STAT-1 DEPRESSION COULD PREDICT SUSCEPTIBILITY TO HISTONE DEACYLASE AND KILLING THROUGH UPREGULATION OF Fas PATHWAY.
We have recently presented a case of a 38 YOF diagnosed with an unresectable Angiosarcoma
Her tumor was positive for factor 8, CD31, CD34 ad Ki-67. This immunostaining profile was used to support the reading of the pathologist, CD31, a platelet adhesion molecule (PECAM-1) is extensively found on the endothelial cells. But the presence of factor 8 raises the possibility of Interferon Regulated Factor 8 (IRF8), Therapeutically this would be interesting because not only it raises the possibility of Using Interferon gamma in this woman, but also Histone Deacetylators.
Our question, DOES EXPRESSION OF FACTOR 8 SUGGESTS SUSCEPTIBILITY TO HISTONE DEACETYLASE AND KILLING THROUGH UPREGULATION OF Fas IN PATIENT WITH STAT-1 DEPRESSION.
IT IS ESTABLISHED THAT INTERFERON HAS SOME ACTIVITY IN ANGIOSARCOMA, AND SO DOES ALL ANTI-VEGF AND POTENTIALLY ALL ANTI-MEK
Wednesday, February 13, 2013
ACUTE MYELOID LEUKEMIA : SOME NOTES FROM DR FREDERICK APPELBAUM COMMENTS
* classification under the FAB was abandoned because it did not give prognosis information
* 4 groups based on Cytogenetics
1. No significant Cytogenetic abnormality : considered the INTERMEDIATE GROUP
2. Unfavorable group with 5q - 7(Monosomy)
3. Favorable group Inv 16, (15,17), (8,21)
4. Unclassified
The favorable have 55% 5 Year survival
Intermediate have 38% 5 year survival
Unfavorable had 11% 5 year survival
ADD NPM1 as good prognosis
ADD CEBPA as good
BUT FLT-3 as bad despite favorable basic category
C-KIT positive is also bad in Adult only
other cytogenetic of interest N-RAS, NPM and IDH1 Mutation
15 other Mutations for our BUFF in genetic
KIT MLL CBL PTEN JAK2 DNMT3A EZHZ TET2 WT-1
IDH-1 N-RAS P53 RUNX-1 ASXL-1 PHF-6
--------------------------------------------------------------------------------------------------
IF YOU FINISH LOOKING AT THE 15
WELL LOOK ALSO ERG MN1 EVI-1 BAALC CD34
---------------------------------------PLUS MICRO--RNA, METHYLATION
ADD TO DNA SEQUENCING , TRANSPTOSOME SEQUENCING TO SEE FURTHER
ELN 2012
CATEGORIES OF AML
1. favorable include Inv 16,( 8,21), NPM1, CEBPA and wild type FLT-3
2. Int-1 NPM1 Mutated and FLT3 Mutation
3. int-2 t(9,11) and NOS
4. Unfavorable inv 3 (3,3) t(6,9) -5 -7 17p and complex abnormalities
remember good or favorable is not good or favorable anymore if noted after chemotherapy for another primary.
----------------------------------------------------------------------------------
In all patients, obtain (I will send you an angry letter if H&P not completed in EMR!) OK!
1. CBC DIFF and Comprehensivve Metabolic panel
2. Uric acid level ---not high, start Allopurinol
---high start Rasburicase
3.PT and PTT if DIC start ATRA
4. Bone marrow Biopsy
5.Immunophenotyping
to detect the 1% of Mixed phenotype which is of poorer prognosis
and to be able to detect persistence of disease with PCR better accomplished through this method
6.Cytogenetic which should include CEBPA, FLT-3, and NPM-1, C-Kit
7.HLA typing NOW NOW NOW!
-------------------------------------------------------------------------
Please note age (65) and comorbidities as you ponder if patient can sustain high dose treatment
----------------------------------------------------------------------------------------
Treatment
-start Hydration and Alkalinization
-Allopurinol Vs Rasburicase based on Uric Acid level
-DIC start ATRA no matter what
-start Antibiotic, antiViral and antifunga Coverages NOW
-Consider Fertility Issue now
-speak to family
and start Induction
and consider consolidation based on circumstances per standard of care
In elderly >65, or >60 with significant comorbidity
Death occurs during induction
so please consider
1.LOW DOSE ARAC-C
2. 5-AZACYTIDINE
3. DECITABINE
4. CLOFARABINE
5. FOR 5q- TRY REVLIMID!
-----------------------these are my notes------------
* classification under the FAB was abandoned because it did not give prognosis information
* 4 groups based on Cytogenetics
1. No significant Cytogenetic abnormality : considered the INTERMEDIATE GROUP
2. Unfavorable group with 5q - 7(Monosomy)
3. Favorable group Inv 16, (15,17), (8,21)
4. Unclassified
The favorable have 55% 5 Year survival
Intermediate have 38% 5 year survival
Unfavorable had 11% 5 year survival
ADD NPM1 as good prognosis
ADD CEBPA as good
BUT FLT-3 as bad despite favorable basic category
C-KIT positive is also bad in Adult only
other cytogenetic of interest N-RAS, NPM and IDH1 Mutation
15 other Mutations for our BUFF in genetic
KIT MLL CBL PTEN JAK2 DNMT3A EZHZ TET2 WT-1
IDH-1 N-RAS P53 RUNX-1 ASXL-1 PHF-6
--------------------------------------------------------------------------------------------------
IF YOU FINISH LOOKING AT THE 15
WELL LOOK ALSO ERG MN1 EVI-1 BAALC CD34
---------------------------------------PLUS MICRO--RNA, METHYLATION
ADD TO DNA SEQUENCING , TRANSPTOSOME SEQUENCING TO SEE FURTHER
ELN 2012
CATEGORIES OF AML
1. favorable include Inv 16,( 8,21), NPM1, CEBPA and wild type FLT-3
2. Int-1 NPM1 Mutated and FLT3 Mutation
3. int-2 t(9,11) and NOS
4. Unfavorable inv 3 (3,3) t(6,9) -5 -7 17p and complex abnormalities
remember good or favorable is not good or favorable anymore if noted after chemotherapy for another primary.
----------------------------------------------------------------------------------
In all patients, obtain (I will send you an angry letter if H&P not completed in EMR!) OK!
1. CBC DIFF and Comprehensivve Metabolic panel
2. Uric acid level ---not high, start Allopurinol
---high start Rasburicase
3.PT and PTT if DIC start ATRA
4. Bone marrow Biopsy
5.Immunophenotyping
to detect the 1% of Mixed phenotype which is of poorer prognosis
and to be able to detect persistence of disease with PCR better accomplished through this method
6.Cytogenetic which should include CEBPA, FLT-3, and NPM-1, C-Kit
7.HLA typing NOW NOW NOW!
-------------------------------------------------------------------------
Please note age (65) and comorbidities as you ponder if patient can sustain high dose treatment
----------------------------------------------------------------------------------------
Treatment
-start Hydration and Alkalinization
-Allopurinol Vs Rasburicase based on Uric Acid level
-DIC start ATRA no matter what
-start Antibiotic, antiViral and antifunga Coverages NOW
-Consider Fertility Issue now
-speak to family
and start Induction
and consider consolidation based on circumstances per standard of care
In elderly >65, or >60 with significant comorbidity
Death occurs during induction
so please consider
1.LOW DOSE ARAC-C
2. 5-AZACYTIDINE
3. DECITABINE
4. CLOFARABINE
5. FOR 5q- TRY REVLIMID!
-----------------------these are my notes------------
MA-27 NO SUPERIORITY OF AROMASINE OVER ARIMIDEX IN ADJUVANT SETTING
MA-27
NO SUPERIORITY OF AROMASINE OVER ARIMIDEX IN ADJUVANT SETTING.
NO SUPERIORITY EXTENDS EVEN TO BONE EFFECT FEARED TO BE WORSE WITH ARIMIDEX.
GOOD THING TO KNOW EVEN IF IT DOES NOT CHANGE PRACTICE! IT IS JUST A GOOD THING TO KNOW AS WE TALK TO WOMEN WITH ER POSITIVE BREAST CANCER.
THIS IS AN EXAMPLE OF A GOOD NEGATIVE STUDY. IT HELPS CLEAR THE AIR!
NO SUPERIORITY OF AROMASINE OVER ARIMIDEX IN ADJUVANT SETTING.
NO SUPERIORITY EXTENDS EVEN TO BONE EFFECT FEARED TO BE WORSE WITH ARIMIDEX.
GOOD THING TO KNOW EVEN IF IT DOES NOT CHANGE PRACTICE! IT IS JUST A GOOD THING TO KNOW AS WE TALK TO WOMEN WITH ER POSITIVE BREAST CANCER.
THIS IS AN EXAMPLE OF A GOOD NEGATIVE STUDY. IT HELPS CLEAR THE AIR!
GENES OF CELLULAR DEATH.
