Showing posts with label histone. Show all posts
Showing posts with label histone. Show all posts

Tuesday, April 30, 2013


The reading about mechanisms of resistance of to Taxol calls for a new strategy for treatment of triple negative breast cancer; while it is true that PARP inhibitor should still be considered in BRCA positive cancers, adding AURORA inhibitors seems to offer logically the best opportunity to increase the activity of proposed first line drugs.

Indeed, triple negative breast cancer assumes that the receptors to conventional stimulants of the breast cancer cell are not functional or responsive.  Therefore, increasing the role of a direct attack of either the nuclear material or the microfilament/microtubule.  Taxol - Cisplatin combination achieves that!  Adding Avastin and other receptor stimulators could be a riskier proposition if you assume a questionable sensitivity of receptor in general.  Your best bet is an action on the Histones and further DNA destruction.  The cell division is your focus here and this is re-emphasized by the importance of CDKs as described by MD Anderson researchers.  As a matter of fact, the AURORA inhibitors by binding to Adenine and to the Histone appear to offer a potential and logical choice to recruit in first line to boost response rates!  So, pending proof of concept, we support the idea of adding Aurora inhibitors to a Taxane-Cisplatin core combination. Some of the Aurora Kinase also target CDKs and JAK2.  These will be my choice for new trials!

After the cancer has seen chemotherapy, endothelial cells have been altered, hypoxia has been triggered by closure of some of the blood vessel closure, the MTOR has been stimulated, we believe adding the MTOR makes more sense.  This has been also suggested after failure of Avastin,  These concepts have been publicized, It is time to move to clinical trial! (FOR THOSE WHO CAN, WE HAVE OUR HANDS TIED BY HUMAN HISTORY!)

Saturday, March 30, 2013


A living cell is in constant motion. At any given time, there are periods of chemical reactions unfolding in a living cell. These processes are occurring 24/7. Despite their large number, they are not random, but are coordinated and purposeful. They have one overall objective which is the survival of the cell against all odds. However, when they cannot preserve life, they initiate the programmed cellular death. 
These cellular reactions respect basic chemical laws of ion and atom interactions. However, the general direction from reactions is imposed by the cellular mission which is clearly determined by the location of the cell in a tissue or organ and the expected function to be performed by the organ. At any given point in time, the cell is either in differentiation or proliferation, or changing to adapt to current circumstances of the cell. These functions and adaptations are caused by environmental stimuli reaching the cell.
 These stimuli could be chemical, hormonal, traumatic or electric and they reach receptors which cross the cellular boundaries or membrane, and affect the molecules belonging to a signal transduction pathway. The signal goes on to affect genes in the nucleus of the cell where DNA will be replicated to achieve or respond to the stimuli accordingly. All reactions follow a certain flow to achieve a purpose for the cell. To control the general direction of reaction the cell uses several methods: the first is to silence un-needed genes and to amplify the expression of needed genes that carry the code for the mission to be performed. 
The cell will enter division and proliferation of those genes to impose the general direction or flow of the reaction. The second method used to impose the general direction is the formation of genes that can catalyze or force the reaction to go a certain way: these are called "enzymes" for that particular reaction. If an enzyme is not formed, the reaction is not allowed to progress. Therefore, the control of what is happening is occurring this way. A third way to control the flow of direction is to promote proteins called "regulators". The more the regulators in a reaction, the more likely that regulated reaction can occur in a controlled fashion. The fourth way of controlling reaction is mole fraction which puts together certain regulators and enzymes or proteins in general which are aligned in a chain and forces molecules to go from one protein to another in the mole in a certain direction so that the output is what is needed for the mission. 
These mole-like complexes of proteins are called "core binding factors". Any protein function not needed will not be incorporated in the complex. Genes are silenced by methylation, or simply by being attached to patches of molecules that belong to the histones, the histones that cover genetic material. At any given point, when a gene is needed, the cover can be re-opened or pulled back, which is called "gene remodeling". A cancer cell will tend to move away from the location where it is located not because of its intention to kill the host, but because in that location the nutrients and local conditions will be inadequate eventually to allow further growth. It will seek another location to survive. Before it moves away, it has to take steps to protect its survival. It will break adhesion to surrounding cells; this is mostly achieved by decreasing its surface adhesion molecules. It will secrete proteins that can break fibers on its way in order to get through and detection of these proteins called “metalloproteases” can signal doctors that the disease, the cancer, is on the move. In certain circumstances, it produces a mucus to protect itself against detection by the immune system. 
When it arrives in the new location, the cell will produce a hormone or growth factor which gives itself advantage over the already present cells in that location. This is generally called a “tumor growth factor”. The potential for proliferation, division and growth advantage is driven through the signal transduction pathway inside the cell. This is generally achieved by the expression of a driver gene which is amplified or over-expressed forcing reaction for downstream pathways. This is called a “driver mutation”. 
Experience with chemotherapy which was like a bomb with an indiscriminate effect affecting both good and bad cells of the host has only been able to achieve 20 to 30% of cure. Today, scientists are targeting the driver mutations to stop pathways of growth of cancer cells. We are now getting higher response rates and starting to see response in cancers that were resistant to chemotherapy, e.g. melanoma. People used to talk about cure without believing in their own statement, but with the advance of target therapy, cure is a real possibility. We are just at the beginning of our understanding of the various targets. Cure will be achieved.

