and RAL/CDC42.   But remember these are stressful stimulations, so instead of the standard MAPK, the stimulation is imposing on RAS to awake the NFkB pathway, the c_JUN and at nuclear level the FOS which results in inflammatory proteins stimulation including cyclin production or liberation from membranes with extracellular release of Metalloproteases. Cyclins combining to CDCs will exacerbate cell divisions and proliferation, growth factors will promote cell growth, there is an associated ligase proliferation that will impact P53 (through MDM2) and  c-MYC, NOTCH, and even c_JUN itself through FBW7/hCDC4.  This is how the proteasomes come into play!

By now you now
1. that amplification of c-MYC exacerbate proliferation by allowing progression of cells int S-phase and bolster DNA replication, imparting bad prognosis to cancer cells.
(nature is kind and gies you a chance to affect here by freeing RB1 and increasing FBW7.  Oh! also find MYCN and the p isoform to q for answers!)

2 Rb1 does sequester E2F.   you can look at it both ways.  that E2F stabilize Rb1 instead,  whichever way one stop the other for acting!   Remember E2F activates CPP32 which increase APOPTOSIS!  (DRUM UP THOSE TARGET THERAPY!)

3.REMEMBER RAS NEEDS A FATTY ACID MOIETY TO STAY AT THE MEMBRANE FOR ITS ACTIVITY (THIS IS ITS SO CALLED POST-TRANSLATIONAL MODIFICATION) BY THIS PHRENYLATION IS IMPAIRED BY THE FARNESYL TRANSFERASE INHIBITOR
(ie. TIPIFARNIB) THAT WE DO NOT USE ENOUGH I FEEL!  ALTHOUGH I AGREE THAT SIDE EFFECTS MAY BE PROHIBITIVE GIVEN THE EXTENT OF WHICH NORMAL CELLS WILL ALSO BE COMPROMISED.  BUT IT GOES TO THE FACT THAT WE NEED TO FURTHER TWEAK THIS MODALITY TO MAKE IT USABLE IN CANCERS!
ANTI-MEK HAVE DEMONSTRATED USE IN KRAS MUTATION CANCERS!  MAY BE ESOPHAGEAL CANCERS WILL BENEFIT HERE!

4Role of combining Velcade and Carfilzomib in Esophageal cancer to see if c-Myc can be affected?   Will it increase the right Ligand (FBW7)?

TAXOTERE-CISPLATIN SUPERIOR TO TAXOTERE-XELODA IN TRIPLE NEGATIVE BREAST CANCER

In a recent article published in the Annals of Oncology, Researcher published that Taxotere Cisplatin was a better combination for initial therapy in Metastatic triple negative breast cancer:
"Results:

• The median follow-up was 24 months. ORR was higher in the TP group than in the TX group (63.0% versus 15.4%, P = 0.001).
• PFS was more than doubled (10.9 months versus 4.8 months, P < 0.001) and median OS was also greatly improved (32.8 months versus 21.5 months, P = 0.027).
• Toxic effects were not different except G3/4 vomiting and G2/3 hand-foot syndrome.

Read more: http://www.mdlinx.com/oncology/news-article.cfm/4317563"

These results corroborate or tend to support many facts:

1. That triple negative Breast cancer genome was closer to ovarian cancer, a disease in which   Taxol -Carboplatin is still standard of care particularly in metastatic setting.

2.  That Cisplatin alteration of DNA is more likely to induce P53 cell cycle arrest. (1st law)

3.  That adding Taxotere and its disruption of Macrotubules recruits effectively the 2nd law.   This lead to a doubling  of PROGRESSION FREE SURVIVAL.

Again it would be of interest to see what an Anti-kinesin  (anti-Actin) or Velcade addition would mean in a  clinical trial.   Most molecules involved in programmed cell death such as Cytochrome C are attached to membrane within the organel where they reside.  Disrupting that anchor would most likely boost Apoptosis.  Without further determining the nature of that Anchor, we know that the cytoskeleton is most likely Actinic in nature.  Disruption of the the Cytoskeleton could induced Anoikis, and freedom of molecules attached to membranes leading to major disruption including that of signal pathways.

Velcade main additional effect is disruption of DNA replication restarting after P53 arrest by its affect anti-proteasomic.  Protein restarting the replication are generally ubiquitinated making the front and center to proteasome role!  The issue really remains the determination of how much of a Driver this pathway is in solid tumor.  This determination is one of the major challenge oncologist face today! 

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! 

Apoptosis. 2006 Feb;11(2):143-9.

Cathepsin-regulated apoptosis.

Chwieralski CE, Welte T, Bühling F.

Source

Institute of Immunology, Otto-von-Guericke-University, Magdeburg, Germany.

Abstract

Apoptosis can be mediated by different mechanisms. There is growing evidence that different proteolytic enzymes are involved in the regulation of apoptosis. Cathepsins are proteases which, under physiologic conditions, are localized intralysosomally. In response to certain signals they are released from the lysosomes into the cytoplasm where they trigger apoptotic cell death via various pathways, including the activation of caspases or the release of proapoptotic factors from the mitochondria. Here, we review different mechanisms that induce the release of lysosomal enzymes, and the functional relevance of defined cathepsins in defined models of apoptosis.

PMID:

16502253

[PubMed - indexed for MEDLINE] 

===========================================================

Once again we remind our readers that the failure of chemotherapy to lead to a cure has led to the belief that trying to kill the cell indiscriminately has proven somewhat futile.

Giving only less than 20% cure rates.  We needed to be smart by exploiting natural path to death. Indeed the cell has a naturally programmed death called Apoptosis.  Our approach to cure is to find ways to induce cancer cells into Apoptosis.  It is apparent that Apoptosis whenever triggered appears to be better in achieving death of cancer cells.  There are also some non Apoptotic ways to cancer cell death that we discussed in our previous posts.