1. BIM or BCL2-L11
Bcl-2-like protein 11 is a protein that in humans is encoded by the BCL2L11 gene.[1][2]
The protein encoded by this gene belongs to the BCL-2 protein family. BCL-2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. The protein encoded by this gene contains a Bcl-2 homology domain 3 (BH3). It has been shown to interact with other members of the BCL-2 protein family, including BCL2, BCL2L1/BCL-X(L), and MCL1, and to act as an apoptotic activator. The expression of this gene can be induced by nerve growth factor (NGF), as well as by the forkhead transcription factor FKHR-L1, which suggests a role of this gene in neuronal and lymphocyte apoptosis. Transgenic studies of the mouse counterpart suggested that this gene functions as an essential initiator of apoptosis in thymocyte-negative selection. Several alternatively spliced transcript variants of this gene have been identified.[3]
Interactions
BCL2L11 has been shown to interact with DYNLL1,[4][5] MCL1,[1][6][7] BCL2-like 1,[1][2][6][8] BCL2L2[1][2] and Bcl-2.[1][2][6]
========================================================================================
COMMENTS:
BIM IS IN FACT CONSIDERED A MEMBER OF THE BCL FAMILY ONLY BECAUSE IT HAS A BH3
IN FACT AS STATED IT INITIATES APOPTOSIS. IT ACTUALLY BINDS BCL FAMILY MEMBER AND DESACTIVATES THEM OR VICE VERSA. MEANING THE MORE IT IT IS ATTACHED TO OTHER MEMBERS IF THERE IS ENOUGH BCL2 LEFT THE CELL IS PROTECTED. BUT IF NOT, THE CELL IS OPEN TO DEATH. IT IS DEGRADED THROUGH THE PROTEASOME. IT IS THEREFORE UPREGULATED BY VELCADE. TAXANE DOWNREGULATES BIM THEREFORE BIM IS PART OF TAXANE INEFFICIENCY LEADING RESEARCHER TO BELIEVE TO THE VALUE OF TAXANE VELCADE COMBINATION.
LEVEL OF BIM COULD THEREFORE BE A SURROGATE FOR MEASUREMENT ON WHETHER DRUGS ARE ADDITIVE OR COUNTERPRODUCTIVE IN LABORATORY WHEN IT COMES TO THE CURE.
2. BID
3.BAD
4.NOXA
5.PUMA (HIDING BEHIND FOXO3 AND THE MTOR ALREADY DISCUSSED)
6.BH3 UPREGULATION
7.DEPRESSION OF Bcl-XL
8.BAX
9.Fas PLUS FASL FORM DISC
10.Death Receptor
1. BIM or BCL2-L11
BCL2L11
From Wikipedia, the free encyclopedia
| BCL2-like 11 (apoptosis facilitator) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
 Rendering based on PDB 2K7W. |
|||||||||||
|
|||||||||||
| Identifiers | |||||||||||
| Symbols | BCL2L11; BAM; BIM; BOD | ||||||||||
| External IDs | OMIM: 603827 MGI: 1197519 HomoloGene: 7643 ChEMBL: 5777 GeneCards: BCL2L11 Gene | ||||||||||
|
|||||||||||
| RNA expression pattern | |||||||||||
 |
|||||||||||
 |
|||||||||||
| More reference expression data | |||||||||||
| Orthologs | |||||||||||
| Species | Human | Mouse | |||||||||
| Entrez | 10018 | 12125 | |||||||||
| Ensembl | ENSG00000153094 | ENSMUSG00000027381 | |||||||||
| UniProt | O43521 | O54918 | |||||||||
| RefSeq (mRNA) | NM_001204106.1 | NM_009754.3 | |||||||||
| RefSeq (protein) | NP_001191035.1 | NP_033884.1 | |||||||||
| Location (UCSC) | Chr 2: 111.88 – 111.92 Mb |
Chr 2: 128.13 – 128.16 Mb |
|||||||||
| PubMed search | [1] | [2] | |||||||||
The protein encoded by this gene belongs to the BCL-2 protein family. BCL-2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. The protein encoded by this gene contains a Bcl-2 homology domain 3 (BH3). It has been shown to interact with other members of the BCL-2 protein family, including BCL2, BCL2L1/BCL-X(L), and MCL1, and to act as an apoptotic activator. The expression of this gene can be induced by nerve growth factor (NGF), as well as by the forkhead transcription factor FKHR-L1, which suggests a role of this gene in neuronal and lymphocyte apoptosis. Transgenic studies of the mouse counterpart suggested that this gene functions as an essential initiator of apoptosis in thymocyte-negative selection. Several alternatively spliced transcript variants of this gene have been identified.[3]
========================================================================================
COMMENTS:
BIM IS IN FACT CONSIDERED A MEMBER OF THE BCL FAMILY ONLY BECAUSE IT HAS A BH3
IN FACT AS STATED IT INITIATES APOPTOSIS. IT ACTUALLY BINDS BCL FAMILY MEMBER AND DESACTIVATES THEM OR VICE VERSA. MEANING THE MORE IT IT IS ATTACHED TO OTHER MEMBERS IF THERE IS ENOUGH BCL2 LEFT THE CELL IS PROTECTED. BUT IF NOT, THE CELL IS OPEN TO DEATH. IT IS DEGRADED THROUGH THE PROTEASOME. IT IS THEREFORE UPREGULATED BY VELCADE. TAXANE DOWNREGULATES BIM THEREFORE BIM IS PART OF TAXANE INEFFICIENCY LEADING RESEARCHER TO BELIEVE TO THE VALUE OF TAXANE VELCADE COMBINATION.
LEVEL OF BIM COULD THEREFORE BE A SURROGATE FOR MEASUREMENT ON WHETHER DRUGS ARE ADDITIVE OR COUNTERPRODUCTIVE IN LABORATORY WHEN IT COMES TO THE CURE.
2. BID
3.BAD
4.NOXA
5.PUMA (HIDING BEHIND FOXO3 AND THE MTOR ALREADY DISCUSSED)
6.BH3 UPREGULATION
7.DEPRESSION OF Bcl-XL
8.BAX
9.Fas PLUS FASL FORM DISC
10.Death Receptor
SCIENCE DOES NOT BELONG TO ANY ONE:
One thing about Biological Sciences is that it does not care if you are rich or poor. It just there to be discovered and understood. Of course the more the observer, the more you can understand it. But it is a function of what cards you are given, what chances you have and once in a while what luck you have. Perseverance comes in handy so never give up. And in research, no road should remain unturned because you just don't know where it may lead. And no road should be left unchallenged. Even a negative study established a fact suspected or unsuspected. It warns to those who come after us not to repeat the mistake our predecessors made.
Basic principle are the same but cells have shown adaptation to the environment. It got to since our environment is randomly and constantly changing, with at time coordinated progression. The key is in the work, working hard and long leads to success whatever success means!
From a scientific point of view, life emerges from an incredible amount of chains of reactions which apparently are following a certain logic which makes the law of nature. These reactions are contained within a controlled environment capable of migration, differentiation, proliferation, angiogenesis, embryogenesis and energy production and consumption, senescence and programed death.
With the arrival of new stimuli created in the environment, membrane receptors constantly expand the panoply of their ligands. And cells solicit their NF-kB and C-jun to adapt and offer an adaption response. The cell solicits it genes and creates transcription factors to formulate and express the response. When it potentials are exhausted, program death is initiated, Death traps are hidden through out the cell from the membrane where are located Death Receptors, to the Cytosol where various caspases and capsaicins. Cellular death can happen also with Necrosis and Anoikis. AUTOPHAGIA CAN KILL CELLS BUT MOST OF THE TIME IT IS PROTECTIVE, OCCURS WITH STRESS!
GENENTEC REPORTED ALSO!
"
Intrinsic pathway
Extrinsic pathway
This pathway is often activated in response to signals resulting from DNA damage, loss of cell-survival factors, or other types of severe cell stress. Normally, pro-apoptotic proteins are released from the mitochondria to activate caspase proteases and trigger apoptosis.3
Enlarge this image
When these pro-apoptotic signals are not released, the cell cannot die.1 The intrinsic pathway hinges on the balance of activity between pro- and anti-apoptotic signals of the Bcl-2 family.14
Preclinical studies indicate that members of the Bcl-2 family regulate
the permeability of the mitochondrial membrane and determine whether a
pro- or anti-apoptotic signal will be released inside the cell.15
Research implies that in this cascade, the anti-apoptotic proteins (eg, Bcl-XL) antagonize Bax and Bak by binding to their BH3 domains. This antagonism is relieved by BH3-only, pro-apoptotic proteins (eg, BIM, BID, BAD, NOXA, PUMA), which alternately bind to anti-apoptotic proteins, like Bcl-XL. In normal cells, cellular stress would result in an upregulation of these BH3-only proteins in order to initiate apoptosis via the intrinsic apoptotic pathway.3
Currently, the intrinsic pathway is more widely implicated as a blockade to tumorigenesis.2
Preclinical studies show that ligand binding causes receptors to cluster and ultimately form a death-inducing signaling complex (DISC).12
Upon DISC activation, the extrinsic pathway has been seen to adopt the same effector caspase machinery as the intrinsic pathway.12"
==========================================
WHATEVER YOU RESEARCH CURE OF CANCER MAINLY HAPPENS WHEN CANCER CELL DEATH OCCURS. KEEP YOU EYES ON THE BALL.
One thing about Biological Sciences is that it does not care if you are rich or poor. It just there to be discovered and understood. Of course the more the observer, the more you can understand it. But it is a function of what cards you are given, what chances you have and once in a while what luck you have. Perseverance comes in handy so never give up. And in research, no road should remain unturned because you just don't know where it may lead. And no road should be left unchallenged. Even a negative study established a fact suspected or unsuspected. It warns to those who come after us not to repeat the mistake our predecessors made.
Basic principle are the same but cells have shown adaptation to the environment. It got to since our environment is randomly and constantly changing, with at time coordinated progression. The key is in the work, working hard and long leads to success whatever success means!
From a scientific point of view, life emerges from an incredible amount of chains of reactions which apparently are following a certain logic which makes the law of nature. These reactions are contained within a controlled environment capable of migration, differentiation, proliferation, angiogenesis, embryogenesis and energy production and consumption, senescence and programed death.
