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! 

APPROACHES TO CANCER CURE!

As we are moving forward to cancer cure, one realizes several facts

1.  Translational research reveals to us that Medical science is too much compartmentalized.
- Our biologists focus on giving us Molecular basis, chemistry basis to various organelles and even smaller molecules important in the patho-physiology, homeostasis, metabolism at cell level.
- Our Biotech and /or pharmaceutical companies focus on taking this information and developing localized therapeutic targets.  They operate under significant stress to be first and patented!
- Clinical researcher take these  target therapy into clinical trials
- Our Medical Oncologists await the results of clinical trial to use the drug and formulate patterns of treatments based on experience on broader population (Phase IV post market tracking).

At each step, necessary check and balances occur, but it is also true that information is lost, diluted or missed.  This slows down translational research results' implementation. An integrated approach will allow for faster pace of implementation.  We need a TRANSLATIONAL  ONCOLOGY CLINIC WHERE ALL GROUPS WILL SIT TOGETHER AND PRIORITIZE THE THINGS TO DO!

2. Cure is not going to be the same for every cancer.   The reason is in some cancers there are DRIVER Oncogenes, in others, there are DRIVER Pathways.  At least so far, evidence seems to suggest that the success in targeting steps in pathways seems more promising in hematologic malignancies then in treatment of solid tumors.  This impression may change as we move forward.  We are now seeing response rates of 70+ percent in lung cancer when the right driver oncogene is disabled.  This is new!

3. One of the major clinical differences between a basal cell cancer of the skin and  Melanoma is in their ability to spread and multiply.  And one cannot talk about multiplication without looking at events in the Podosomes where actin, paxillin, cortactin and integrin B are main events.  We are reviewing the literature to see what has been accomplished with these potential targets!  Many pathways start in the Podosome and a whole lot of Enzymes are also here!

4. ACTIN (closely liked to 2nd law) is the core of the cell Cytoskeleton and the nervous system of the cell.
What types of Microfilaments/Microtubule/Actin exist,  can some anti-Actin work better than others...? Its relationship with metabolism and physiology of CA++/Calmodulin?  This is important stuff for Brain tumors!
We are working hard at CRBCM!

AT A CHECK POINT IN CELL DIVISION 2 MAIN THINGS HAPPEN:

1. DNA is checked for mistakes and corrections are undertaken.2. Chromosome segregation to eventual daughter cells is checked to avoid uneven distribution of the chromosome. 
This last event seems to rely heavily on activity on unattached chinetochores where check point proteins (MAS 1 & 2, UB1 etc.) accumulate and block the APX (Anaphase promoting complex) until the checking is completed and Cyclin B and Securins are ubiquitinated and destroyed to release the check hold and allow mitosis to proceed.

The need for ubiquitination of Cyclin B elevate the role of Proteasome. That is why Antiproteasome appears very important in hematologic conditions where signal transduction and subsequent cyclin activity are the driving forces toward multiplictaion of cancer cells as we stated.

When all this is  going on, the cancer cell is at its weak point. That is why chemotherapy, particularly the Taxanes and the Vinca-alkaloids, is more effective. It not only disturbs the microtubule (inducing the 2nd law), but also breaks the actinic anchors to the cytoskeleton of membranes and cellular matrix causing the "Anoikis" like phenomenon within the cell. Lesion to actin like molecules (anchors) within the central nervous system could lead to neuropathy. As we know it has the side effect of these drugs (proof of concept to follow).

ANOIKIS, detachment induced cell death

Review: Nature Reviews Cancer 7, 429–440 (1 June 2007) |

The cofilin pathway in breast cancer invasion and metastasis

Weigang Wang , Robert Eddy & John Condeelis

Abstract

Recent evidence indicates that metastatic capacity is an inherent feature of breast tumors and not a rare, late acquired event. This has led to new models of metastasis. The interpretation of expression-profiling data in the context of these new models has identified the cofilin pathway as a major determinant of metastasis. Recent studies indicate that the overall activity of the cofilin pathway, and not that of any single gene within the pathway, determines the invasive and metastatic phenotype of tumor cells. These results predict that inhibitors directed at the output of the cofilin pathway will have therapeutic benefit in combating metastasis.

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Also read:

Thymosin B

Sling Shot Homolog

Chronofin

Filamin

staurosporin

Coronin-1

HMW Isoform TM-1

Anti Rho Kinase

ADF

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This strategy of fighting cancer  is an important one; one of the main differences between a benign tumor and a malignant one is its ability to spread.  It is by spreading that the cancer will invade sensitive tissues of the host and lead to killing them by causing failure of that tissue.

We can't obviously protect against abnormality to occur and cause cancer,  the approach emphasized here is to block the cancer from spreading.  It is an important approach.

One of the ways to achieve this is ANOIKIS (detachment induced cell death). Cells within a tissue are destined to live together.  And any cell that becomes undone, will trigger more likely the 2nd law of nature through its cytoskeleton alteration and enter Apoptosis or programmed cell death.  It appears that the cancer cell prepares its departure by changing its membrane receptor composition, altering its cytoskeleton and undergo numerous changes before embarking in the metastatic process.  The Cofilin system described above by scientists is linked to the activity of ACTIN, a major component of the Cytoskeleton.  It is suspected that the entire cell has a nerve system made of Actin based complex which makes the microfilament.  This is why our 2nd law is so powerful.  Destabilization of the microfilament apparatus in the cell will beak loose all things attached to cell membrane (including Cytochrome C, the activator of caspases but also cause detachment of organelles attached to sarcoplasmic or reticulum membranes).  Again, the second law is so powerful because it is caused basically by Actin change or break.  Attacking Actin for the cell  is like attacking the skeletal and nervous system of the human being.  At the Nuclear level, attacking Actin seems to activate Endonucleases which in turn will break the DNA and trigger the first law. We are still working at the CRBCM to ascertain some of the proofs of principle mentioned here!