Showing posts with label velcade. Show all posts
Showing posts with label velcade. Show all posts

Tuesday, October 29, 2013

Progress in Genome studies: case in point the DIGITAL PCR.

If what they promise is real, we are entering an important phase where not only we can count mutations,  but can also try to determine levels of gene amplifications  that are secondary, versus those that are in response or a consequence of upstream genes normally amplified or amplified because they are mutated!

" Next-generation sequencing technology has transformed cancer genomics, but faces the challenge of genome and transcriptome heterogeneity inherent to any tumor sample. One strategy for capturing the complex landscape of mutational processes, clonal evolution/amplification and tissue invasion is the application of digital PCR, which enables the identification and precise quantitation of individual mutations - including those present at a very low frequency."(Biomedcentral)

This new technology will open new evaluations of gene quantities as to their meaning and trigger!  It will allow also to detect levels of suppression of a normal gene when it is found in an unexpected amount.  We know for example that in many lung cancers PTEN is suppressed.  Whether  this is a primary happening or secondary can be further debated.  In Ovarian cancer DAB2 is suppressed. ("The down-regulation of DAB2 may play an important role in ovarian carcinogenesis. This gene was initially named DOC2 (for Differentially expressed in Ovarian Cancer) and is distinct from the DOC2A and DOC2B genes (for double C2-like domains, alpha and beta).[3]

 Most of these suppressions are the result of an amplification of an upstream gene or an overexpression of an inhibitory protein.  When it comes to DAB2, it is important to report that this gives the cancerous process some teeth and bad prognosis.  Indeed, the suppression of DOC2 gives the tumor ways of escaping proliferation control by the cancerous cell by activating E3 (removing by unbiquitilation of the inhibitor of the inhibitor of E3).  This new technology will allow direct quantification of the 2 inhibitors or the E3 for that matter.  It may also clarify how Velcade works in relation to the 3 compounds!

Tuesday, April 23, 2013

THE Wnt PATHWAY

THE Wnt PATHWAY
It is one of the most complex and versatile pathways.  It is a powerful pathway because Mutations here have direct impact on cell totipotentiality, metastasis and cell differentiation and survival. It involves the most genes .
1.The Wnt interacts with E-Cadherin and therefore intervenes in the Cell Adhesion and Metastatic spread of cancers.
2. The Wnt influences Calcium concentration in the cell.
Remenber Calcium have influence on Calmodulin function and in Alzheimer dementia, microtubule entanglement is worsened by influx of Calcium
3.  Interaction with the Frizzled assure membrane polarity
?control of the flippase or calcium channels?
4. It has nuclear effect through activation of beta-Catenin (through activation OCT4) which is normally degraded by Ubiquitination, therefore opening the door to Velcade
5. Totipotentiality of cells comes back through the Wnt (through Nanog derepression by removing TCF3 influence)
6. Activate the MTOR to ensure cell survival (through GSK)
8. It controls Mesodermal differentiation (through FLK1)
9. It attenuates the Sonic HedgeHog (through GSK)
10. It has full control of the Neurologic sytem of the cell, and through is wingless system, determines where the function will be displayed
11. It is a stimulator of the c-JUN through RAC-1
12. It confers the status of Neuroendocrine differentiation, control where nerves go or do not go!
It is why Cisplatin has a role in in Neuroendocrine differentiated tumor
13. It is the master of Embryonal Gastrulation
Watch out: attacking Wnt can activate the cancer because of its c-JUN connection which leads to Tumor Growth factor!
14. Viral penetration involves the Wnt
15. It controls cell morphology, migration, endocytosis and cell cycle progression (through Cdc42)

I have to stop to spare you!  Look, I have not started to talk about how it leads to Metastasis...I just have to stop.  The Wnt, a powerful pathway!

Friday, February 8, 2013

SUGGESTION OF TREATMENT OPTIONS IN PATIENTS WITH ACTIVATED B CELL LYMPHOMA AFTER FAILURE OF R-CHOP IF PATIENT IS A POOR CANDIDATE

IN Not transplant candidates:
The options are:

1.Revlimid+ Rituxan
2.Rev+RICE is being trial
3.Reduced Conditioning Allogeneic Transplant
4.R+Bendamustine
5.Whyndam  R-EPOCH,
6.Velcade + Chemotherapy in the ABC subtype

Nn CNS prophylaxis, with addition of RITUXAN,  the  incidence of CNs relapse has decreased.
Large Cell lymphoma with Bone Marrow infiltration in 50% of case it is because of small cell component is actually infiltrating which does impact the  prognosis considerably.  So, NO CNS prophylaxis supported.
-------------------------------------------------------------------------------------------------------
TREATMENT OPTIONS IN MANTLE CELL (SOX 11 MARKS AN INDOLENT COURSE)

1.R-HYPERCVAD (MODIFIED)
2.R-BENDAMUSTINE
3. 4 CYCLES OF R-DHAP (LYMA TRIAL), COULD BE  FOLLOWED BY REVELIMD OR RITUXAN MAINTENANCE
4.HIGH DOSE ARA-C CONTAINING REGIMEN
5 R-CHOP ALTERNATING WITH R-DHAP
6. IBRUTINIB
--------------------------------------------------------------------------------------------------

CLL, TREATMENT OPTION

1.RITUXAN-BENDAMUSTINE
2.FLUDARABINE, CYTOXAN, RITUXAN (FCR)
3.FOR AUTOIMMUNE HEMOLYTIC ANEMIA- PREDNISONE, IV IG , RITUXAN COMBINATION PRIOR TO STARTING THERAPY.
4. IBRUTINIB
5. LOW INTENSITY ALLO TRANSPLANT




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Tailored Hematology: Challenging Community Cases in Non-Hodgkin Lymphoma

February 8, 2013
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Wednesday, January 9, 2013

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! 

Wednesday, December 19, 2012

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!