With the arrival of new stimuli created in the environment, membrane receptors constantly expand the panoply of their ligands. And cells solicit their NF-kB and C-jun to adapt and offer an adaption response. The cell solicits it genes and creates transcription factors to formulate and express the response. When it potentials are exhausted, program death is initiated, Death traps are hidden through out the cell from the membrane where are located Death Receptors, to the Cytosol where various caspases and capsaicins. Cellular death can happen also with Necrosis and Anoikis. AUTOPHAGIA CAN KILL CELLS BUT MOST OF THE TIME IT IS PROTECTIVE, OCCURS WITH STRESS!
GENENTEC REPORTED ALSO!
"
Apoptotic pathways
Apoptosis is triggered through 2 signaling pathways2:Intrinsic pathway
Extrinsic pathway
Intrinsic pathway
As its name suggests, the intrinsic, or mitochondrial, pathway is initiated from within the cell (Figure 3.1).3This pathway is often activated in response to signals resulting from DNA damage, loss of cell-survival factors, or other types of severe cell stress. Normally, pro-apoptotic proteins are released from the mitochondria to activate caspase proteases and trigger apoptosis.3
Research implies that in this cascade, the anti-apoptotic proteins (eg, Bcl-XL) antagonize Bax and Bak by binding to their BH3 domains. This antagonism is relieved by BH3-only, pro-apoptotic proteins (eg, BIM, BID, BAD, NOXA, PUMA), which alternately bind to anti-apoptotic proteins, like Bcl-XL. In normal cells, cellular stress would result in an upregulation of these BH3-only proteins in order to initiate apoptosis via the intrinsic apoptotic pathway.3
Currently, the intrinsic pathway is more widely implicated as a blockade to tumorigenesis.2
Extrinsic pathway
The extrinsic pathway begins outside the cell through activation of pro-apoptotic receptors on the cell surface. These are activated by molecules known as pro-apoptotic ligands.12Preclinical studies show that ligand binding causes receptors to cluster and ultimately form a death-inducing signaling complex (DISC).12
Upon DISC activation, the extrinsic pathway has been seen to adopt the same effector caspase machinery as the intrinsic pathway.12"
==========================================
WHATEVER YOU RESEARCH CURE OF CANCER MAINLY HAPPENS WHEN CANCER CELL DEATH OCCURS. KEEP YOU EYES ON THE BALL.
FDA WATCH LIST
4 Medications are back on the watch list of the FDA:
1. VIMPAT which could cause Neutropenia, meaning it has bone marrow suppression
2. Ampyra resported to cause Anaphylactic reaction
3. ARZERRA use can reactivate viral infections
4. Banana Boat sunscreen which can light up before it is dried on the skin if exposed to light
(the manufacturer has pulled this one from the Market.)
1. VIMPAT which could cause Neutropenia, meaning it has bone marrow suppression
2. Ampyra resported to cause Anaphylactic reaction
3. ARZERRA use can reactivate viral infections
4. Banana Boat sunscreen which can light up before it is dried on the skin if exposed to light
(the manufacturer has pulled this one from the Market.)
Tuesday, February 12, 2013
FREE CPRIT/ CPRIT IS ON ITS WAY BACK !
We learned today that The Health and Human Services passed a preliminary bill suggesting measures that will offer a tighter Oversight at CPRIT. The bill goes to the full chamber for approval. CPRIT represents the largest opportunity for fight against cancer in Texas primarily, but also the United States given the sparsity of available funds for cancer research and PREVENTION.
In general chances to obtain a grant is around 10% in the United States according to professors at the University of Texas in El Paso (UTEP) . According to the Audit conducted at CPRIT, the MD Anderson was reported to have received 42% of the approximated one billion so far distributed by CPRIT. This money comes from all Texans. Most of them will never see the doors of the MD Anderson when they will need care because they can not afford it! In El Paso, when you are found with a rare cancer such as a liver Angiosarcoma found recently in a 38 year old woman with no health insurance. Her chance to participate in a MD Anderson study is more likely less than 10 percent also if that. Likely enough, drug company are looking to provide some help for the Avastin we recommended as part of her treatment.
We are also currently fighting to locate funds for another man, also with lack of insurance with metastatic penile cancer with positive pathology in inguinal nodes. For these patients the prospect of going to Houston, live in a hotel to take part to a trial and afford it, is non-existent despite their participation to CPRIT funding.
For these reason alone CPRIT should not continue the current pattern of funding. El Paso has received 0.2% of funding so far despite being the 4th city in Texas. A cry for fairness is being conveyed here at CRBCM.
We look at CPRIT for fair leadership, we look at CPRIT to save life today and more in the future.
Somebody at CPRIT answer the call and fund projects that will help here, today! Help us put together programs and infrastructure to fight cancer today for a better tomorrow and for the Cure in EL Paso. Not every one can afford the trip to Houston!
We learned today that The Health and Human Services passed a preliminary bill suggesting measures that will offer a tighter Oversight at CPRIT. The bill goes to the full chamber for approval. CPRIT represents the largest opportunity for fight against cancer in Texas primarily, but also the United States given the sparsity of available funds for cancer research and PREVENTION.
In general chances to obtain a grant is around 10% in the United States according to professors at the University of Texas in El Paso (UTEP) . According to the Audit conducted at CPRIT, the MD Anderson was reported to have received 42% of the approximated one billion so far distributed by CPRIT. This money comes from all Texans. Most of them will never see the doors of the MD Anderson when they will need care because they can not afford it! In El Paso, when you are found with a rare cancer such as a liver Angiosarcoma found recently in a 38 year old woman with no health insurance. Her chance to participate in a MD Anderson study is more likely less than 10 percent also if that. Likely enough, drug company are looking to provide some help for the Avastin we recommended as part of her treatment.
We are also currently fighting to locate funds for another man, also with lack of insurance with metastatic penile cancer with positive pathology in inguinal nodes. For these patients the prospect of going to Houston, live in a hotel to take part to a trial and afford it, is non-existent despite their participation to CPRIT funding.
For these reason alone CPRIT should not continue the current pattern of funding. El Paso has received 0.2% of funding so far despite being the 4th city in Texas. A cry for fairness is being conveyed here at CRBCM.
We look at CPRIT for fair leadership, we look at CPRIT to save life today and more in the future.
Somebody at CPRIT answer the call and fund projects that will help here, today! Help us put together programs and infrastructure to fight cancer today for a better tomorrow and for the Cure in EL Paso. Not every one can afford the trip to Houston!
FDA APPROVED THE GENERIC DOXIL IN REPONSE TO SHORTAGE AND ITS CONSEQUENCES ON ONCOLOGY PRACTICES ACROSS THE UNITED STATES.
The Generic version is manufactured by SUN PHARMA GLOBAL FZE.
Shortage was first believed to be a commercial ploy to increase the price until it became real. This approval will limit chances of new shortage and will help patients with Myeloma, Kaposi sarcoma and Ovarian Cancers who need this medication the most.
The Generic version is manufactured by SUN PHARMA GLOBAL FZE.
Shortage was first believed to be a commercial ploy to increase the price until it became real. This approval will limit chances of new shortage and will help patients with Myeloma, Kaposi sarcoma and Ovarian Cancers who need this medication the most.
PLATELET DERIVED GROWTH FACTOR, A DEADLY MISNOMER
====================================================
By naming this compound PDGF, the scientist who described this cytokine not only picked the wrong name,
but also sent researchers on the wrong path to understanding just how important this growth factor is. As a result, some people are probably dying because the emphasis brought by the name was not clearly defined.
First of all, PDGF does not come solely from Platelets alone. It is made by a number of cells including Muscle cells, Endothelial cells and even Macrophages.
And when you think of Platelets, Coagulation comes to mind, weakening of platelets and the like. If this PDGF does this, it is at a strictly minimal or insignificant level. The effect on Platelets is only mentioned by those who clearly have been fooled and kept looking for rare effects which eventually can be found. This PDGF works on Mesenchymal cells since creation. It participates in Embryogenesis, cell survival, proliferation, angiogenesis and differentiation. In adults, its main effect is on Fibroblast and Glial cells.
When you think Platelet, platelet Aggregation, adhesion and so forth. PDGF kills by Fibrosis in cirrhosis of the liver and Pulmonary hypertension, one of the worse silent killers of our time. Pulmonary Hypertension is a deadly killer because physicians don't know how to best monitor it. AND BECAUSE WE CLEARLY DO NOT TREAT IT AGGRESSIVELY. HOW MANY PHYSICIAN GIVE CIALIS TO THEIR PATIENT FOR PULMONARY HYPERTENSION? If you raise your hand, you are my hero!
The point is that by misnaming the PDGF, people will assume Aspirin would be the more likely inhibitor. Think again. There are almost 20 inhibitors of PDGF listed on the SELLECHEM list. Believe me it starts with Nexavar and Sutent. Aspirin is not on the list!
HOW MANY PEOPLE THINK OF NEXAVAR IN THEIR TREATMENT OF SCLERODERMA, A DISEASE KNOW TO HAVE PROMINENCE OF PDGF ACTIVITY? HOW MANY ONCOLOGISTS GIVE GLEEVEC TO TREAT THEIR GLIOBLASTOMA. (CLUE, AVASTIN IS INDICATED IN REFRACTORY BRAIN DISEASE-YOU THINK AVASTIN-ANGIOGENESIS, THINK NEXAVAR, TELLS SELLECHEM).
In a short study, 11 out of 12 GLIOBLASTOMAS had amplification of PDGF. This is one of the drivers of GBM. Forget Platelet, think Mesenchymal derived growth factor, and let us put the right emphasis on this Cytokine!