Thursday, January 24, 2013


Overall, life at the cellular level enters a new phase as the sperm enters the Ovocyte, here the activity of life is driven by Nuclear events; cell division (and motility of cells) is the driving trend of forces to be amplified and the Embryo formation (Embryogenesis) is the ultimate objective.  As the embryo is being formed, there a transition of forces from proliferation to tissue differentiation. This transition from PROLIFERATION with an AMPLIFIED MITOSIS AND MOVEMENT OF CELL FOR POSITIONING IN THE BODY OF THE EMBRYO characterizes early life and is driven by promoter genes, amplified pathways, driven metabolism at Ribosome, histone, and genetic levels.  The processing of internal and external stimuli triggers the flow of forces.  A change of stimuli eventually occurs, followed by responses imposed by growth factors, variation in needs, and overall  cellular communications, and soon enough the trend of forces is toward differentiation.  In order to protect future life, SANCTUARY tissues are created to keep DIVISION POTENTIAL ACTIVE (Ovaries, testicles keep proliferative potential and controlled activity).   DIFFERENTIATION becomes the name of the game and is AMPLIFIED.  To commit resouces to this activity exclusively, proliferation is shut down at genes, enzymes, and chromatin levels to shield proliferation related  promoters.  Tissue differentiation is pushed to allow life, survival and adaptation leading to races and other phenotypic differentiation.  Each step is amplified to perfection (whatever the perfection is or implied).  REPRESSION OF A GENE THAT NORMALLY SHOULD BE AMPLIFIED OR STAT TRANSCRIPTION UNDER THESE CIRCUMSTANCES, MEANS ONCOGENIC SUPPRESSION AND A SIGN OF MALIGNANT PROLIFERATION AND POTENTIALLY ASSOCIATED RESUMPTION OF MITOSIS AND MIGRATION (METASTASIS).  IT IS ALSO ASSOCIATED WITH LOSS OF DIFFERENTIATION AND ATYPICAL PHENOTYPIC TRANSFORMATION.

This implies that whenever cancerous trending forces are triggered, they happen in a cell which will de-differentiate, but will switch to proliferation, mobility and perfect for survival and adaptation.  A cell trained to escape mechanism of local and distant defense, and full of survival and adaptation skills!  The ESCAPE include eluding local attacks by change in receptors, glycocalyx and level of pump and MDR gene expression,   but also distant (escape Anoikis) cell rejection.

Cancer is a formidable opponent with so many opportunities for target intervention if you know where to touch or block the flow of things for the cure.  The timing of change of the flow of forces/trends provides as much opportunity as a check point.  One may want to target these events.