In Mitochondria, membranous events release Cytochrome C which in turn activates the Caspase family to lead to cell death.  (BAX is linked to Caspase activation)

In the Lysosmes, membranous events seems to free more Cathepsins to lead to Cell death.  We also have shown that Ion Pumps maintain intralysosomal Ph gradiant to allow function of various Hydrolases which function only at Acidic Ph.

Autophagia and Necrosis are some of the other path to cell death.  Our task is to know how to harness these powerful pathways to death.  Response rates are up to 75% in LUNG CANCER using current Oncogene drivers recommendation.

STRATEGIES FOR THE CURE

Since the work of Weinberg and Hanahan, we know that despite the varieties of cancer, 6 driving forces lead to cancer cell survival.  The "Hallmarks of cancer" result from:

1.Self sufficiency in growth signals: Cancer cells escape Anoikis,  They secrete their own growth factors to achieve an autocrine stimulation.

2.Insensitivity to anti-growth signals. This is achieved by changing membranes' receptors composition and number, boosting its own global growth, and secreting Tumor Necrosis factors to tamper with surrounding cell machinery.

3.Sustained Angiogenesis, to maintain "feeding" of the new tumor mass.  This is mostly critical for solid tumors.  It is critical in tumors that bleed easily such as renal cell cancers.

4.Limitless replicative potential.  By removing stops to mass formation, natural boundary sensors which contribute to shaping organs, Telomerase activation again.

5. Suppressing or escaping Apoptosis: By using cyclins and Bcl-2 and related molecules. Shielding Mitochondria and avoiding FAS/BAX, activating loopholes routes and impairing ubiquitination of growth molecules!

6.Tissue invasion and metastasis. Here the tumor cells alter composition, nature and amount of the cell receptors and adhsions molecules, cluster of differentiation (CD), and produce Tumor growth factors (TGF) which give it growth advantage vis-a-vis the surrounding tissue.

This list is by no mean exhaustive given the variety of possible oncogene mutations.  However, when one gene is causing one of the 6 pathways, it is dubbed a DRIVER mutation for that cancer, and may have significant therapeutic importance.

This 6 venues are made of important molecular structures that can be a Target for therapy. Researcher are combing them one by one and targeting them.  The successful experience with Multikinase therapy suggest that interrupting several points of the cascade appears beneficial.  Computer models are being developed to see if sequential attacks or coordinated combinations would be better models for future therapies.  The CRBCM is working to develop such a model. Our model will be complete after we enumerate all laws of nature (see our related series).

Model of cures should embrace these 6 venues in a mathematical equation...the challenge is launched!
 

Managing the loopholes in the cell cycle

Cure to cancer is within reach and is within the management of LOOPHOLES. Cancer cells have within their pathways, redundancy that protects these pathways to maintain life of the malignant cell. You close one door, just to see another one open up to ensure that the life of the cancer cell is maintained. So, unless you hit a critical pathway with no escape routes, the treatment result will be partial and temporary. To succeed we need to hit several targets in total and and sometimes sequentially to impose on the cell to choose the path to its natural death (apoptosis). So most treatments which are limited to one or only a few targets prove partially and temporary effective. This is why building an electronic Cell and being able to put in all the pathways and observe where they lead to, what doors open and which ones are closed or closing, which are critical and which lead to apoptosis (natural cell death) is crucial. Which sequence of shut down leads to sure cell death? Right now we are at the step where we are learning about shutting or opening one door and evaluating the sequence of events that follow. But with our model in hand, we can be more comprehensive in our approach. The model will help determine effects on cancer cells by shutting several doors at once, "closing Loopholes" as Tax people would love to say. This approach with target therapy has led to breaking resistance to certain types of cancers that were notoriously resistant. Today, we are starting to have response rates in Melanoma. We have double or triple longevity in Chronic Myeloid Leukemia, GIST, Myeloma etc...Just wait to see what we will get once we manage to give Multistage Multitarget Therapies (MMT). Cure is within the management of Loopholes!

The secret for Cure of cancer is located in the selective apoptosis, or cancer cell death

We know there are several ways that lead to cell death.  The main 2 ways are through the Extrinsic pathway which uses Receptors located at the skin of the cell called cellular membrane (receptors such as TNF-R1 and FAS) and Intrinsic pathways that use internal proteins (i.e. Caspases) that may destroy or paralyze  the breathing and energy producing organs of the cell called mitochondria. The challenge is to control these processes in the cell, know how to trigger them, and to do this only in the cancer cells without affecting the normal cells.  We need to know how to tag cancer cells, give that tag to a killing molecule that can attach to the apoptosis receptor.  This is just one way to be looking for a cure.  The complexity and multitude of metabolic pathways presents a problem, but also opportunities to kill the cancer cell.We are in the wee hours of learning them.Target therapy is in its early hour.

When there is a mistake in the gene during replication, there is a repair mechanism. To allow that repair,
the cell needs to be slowed down in its life cycle. This slowing seems to be the main action of P53. If repair does not occur, P53 leads the cell to cell destruction/apoptosis.  That's why most cancers remove or change the P53 to stay alive. Like most Molecules in the cell, the P53 has its own path to destruction. MDM2 seems to be that path to the loss of this so important P53.  Scientists are looking at knocking down MDM2 to see if this may restore the P53 function in those conditions where the P53 is not fundamentally altered.  We will follow this for you and give an update!

The Cure is achievable we know that for sure, we need just need to become better "cell mechanics"....stay tuned...

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!