====================================================
By naming this compound PDGF, the scientist who described this cytokine not only picked the wrong name,
but also sent researchers on the wrong path to understanding just how important this growth factor is. As a result, some people are probably dying because the emphasis brought by the name was not clearly defined.
First of all, PDGF does not come solely from Platelets alone. It is made by a number of cells including Muscle cells, Endothelial cells and even Macrophages.
And when you think of Platelets, Coagulation comes to mind, weakening of platelets and the like. If this PDGF does this, it is at a strictly minimal or insignificant level. The effect on Platelets is only mentioned by those who clearly have been fooled and kept looking for rare effects which eventually can be found. This PDGF works on Mesenchymal cells since creation. It participates in Embryogenesis, cell survival, proliferation, angiogenesis and differentiation. In adults, its main effect is on Fibroblast and Glial cells.
When you think Platelet, platelet Aggregation, adhesion and so forth. PDGF kills by Fibrosis in cirrhosis of the liver and Pulmonary hypertension, one of the worse silent killers of our time. Pulmonary Hypertension is a deadly killer because physicians don't know how to best monitor it. AND BECAUSE WE CLEARLY DO NOT TREAT IT AGGRESSIVELY. HOW MANY PHYSICIAN GIVE CIALIS TO THEIR PATIENT FOR PULMONARY HYPERTENSION? If you raise your hand, you are my hero!
The point is that by misnaming the PDGF, people will assume Aspirin would be the more likely inhibitor. Think again. There are almost 20 inhibitors of PDGF listed on the SELLECHEM list. Believe me it starts with Nexavar and Sutent. Aspirin is not on the list!
HOW MANY PEOPLE THINK OF NEXAVAR IN THEIR TREATMENT OF SCLERODERMA, A DISEASE KNOW TO HAVE PROMINENCE OF PDGF ACTIVITY? HOW MANY ONCOLOGISTS GIVE GLEEVEC TO TREAT THEIR GLIOBLASTOMA. (CLUE, AVASTIN IS INDICATED IN REFRACTORY BRAIN DISEASE-YOU THINK AVASTIN-ANGIOGENESIS, THINK NEXAVAR, TELLS SELLECHEM).
In a short study, 11 out of 12 GLIOBLASTOMAS had amplification of PDGF. This is one of the drivers of GBM. Forget Platelet, think Mesenchymal derived growth factor, and let us put the right emphasis on this Cytokine!
Monday, February 11, 2013
LBK1, A CONFUSING MARKER OF CANCER
===================================
In lung cancer, Harvard researchers have pushed us now to request a lengthy list of Markers in order to direct our treatment. The many options of therapeutic interventions have to be selected more sharply as new Driver mutations are discovered and new Target therapy drugs are made available. We made a summary of drugs and their relevant Driver Mutations in our previous blog. (KRAS, EGFR, ALK, HER-2, BRAF, ROS-1,RET, MEK-1,NRAS, MET etc. for Driver Mutations.....Medications included Erlotinib, Gefitinib, Herceptin, Lapatinib, Veramufenib, Cabozantinib, Crizotinib etc. - SEE OUR BLOG)
But for a while, 5 Mutations were mostly adopted: KRAS, BRAF, EGFR, ALK and LBK1.
The surprise choice of LBK1 has remained somewhat of a confusion. Because no one knows what to do with the information despite the fact that we know a bit about the gene. In these days, any Mutation or suppressed gene is suspect and prognosis conclusions are down. Presence of Mutation at LBK1 is considered of poor prognosis. But wait a second! Let me shake a bit this notion:
Where do we find LBK1 alteration?
In DCIS
and In Polyps
and in Hamartomas ( Peutz Jeggers) : These do not sound like invasive cancers to me!
The DCIS case: Clinicians have maintained that DCIS do not invade, and Lymph node biopsy is generally not performed in case of DCIS. Malignant transformation occurs here at 1% a year. So we need additional Mutations for DCIS to adopt a cancerous profile.
In Peuts Jeggers, despite the presence of LBK1 (STK-1), polyps take their time to transform. There the patient could develop pancreatic cancers for sure, but only after additional mutated genes come to bear! And the likelihood of this is high since a number of known substrates have been recognized to interact with LBK1.
Through Wikipedia:
SUBSTRATES OF LBK1 INCLUDE:
1. BRSK 1&2 --------Through these substrate, it insure Neuronal Polarity. And control length of neurons.
I should come to cellular polarity in a bit! But here also comes its power to organize Microtubules and could have implications on resistance vs sensitivity to Taxanes!
2. MARK 1&2--------This is where it controls Apico-basal cell Polarity, it may be controlling the popular topic of Flippase, Floppase and Scramblase.
3. SIK 1,2 : Through this substrate and its co-activator TORC2, LBK1 finds its inhibitory effect on Gluconeogesis.
4. AMPK signal pathways which favor proteins formation and translation while blocking lipogenesis. Metabolically, it favors Catalysis with generation of ATP while blocking reactions requiring consumption of ATP. At the cellular membrane the exchange of phosphorylated groups drive GTPase. Putting LBK1 center to pathways activation. At the Mitochondrial Membrane this has even more of an impact.
5. NUAK 1,&2 which regulate Apoptosis through P53. It is speculated that the overall effect of LBK1 is naturally anti-tumor. Its alteration stops Apoptosis.
6. In the Embryo, LBK1 has demonstrated a role in Angiogenesis. MEK or VEGF interaction is assumed.
One speculated that chronic exposure to Insulin like growth factor stimulation, or Estrogenic stimulation or inflammation or chronic mechanical stimulation forces desensitization through SPRADD or other genes altering LBK1 leading to loss of polarity and linear arrangement of cells by dysfunctional adhesion leading to "benign tumorous formations called polyps. Further alterations happen as abnormal genetic evolution occurs and progresses into a full blown Malignancy.
It is also believed that once malignant transformation happens, LBK1 functions could "amplify" then the transformation favoring cell migration.
Many questions remain to be solved when it comes to LBK1...
===================================
In lung cancer, Harvard researchers have pushed us now to request a lengthy list of Markers in order to direct our treatment. The many options of therapeutic interventions have to be selected more sharply as new Driver mutations are discovered and new Target therapy drugs are made available. We made a summary of drugs and their relevant Driver Mutations in our previous blog. (KRAS, EGFR, ALK, HER-2, BRAF, ROS-1,RET, MEK-1,NRAS, MET etc. for Driver Mutations.....Medications included Erlotinib, Gefitinib, Herceptin, Lapatinib, Veramufenib, Cabozantinib, Crizotinib etc. - SEE OUR BLOG)
But for a while, 5 Mutations were mostly adopted: KRAS, BRAF, EGFR, ALK and LBK1.
The surprise choice of LBK1 has remained somewhat of a confusion. Because no one knows what to do with the information despite the fact that we know a bit about the gene. In these days, any Mutation or suppressed gene is suspect and prognosis conclusions are down. Presence of Mutation at LBK1 is considered of poor prognosis. But wait a second! Let me shake a bit this notion:
Where do we find LBK1 alteration?
In DCIS
and In Polyps
and in Hamartomas ( Peutz Jeggers) : These do not sound like invasive cancers to me!
The DCIS case: Clinicians have maintained that DCIS do not invade, and Lymph node biopsy is generally not performed in case of DCIS. Malignant transformation occurs here at 1% a year. So we need additional Mutations for DCIS to adopt a cancerous profile.
In Peuts Jeggers, despite the presence of LBK1 (STK-1), polyps take their time to transform. There the patient could develop pancreatic cancers for sure, but only after additional mutated genes come to bear! And the likelihood of this is high since a number of known substrates have been recognized to interact with LBK1.
Through Wikipedia:
SUBSTRATES OF LBK1 INCLUDE:
1. BRSK 1&2 --------Through these substrate, it insure Neuronal Polarity. And control length of neurons.
I should come to cellular polarity in a bit! But here also comes its power to organize Microtubules and could have implications on resistance vs sensitivity to Taxanes!
2. MARK 1&2--------This is where it controls Apico-basal cell Polarity, it may be controlling the popular topic of Flippase, Floppase and Scramblase.
3. SIK 1,2 : Through this substrate and its co-activator TORC2, LBK1 finds its inhibitory effect on Gluconeogesis.
4. AMPK signal pathways which favor proteins formation and translation while blocking lipogenesis. Metabolically, it favors Catalysis with generation of ATP while blocking reactions requiring consumption of ATP. At the cellular membrane the exchange of phosphorylated groups drive GTPase. Putting LBK1 center to pathways activation. At the Mitochondrial Membrane this has even more of an impact.
5. NUAK 1,&2 which regulate Apoptosis through P53. It is speculated that the overall effect of LBK1 is naturally anti-tumor. Its alteration stops Apoptosis.
6. In the Embryo, LBK1 has demonstrated a role in Angiogenesis. MEK or VEGF interaction is assumed.
One speculated that chronic exposure to Insulin like growth factor stimulation, or Estrogenic stimulation or inflammation or chronic mechanical stimulation forces desensitization through SPRADD or other genes altering LBK1 leading to loss of polarity and linear arrangement of cells by dysfunctional adhesion leading to "benign tumorous formations called polyps. Further alterations happen as abnormal genetic evolution occurs and progresses into a full blown Malignancy.
It is also believed that once malignant transformation happens, LBK1 functions could "amplify" then the transformation favoring cell migration.
Many questions remain to be solved when it comes to LBK1...
SPLICEOSOME MACHINERY AND MYELOID MALIGNANCIES
--------------------------------------------------------------------------
Spliceosome
-------------------------------------------------------------------------------
Spliceosome contains 300 different proteins and 5 RNAs (U1-6). making a very large complex.
-------------------------------------------------------------------------------------------------
In Myeliod Malignancies, Hamilton et al. reported that Spliceosomal Mutations had prognostic implications in patients undergoing Hematopoietic Cell Transplantation.
SF3B1 having the better survival in MDS patients while
Mutants in SRSF and U2AF1 had worse prognosis. Transplant is more indicated in these!
-------------------------------------------------------------------------------------------------
WE DISCUSSED HOW SPLICING IS INCLUDED IN DIFFERENTIATION BECAUSE WHERE IT OCCURS DETERMINES THE LENGTH, NATURE AND MORPHOLOGY OF THE RESULTING PROTEINS.
--------------------------------------------------------------------------
Spliceosome
From Wikipedia,
A spliceosome is a complex of snRNA and protein subunits that removes introns from a transcribed pre-mRNA (hnRNA) segment. This process is generally referred to as splicing.-------------------------------------------------------------------------------
Spliceosome contains 300 different proteins and 5 RNAs (U1-6). making a very large complex.
-------------------------------------------------------------------------------------------------
In Myeliod Malignancies, Hamilton et al. reported that Spliceosomal Mutations had prognostic implications in patients undergoing Hematopoietic Cell Transplantation.
SF3B1 having the better survival in MDS patients while
Mutants in SRSF and U2AF1 had worse prognosis. Transplant is more indicated in these!
-------------------------------------------------------------------------------------------------
WE DISCUSSED HOW SPLICING IS INCLUDED IN DIFFERENTIATION BECAUSE WHERE IT OCCURS DETERMINES THE LENGTH, NATURE AND MORPHOLOGY OF THE RESULTING PROTEINS.
Sunday, February 10, 2013
SHIFTING WAR FRONT AT CPRIT, FOCUS ON THE "FOUNDATION"
----------------------------------------
The war at CPRIT has moved from CPRIT proper to its related Foundation. The foundation had received from senators a request to disclose communications that occurred, and could incriminate Foundation officials in secret dealings with donors who happened to be from the CPRIT governing board and oversight committee, and at the same token beneficiaries of CPRIT funds. The request had been made under obligatory disclosure laws that rule Government agencies.The executive Director of the CPRIT Foundation argue that disclosure rule should not be enforced in this case because the funding of the foundation comes from donors who's communications is the target of the request. It is a surprise a position since just few days back the foundation had released the list of its donors. Speculation is that the consequences of that release made the Foundation rethink its strategy.
Senator Wendy Davis has filed reportedly the argument that since the CPRIT Foundation was created and mentioned within the law that brought to life CPRIT proper, the Foundation is a public institution and should submit to the request for information disclosure law. The District Attorney has 30 day to take a position on this matter by law. All this is good for transparency at CPRIT but hold the program hostage! FREE CPRIT IS WHAT WE ASK.
STOP THIS TUG-O-WAR ROPE GAME IF THERE IS NOTHING TO HIDE!
,
----------------------------------------
The war at CPRIT has moved from CPRIT proper to its related Foundation. The foundation had received from senators a request to disclose communications that occurred, and could incriminate Foundation officials in secret dealings with donors who happened to be from the CPRIT governing board and oversight committee, and at the same token beneficiaries of CPRIT funds. The request had been made under obligatory disclosure laws that rule Government agencies.The executive Director of the CPRIT Foundation argue that disclosure rule should not be enforced in this case because the funding of the foundation comes from donors who's communications is the target of the request. It is a surprise a position since just few days back the foundation had released the list of its donors. Speculation is that the consequences of that release made the Foundation rethink its strategy.
Senator Wendy Davis has filed reportedly the argument that since the CPRIT Foundation was created and mentioned within the law that brought to life CPRIT proper, the Foundation is a public institution and should submit to the request for information disclosure law. The District Attorney has 30 day to take a position on this matter by law. All this is good for transparency at CPRIT but hold the program hostage! FREE CPRIT IS WHAT WE ASK.
STOP THIS TUG-O-WAR ROPE GAME IF THERE IS NOTHING TO HIDE!
,
Follow-up at SAN ANTONIO
Researcher from Vanderbilt, namely Justin M Balko submitted a report where they examined tissue from 81 women who had undergone Neoadjuvant chemotherapy, in their study, they examined 450 genes as opposed to the 180 reported earlier.
90% of of all patient had at least 1 aberration in 5 signal pathways
1- PI3K/MTOR (therefore opening the door to Afinitor and related agents)
2. DNA repair (May be PARP will have a role here)
3. Ras/MAP kinase (Anti Myc /MEK inhibitor)
4. Cell cycle division (May be the Histone Deacetylase transferase inhibitor)
5. Growth Factor (Interferon and Interleukins)
Most common Mutations were in
-P53 (role of Vitamin D can be discussed here)
- MCL-1(found in 56% of tissue) and Myc, found in 36% (Histone deacyltransferase inhibitors here but also role of anti-actin/anti-Microtubule/anti-calmodulin )
The finding of prominent MCL-1, a Bcl-2 member goes directly to basic resistance to chemotherapy and actually could be reactive or an expression of primary refractoriness to chemotherapy.
JAK-2 was found in 11% (JAK2 inhitors could be tried)
Amplification in the MEK (cabozantinib)
PIM-1 would bring to bear Inteferon and Interleukins as therapeutic drugs (watch out PIM1 is an indicator that cyclins are an important drivers as they affect STAT3,5
The corollary question is whether to give the target therapy in maintenance setting or at time of progression.
-------------------------------------------
Medications and MCL-1 comment suggested here were not part of the report. We are working hard at CRBCM!
A New Way to Tackle Triple-Negative Breast Cancer?
Introductions
Kathy D. Miller, MD: Hello. I am Kathy Miller, Associate Professor of Medicine at the Indiana University School of Medicine in Indianapolis. This is Medscape Oncology Insights, coming to you from the 2012 San Antonio Breast Cancer Symposium. Joining me today is Dr. Carlos Arteaga, Associate Director for Clinical Research and Director of the Breast Cancer Program at the Vanderbilt Ingram Cancer Center at Vanderbilt University in Nashville. Welcome, Carlos.Carlos L. Arteaga, MD: How are you?
Cleaning Up the Micrometastases
Dr. Miller: Thank you for taking the time to come. I am looking forward to talking with you about your profiling work on the genetic diversity found in triple-negative breast cancer. This was started by your group and Jennifer Pietenpol, but the work you are presenting here takes it to another level, looking at whether metastasis is best predicted by the primary or residual disease. Tell me how you did that study.[1]Dr. Arteaga: We speculated that patients with residual tumors after neoadjuvant chemotherapy are drug-resistant and may harbor targetable alterations that mirror what is happening in their micrometastases. The standard of care is observation, but we know that these patients tend to have a bad prognosis. We should probably treat them with something, but we don't know what. They have completed neoadjuvant chemotherapy, and they have residual disease (which is a harbinger of high odds of recurrence), so we speculated that we should be able to find targetable lesions in that residual disease that may mirror what is happening in the micrometastasis. If so, we could be in a position to institute early adjuvant trials with targeted therapies to clean up that micrometastatic compartment and potentially change the natural history of recurrence of disease, curing some patients.
Dr. Miller: This is an idea that we have talked about a lot -- that one of the benefits of neoadjuvant therapy is allowing us to know how well that therapy works, specifically for a particular woman and her tumor. We have tended to focus on the successes; the patients who have a pathologic complete response do really well. That has always left us with this problem, that the patients who don't have a pathologic complete response -- particularly if they have aggressive disease histology -- have a very high risk for recurrence, and we don't have a clue clinically what to do about them. Could this give us a way to find therapies for those patients?
Getting an Early Jump on Residual Disease
Dr. Arteaga: That is precisely the purpose of this type of investigation. We still have to prove to ourselves and to everybody else that when those metastatic recurrences occur, they mirror the postchemotherapy residual disease better than the primary disease. I think that we are going to find that the metastatic recurrence, molecularly and by subtyping, resembles more that residual tumor.We are at a point, at least in academic centers that have access to all these technologies, that we should be able to study these tumors in some depth. We already have examples that stem cell signatures are selected by chemotherapy.
There was a beautiful study from the MD Anderson Cancer Center[2] showing that in HER2-positive tumors after neoadjuvant chemotherapy, if HER2 status went from positive to negative, those tumors didn't do well. It suggested the possibility that this therapy had selected a HER2-negative compartment that would not benefit from adjuvant trastuzumab, if in fact it was reflective of the micrometastases in those patients.
Dr. Miller: I have seen some of the data from your work, which is a major tour de force with a large number of samples -- not just paired samples, but a triplet of samples.
Dr. Arteaga: We don't have those data yet. What we showed today was just the profiling of the postchemotherapy residual cancer in the breast. In some cases, we have the metastatic recurrences, and in many patients, we have the pretreatment tumors. We have to complete the triplet and the analysis of the triplets. That's in progress.
No Tumor Stays the Same
Dr. Miller: You would expect the postchemotherapy residual disease to look different from the primary disease in some ways.Dr. Arteaga: It's always going to look different.
Dr. Miller: Is it going to look different because something actually changed in the tumor, or because there was tumor heterogeneity and the proportion of those different populations has shifted?
Dr. Arteaga: Both of those hypotheses can coexist; they are not mutually exclusive. Probably, both things are going on. There is tumor heterogeneity, and in addition, it's possible that for cells that don't die; the 4 months of therapeutic pressure may change them. So, both things could be going on.
Dr. Miller: Would it affect how you would proceed with that patient after her surgery?
Dr. Arteaga: We have to do more studies to confirm and to get more data that those metastatic recurrences share targetable alterations with the posttreatment residual disease. It would be interesting to know whether we are dealing with selection as a function of the heterogeneity or selection as a function of changing our tumor cell autonomous mechanisms, but that would be academic. If we can confirm that they are targetable lesions that are mirrored in the micrometastatic compartment and in the residual disease, we probably have enough evidence to act upon some of these therapeutic targets -- in randomized studies, of course.
Dr. Miller: Let me ask you about the complexity, because you are likely to find not just 1 or 2 potential targets, but a lot of alterations. Do you have any sense from the data so far how wide that complexity might be? How big a number of different therapies are we going to need?
Dr. Arteaga: That is a very good question. We screen for only 182 oncogenes and tumor suppressors. We found that there was not a single prominent lesion, except for p53 mutations, which as you know are not targetable. But 30%-40% of tumors had MCL1, which is a targetable antiapoptotic gene and Myc gene amplification. There were other lesions in the PI3 kinase pathway, alterations in different genes in the pathway.
We could be at a point eventually where we can lump types of alterations in a network and say, "Okay, I see alterations in the RAS/RAF/MAP kinase pathway; should I treat these patients with a Myc inhibitor, or a group of alterations in the PI3 kinase pathway, PI3 kinase, P10, AKT, et cetera, and lump them?" This is going to require collaboration -- multi-institutional studies that would allow us to start exploratory studies where we already have very deep information about the tumors we are treating.
Are Randomized Trials Possible?
Dr. Miller: I am going to ask you about the practicalities of those studies, because it's an intriguing idea to take advantage of what you learn about an individual patient's tumor. It has this alteration, so I will treat the patient with a drug targeting that alteration, but not all of those patients will have recurrence. Some of them live long, happy lives in that setting, although they are a high-risk group. With the complexity of the disease and the number of different mutations, how does that become a randomized study to find out whether those therapies had an impact?Dr. Arteaga: I am not sure that it will be difficult in the following sense. We are not treating the patients who have a pathologic complete response, because we cannot generate data from them; there is no tissue to study. Some of these alterations are going to be associated with a very early recurrence.
For example, in our study, patients who have Myc gene amplification recurred very quickly. So I bet that you can put studies together; it will be multi-institutional studies where you group patients of the same genotype and do a randomized study. It will be a difficult discussion, but you can think of a 2:1 randomization of experimental therapy vs observation, and based on the natural history that we see in these recurrences, we may get an answer pretty soon as to whether we are making an impact. It won't be easy, but at least in these trials we have molecular information before we deploy it, and that's probably a departure from what we have done up to now.
Alter Neoadjuvant Therapy to Match the Tumor
Dr. Miller: Are there other ways in which this information could be helpful? Could you use that information to alter the patient's neoadjuvant therapy at the beginning instead of waiting until she has had standard therapy?
OC468900PROF-D 10/12
Information from Industry
Dr. Miller: Carlos, you have given us a great view of the future. It's a complicated one, but one that has great potential to benefit our patients. We look forward to catching up with your work as it progresses.
Dr. Arteaga: Thank you.
Dr. Miller: Thank you for joining us, and thank you to our audience for joining us for this edition of Medscape Oncology Insights. This is Kathy Miller, signing off from the 2012 San Antonio Breast Cancer Symposium.
FROM MEDSCAPE, SHARING ONLY!
=====================================================================
COMMENT:
This research is an important one as it may open the door to knowledge to genetic pattern of resistant Breast cancers. It will answer a critical question about what to do with residual cancers?
This question is a major one particularly when you give up front all the chemotherapy in Neoadjuvant setting and you still have a residual mass that the surgeon eventually removes. Current recommendation is to proceed with Radiation and no further chemotherapy (Aromatase inhibitor or Tamoxifen in ER positive patient) and basically observe where the chips fall. (in triple negative patients).
By gaining insight into the nature of the residual disease, one may suggest additional intervention to offer to women with partial response after neoadjuvant chemotherapy.
Another important aspect discussed during the discussion is no notion of gene profile of the metastatic disease as it compares to the original presentation Vs the residual disease. This flow of progression in the profile of the gene will be even more important because it will bring out the variation in gene profile with the genetic intervention.
suppose:
A would be the gene profile at presentation
B gene profile in the residual disease after neoadjuvant therapy
C gene profile at Metastasis
difference between A and B
--------------------------------
could be induced by treatment but indeed could be a tumor evolution or both meaning evolution as affected or shaped by Chemotherapy intervention. The nature of the chemotherapy becomes critical. What agents were actually used. We can even detect the pattern of changes imposed by which chemotherapy.
Difference between B and C
-------------------------------
will tell us the true evolution of tumor,
it will point to evanescent effect of chemotherapy, and therefore which gene changes are temporary, due to chemotherapy or fixed.
It will point to important genes that actually drive metastatic progression
Difference in A and C
--------------------------
will point to what gene where not affected by chemotherapy and establish refractoriness and persist despite intervention. It may point to the soul of the cancer. if And C are completely different. True evolution of cancer will be learned.
This exhaustive comparative evaluation point to the fragmentary nature of the study by DR Arteaga SINCE IT FOCUSED B ONLY. It is a necessary step but clearly limited. It also point to the importance of the interpretation of the results obtained or to be obtained at each step!
They are onto something for sure. and 180 genes being looked at. that is impressive, and call for careful interpretation of results. HOW THESE GENES WERE SELECTED FOR SCREENING AGAIN?
===================================================================
Follow-up at SAN ANTONIO
Researcher from Vanderbilt, namely Justin M Balko submitted a report where they examined tissue from 81 women who had undergone Neoadjuvant chemotherapy, in their study, they examined 450 genes as opposed to the 180 reported earlier.
90% of of all patient had at least 1 aberration in 5 signal pathways
1- PI3K/MTOR (therefore opening the door to Afinitor and related agents)
2. DNA repair (May be PARP will have a role here)
3. Ras/MAP kinase (Anti Myc /MEK inhibitor)
4. Cell cycle division (May be the Histone Deacetylase transferase inhibitor)
5. Growth Factor (Interferon and Interleukins)
Most common Mutations were in
-P53 (role of Vitamin D can be discussed here)
- MCL-1(found in 56% of tissue) and Myc, found in 36% (Histone deacyltransferase inhibitors here but also role of anti-actin/anti-Microtubule/anti-calmodulin )
The finding of prominent MCL-1, a Bcl-2 member goes directly to basic resistance to chemotherapy and actually could be reactive or an expression of primary refractoriness to chemotherapy.
JAK-2 was found in 11% (JAK2 inhitors could be tried)
The corollary question is whetehr to give the target therapy in maintenance setting or at time of progression.
Follow-up at SAN ANTONIO
Researcher from Vanderbilt, namely Justin M Balko submitted a report where they examined tissue from 81 women who had undergone Neoadjuvant chemotherapy, in their study, they examined 450 genes as opposed to the 180 reported earlier.
90% of of all patient had at least 1 aberration in 5 signal pathways
1- PI3K/MTOR (therefore opening the door to Afinitor and related agents)
2. DNA repair (May be PARP will have a role here)
3. Ras/MAP kinase (Anti Myc /MEK inhibitor)
4. Cell cycle division (May be the Histone Deacetylase transferase inhibitor)
5. Growth Factor (Interferon and Interleukins)
Most common Mutations were in
-P53 (role of Vitamin D can be discussed here)
- MCL-1(found in 56% of tissue) and Myc, found in 36% (Histone deacyltransferase inhibitors here but also role of anti-actin/anti-Microtubule/anti-calmodulin )
The finding of prominent MCL-1, a Bcl-2 member goes directly to basic resistance to chemotherapy and actually could be reactive or an expression of primary refractoriness to chemotherapy.
JAK-2 was found in 11% (JAK2 inhitors could be tried)
The corollary question is whetehr to give the target therapy in maintenance setting or at time of progression.
A NOTE ON KIDNEY CANCER
As we suggested, there is evidence that the treatment of Clear cell renal cancer should be different from that of papillary cancers. Papillary cancers are MET driven and therefore more treatable with Sutent, Avastin, and Lapatinib. Basically, anti-VEGF will be more likely to work because this is where MET has the strongest influence. The Von Hippel Lindau is more associated with clear cell, and here the driving is non degradation of the Hypoxia-Inducible Factor which then dimerise to exarcebated VEGF, but have more disturbance at mitochondria. An mTor inhibitor should be the driver Medicine. There is VEGF amplification which is secondary. The Hypoxia-Inducible Factor prominence in VHL brings to bear many disturbances not only in the Cytosol (on Amplification of signal transduction pathways, cyclins and growth factors), but also in the Mitochondria where Hypoxia disrupts cellular respiratory function. Nuclear disruptions are more notable in clear cells. The mTor inhibitors really act here more and therefore should be the main drug in the treatment of Clear cell cancer. The Combination of these drugs appears to be a more adequate standard of care, particularly in refractory disease.
In relapse and refractory diseases, addition of Interferon which modulates the cyclins and recruist immune defense to the mix is an option. Cytotoxics (chemotherapy drug such as Gemzar) could have a role, but not alone. anti-VEGF and/or anti-mTor must be left in the mix/combination.
When DR Toni Choueiri was working on Cabozantinib, he included papillary and clear cell alike, and got results in both groups. Cabozantinib is an Anti- c-MET and VEGFR2. The result of that study with a 14.7 months progression free survival stresses the heavy participation of Angiogenesis in Kidney cancer in general, no matter the type.
While it is easy to infer that a combination of these drugs would be the best option to achieve higher response rates, when you look at survival of the patients one is surprised sometimes when sequential administration of these therapeutic options yields equivalent survival in clinical trial.
I should remind the reader that Cabozantinib has activity in prostate Cancer (a lower dosage). And that Axitinib, another Anti-VEGF (1-3), with activity at Platelet derived Growth factor and c-KIT (CD 117) has also a role in Kidney cancer and should not be forgotten. This drug has been combined to Gemzar in Pancreatic cancers.
Of note, "Angiogenesis genes EMCN and NOS3 and immune related genes CCL4, CXCL9" have prognosis value. Other genes of Prognosis Value include CA9, MKI67,CD274, BIRC5 (ALSO CALLED SURVIVIN). (Lancet Oncology pg 9).
The cure is within reach. We work hard at the CRBCM!
In relapse and refractory diseases, addition of Interferon which modulates the cyclins and recruist immune defense to the mix is an option. Cytotoxics (chemotherapy drug such as Gemzar) could have a role, but not alone. anti-VEGF and/or anti-mTor must be left in the mix/combination.
When DR Toni Choueiri was working on Cabozantinib, he included papillary and clear cell alike, and got results in both groups. Cabozantinib is an Anti- c-MET and VEGFR2. The result of that study with a 14.7 months progression free survival stresses the heavy participation of Angiogenesis in Kidney cancer in general, no matter the type.
While it is easy to infer that a combination of these drugs would be the best option to achieve higher response rates, when you look at survival of the patients one is surprised sometimes when sequential administration of these therapeutic options yields equivalent survival in clinical trial.
I should remind the reader that Cabozantinib has activity in prostate Cancer (a lower dosage). And that Axitinib, another Anti-VEGF (1-3), with activity at Platelet derived Growth factor and c-KIT (CD 117) has also a role in Kidney cancer and should not be forgotten. This drug has been combined to Gemzar in Pancreatic cancers.
Of note, "Angiogenesis genes EMCN and NOS3 and immune related genes CCL4, CXCL9" have prognosis value. Other genes of Prognosis Value include CA9, MKI67,CD274, BIRC5 (ALSO CALLED SURVIVIN). (Lancet Oncology pg 9).
The cure is within reach. We work hard at the CRBCM!
Saturday, February 9, 2013
SOME GENES OF METASTASIS
1. miR 126
------------
This gene is the center of Metastatic progression of disease, It is the agent of cellular entrance in vessels to start migration. Activation of miR126 start the metastatic process by controlling events at the cellular membranes by acting on the CRK. Should the cell need more time to engage in multiplication before seeding, it uses IRS-1 to block cell division. By SPRED-1, TOM1, VEGF-A and PIK3-R2, it modulates formation of proper vascular channel through which cancer cell can penetrate blood vessel or vessels in general without leak. Remember cavalier tampering with blood vessel leads to leaks recognized as a risk in the use of Avastin. Same danger recognized in squamous cell lung cancer with the use of certain anti-VEGF.
It also serve as a general amplifier of all Metastatic genes (HOX9).
It even modulates defense cells. (inhibition of GATA3 through POU3F1)
It has been seen in almost all solid tumors and hematologic malignancies.
and is predictive of Metastasis....
miR 126, a huge target during maintenance therapy. No miR 126, No embryogenesis!
2. miR 335
---------------------(there are 750 miR recognized from various species) This one is also common in human cancers.
3. TWIST-1
-------------
The family of TWIST but particularly transcription factor TWIST-1, has been implicated in cell lineage and differentiation. It allows the cell to cope with Hypoxia and to resist Cisplatin attacks. In Metastasis it seems to participate in the upregulation of Metalloproteases, the enzymes that breaks tissue collagens and fibronectin, opening up the road to Migration. Of note, Concurrent upregulation of MYC and TWIST-1 have been detected in Neuroblastoma. The most important function is through its interaction with K-RAS. This is where TWIST-1 shuts down senescence which could lead to Apoptosis. Knocking down TWIST-1 seems to put back the cell through its maturation track. This target can be important in Leukemia in theory.
There is a Notch1/STAT3/TWIST-1/KRAS/EP300 axis here which some how is totally anti-apoptosis through blockage of natural aging of cancerous cell. This has been in worse types of lung cancer.
Through its interaction with EP300, PCAF, it activates the NOTCH-1 and through TCF3, it amplify differentiation and metastasis.
TWIST-1 cause cell detachment by decreasing Claudin4
TWIST-1 shuts cell division by increasing Bmi-1
4. SNA 11, and 12
--------------------
5. MACC-1 in Colon cancer
-------------------------- "MACC1 is a key regulator of the hepatocyte growth factor (HGF; MIM 142409)-HGF receptor (HGFR, or MET; MIM 164860) pathway, which is involved in cellular growth, epithelial-mesenchymal transition, angiogenesis, cell motility, invasiveness, and metastasis. Expression of MACC1 in colon cancer (MIM 114500) specimens is an independent prognostic indicator for metastasis formation and metastasis-free survival (Stein et al., 2009 [PubMed 19098908]).[supplied by OMIM, Mar 2009]"
Mesenchymal expression in any cancer is bad sign but in this particular case this point to adaptation to invaded tissue and its tendency to migrate as if in embryonal state to where these receptors are with seeding intentions!
HGFR -MET will promote angigenesis and is the very reason Avastin is advised in Metastatic colon cancer. And support the idea of "Maintenance therapy" or continued Avastin in progression of diseases.
Presence of MACC-1 and its amplification c-MET are the underlying reason for the success of Nexavar in Hepatocellular cancer where Cabozantinib will certainly have a role!
6. Methaderin in Breast cancer
-------------------------------
Wikipedia says it better:
AEG-1 induces an oncogene called Late SV40 factor (LSF/TFCP2) which is involved in thymidylate synthase (TS) induction and DNA biosynthesis synthesis.[6] Late SV40 factor (LSF/TFCP2) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP9).[7]
Elevated expression of the metastasis gene metadherin (MTDH), which is overexpressed in more than 40% of breast cancers, is associated with poor clinical outcomes. MTDH has a dual role in promoting metastatic seeding and enhancing chemoresistance. MTDH is therefore a potential therapeutic target for enhancing chemotherapy and reducing metastasis.[9]
LSF/TFCP2 plays multifaceted role in chemo resistance, EMT, allergic response, inflammation and Alzheimer’s disease.[10]
AEG-1 controls many hallmarks of oncogenes and cancer. AEG-1/MTDH induces hepato steatosis in mouse liver.[11] The MTDH knockdown by artificial microRNA interference functions as a potential tumor suppressor in breast cancer.[12] Astrocyte elevated gene-1/MTDH undergoes palmitoylation in normal and abnormal physiology of the cell [13].The microgrooved biomaterial titanium substrata can alter the expression of AEG-1 in human primary cells [14]."
Wikipedia says it best:
Discovered at Princeton, present in 30-40% of breast cancers.
7. InterLeukin -11 and PTHR in seeding into the bones:
----------------------------------------------
8. Role of Hepatocyte Growth Factor receptors
------------------------------------------------
9. Role OF DEATH RECEPTOR 3: apparantly by exocytosis, these molecules are thrown into the extra cellular Matrix to play a role of Decoy fooling cellular defense from the neighboring cell
10. ROLE OF RECEPTORS, CLA,LFA-1,CCR-4, CXR-4,Fas, p15, p16
11. Eph-A4: This receptor has a role in cell development. It actually receives molecule or ligand for the neighboring cell. and depend on the ligand (Ephrin Vs others) it know where and when to migrate. It is critical to the development of the central Nervous system. researcher have look at this receptor for development of Melanoma therapy. some Blockers at this receptors may promote Axonal regeneration
Others UNDER REVIEW AT CRBCM.
-----------------------------------------
Group 1 : CCL-5, EREG, MMP-1, LOX, PTGS, ANGPTL-4,
Group_2: CSF2RB, MET,D1
Grooup 3: KISS-1,DARC,GPR, ERBB2,CTNNB1
12. METALLOPROTEASES, AND THEIR RECEPTORS IN METASTASIS.
13. INTEGRINS, ICAM-2, E-CADHERINS, SIALYL LEWIS CARBOHYDRATES, SELECTINS P AND E.
1. miR 126
------------
This gene is the center of Metastatic progression of disease, It is the agent of cellular entrance in vessels to start migration. Activation of miR126 start the metastatic process by controlling events at the cellular membranes by acting on the CRK. Should the cell need more time to engage in multiplication before seeding, it uses IRS-1 to block cell division. By SPRED-1, TOM1, VEGF-A and PIK3-R2, it modulates formation of proper vascular channel through which cancer cell can penetrate blood vessel or vessels in general without leak. Remember cavalier tampering with blood vessel leads to leaks recognized as a risk in the use of Avastin. Same danger recognized in squamous cell lung cancer with the use of certain anti-VEGF.
It also serve as a general amplifier of all Metastatic genes (HOX9).
It even modulates defense cells. (inhibition of GATA3 through POU3F1)
It has been seen in almost all solid tumors and hematologic malignancies.
and is predictive of Metastasis....
miR 126, a huge target during maintenance therapy. No miR 126, No embryogenesis!
2. miR 335
---------------------(there are 750 miR recognized from various species) This one is also common in human cancers.
3. TWIST-1
-------------
The family of TWIST but particularly transcription factor TWIST-1, has been implicated in cell lineage and differentiation. It allows the cell to cope with Hypoxia and to resist Cisplatin attacks. In Metastasis it seems to participate in the upregulation of Metalloproteases, the enzymes that breaks tissue collagens and fibronectin, opening up the road to Migration. Of note, Concurrent upregulation of MYC and TWIST-1 have been detected in Neuroblastoma. The most important function is through its interaction with K-RAS. This is where TWIST-1 shuts down senescence which could lead to Apoptosis. Knocking down TWIST-1 seems to put back the cell through its maturation track. This target can be important in Leukemia in theory.
There is a Notch1/STAT3/TWIST-1/KRAS/EP300 axis here which some how is totally anti-apoptosis through blockage of natural aging of cancerous cell. This has been in worse types of lung cancer.
Through its interaction with EP300, PCAF, it activates the NOTCH-1 and through TCF3, it amplify differentiation and metastasis.
TWIST-1 cause cell detachment by decreasing Claudin4
TWIST-1 shuts cell division by increasing Bmi-1
4. SNA 11, and 12
--------------------
5. MACC-1 in Colon cancer
-------------------------- "MACC1 is a key regulator of the hepatocyte growth factor (HGF; MIM 142409)-HGF receptor (HGFR, or MET; MIM 164860) pathway, which is involved in cellular growth, epithelial-mesenchymal transition, angiogenesis, cell motility, invasiveness, and metastasis. Expression of MACC1 in colon cancer (MIM 114500) specimens is an independent prognostic indicator for metastasis formation and metastasis-free survival (Stein et al., 2009 [PubMed 19098908]).[supplied by OMIM, Mar 2009]"
Mesenchymal expression in any cancer is bad sign but in this particular case this point to adaptation to invaded tissue and its tendency to migrate as if in embryonal state to where these receptors are with seeding intentions!
HGFR -MET will promote angigenesis and is the very reason Avastin is advised in Metastatic colon cancer. And support the idea of "Maintenance therapy" or continued Avastin in progression of diseases.
Presence of MACC-1 and its amplification c-MET are the underlying reason for the success of Nexavar in Hepatocellular cancer where Cabozantinib will certainly have a role!
6. Methaderin in Breast cancer
-------------------------------
Wikipedia says it better:
"'Function
AEG-1 is involved in HIF-1alpha mediated angiogenesis. AEG-1 also interacts with SND1 and involved in RNA-induced silencing complex (RISC) and plays very important role in RISC and miRNA functions.[4][5]AEG-1 induces an oncogene called Late SV40 factor (LSF/TFCP2) which is involved in thymidylate synthase (TS) induction and DNA biosynthesis synthesis.[6] Late SV40 factor (LSF/TFCP2) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP9).[7]
Clinical significance
AEG-1 acts as an oncogene in melanoma, malignant glioma, breast cancer and hepatocellular carcinoma.[8] It is highly expressed in these cancers and helps in progression and development of these cancers. It is induced by c-Myc oncogene and plays very important role in anchorage independent growth of cancer cells.Elevated expression of the metastasis gene metadherin (MTDH), which is overexpressed in more than 40% of breast cancers, is associated with poor clinical outcomes. MTDH has a dual role in promoting metastatic seeding and enhancing chemoresistance. MTDH is therefore a potential therapeutic target for enhancing chemotherapy and reducing metastasis.[9]
LSF/TFCP2 plays multifaceted role in chemo resistance, EMT, allergic response, inflammation and Alzheimer’s disease.[10]
AEG-1 controls many hallmarks of oncogenes and cancer. AEG-1/MTDH induces hepato steatosis in mouse liver.[11] The MTDH knockdown by artificial microRNA interference functions as a potential tumor suppressor in breast cancer.[12] Astrocyte elevated gene-1/MTDH undergoes palmitoylation in normal and abnormal physiology of the cell [13].The microgrooved biomaterial titanium substrata can alter the expression of AEG-1 in human primary cells [14]."
Wikipedia says it best:
Discovered at Princeton, present in 30-40% of breast cancers.
7. InterLeukin -11 and PTHR in seeding into the bones:
----------------------------------------------
8. Role of Hepatocyte Growth Factor receptors
------------------------------------------------
9. Role OF DEATH RECEPTOR 3: apparantly by exocytosis, these molecules are thrown into the extra cellular Matrix to play a role of Decoy fooling cellular defense from the neighboring cell
10. ROLE OF RECEPTORS, CLA,LFA-1,CCR-4, CXR-4,Fas, p15, p16
11. Eph-A4: This receptor has a role in cell development. It actually receives molecule or ligand for the neighboring cell. and depend on the ligand (Ephrin Vs others) it know where and when to migrate. It is critical to the development of the central Nervous system. researcher have look at this receptor for development of Melanoma therapy. some Blockers at this receptors may promote Axonal regeneration
Others UNDER REVIEW AT CRBCM.
-----------------------------------------
Group 1 : CCL-5, EREG, MMP-1, LOX, PTGS, ANGPTL-4,
Group_2: CSF2RB, MET,D1
Grooup 3: KISS-1,DARC,GPR, ERBB2,CTNNB1
12. METALLOPROTEASES, AND THEIR RECEPTORS IN METASTASIS.
13. INTEGRINS, ICAM-2, E-CADHERINS, SIALYL LEWIS CARBOHYDRATES, SELECTINS P AND E.
CANCER METASTASIS AND INVASION
================================
Things seems to become blurry rapidly when you approach this subject because of the intertwined steps involved in these processes. Cancer cells do not spread with intent to kill the host. In solid tumors, Evidences suggest however that in order to survive its local expansion, it needs to find food, building materials and Oxygen elsewhere. Indeed local growth can only support so much, migration of stressed cancer cells will eventually Occur.
Like Many cellular processes, Metastasis and invasion are molecular based and involves:
1. Genes of metastasis initiatiation
2. Proteins formation to trigger and support the necessary functions needed for metastasis
3. Receptors both cytoplasmic and at the cellular membranes to amplify metastasis and cellular growth, migration and invasion. also receptors of autocrine function, cell defense, attachment to future location (Preferential Homing and vascular doors to allow extravascular localization)
4. Through those Receptors, signal transduction pathways are mostly activated but sometimes suppressed and this lead of course to amplifications of certain transcription factors.
5.protection against immune mediated defense, protection against harmful substrate in the Extracellular matrix, protection against host tissue cellular defense)
6.Migration will not start without Detachment from the local site, protection against Anoikis, generation of adhesion molecule to blood vessel, formation of of enzyme to break the path of migration, toward the new home, and
7. Seeding and ensuring new Growth in the new location.
In hematologic malignancies, unless we speak of lymphoma, the malignant cells own the blood environmemts which include the bone Marrow matrix. Homing becomes more of an issue. The skin is one of the major target. Plasmacytoma and Granulocytic Sarcoma have a somewhat wider or different list of locations.
================================
Things seems to become blurry rapidly when you approach this subject because of the intertwined steps involved in these processes. Cancer cells do not spread with intent to kill the host. In solid tumors, Evidences suggest however that in order to survive its local expansion, it needs to find food, building materials and Oxygen elsewhere. Indeed local growth can only support so much, migration of stressed cancer cells will eventually Occur.
Like Many cellular processes, Metastasis and invasion are molecular based and involves:
1. Genes of metastasis initiatiation
2. Proteins formation to trigger and support the necessary functions needed for metastasis
3. Receptors both cytoplasmic and at the cellular membranes to amplify metastasis and cellular growth, migration and invasion. also receptors of autocrine function, cell defense, attachment to future location (Preferential Homing and vascular doors to allow extravascular localization)
4. Through those Receptors, signal transduction pathways are mostly activated but sometimes suppressed and this lead of course to amplifications of certain transcription factors.
5.protection against immune mediated defense, protection against harmful substrate in the Extracellular matrix, protection against host tissue cellular defense)
6.Migration will not start without Detachment from the local site, protection against Anoikis, generation of adhesion molecule to blood vessel, formation of of enzyme to break the path of migration, toward the new home, and
7. Seeding and ensuring new Growth in the new location.
In hematologic malignancies, unless we speak of lymphoma, the malignant cells own the blood environmemts which include the bone Marrow matrix. Homing becomes more of an issue. The skin is one of the major target. Plasmacytoma and Granulocytic Sarcoma have a somewhat wider or different list of locations.
Friday, February 8, 2013
Bevacizumab Extends Survival in Advanced Cervical Cancer
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Drug & Reference Information
Bevacizumab (Avastin, Roche/Genentech)
significantly extended survival by nearly 4 months in patients with
advanced, recurrent, or persistent cervical cancer that was not curable
with standard surgery and/or radiotherapy, according to the National
Cancer Institute (NCI).
This news comes from an interim analysis of the large randomized clinical trial known as Gynecologic Oncology Group (GOG) 240, and is likely to change clinical practice.
Median survival was better in women treated with chemotherapy plus bevacizumab than in those treated with chemotherapy alone (17.0 vs 13.3 months). The 3.7-month difference is "highly statistically significant," according to the NCI.
These findings "are likely to change clinical practice and provide an opportunity to improve outcome in patients with recurrent cervical cancer who have previously had very limited treatment options," said GOG study chair Krishnansu S. Tewari, MD, from the University of California, Irvine, in a press statement.
"This is welcome news, as progress has been very difficult against this cancer," said Jeff Abrams, MD, clinical director of the division of cancer treatment and diagnosis at the NCI.
The trial's data safety monitoring committee recommended that the results be made public because the study met its primary end point when it was demonstrated that overall survival improved in patients who received bevacizumab.
The full interim analysis will likely be presented at the annual meeting of the American Society of Clinical Oncology in June.
A total of 452 patients in the United States and Spain with pretreated metastatic, recurrent, or persistent cervical cancer were enrolled in the GOG 240 trial from 2009 to 2012.
The investigators are evaluating whether topotecan or cisplatin is better in combination with paclitaxel, and whether the addition of bevacizumab to either regimen improves overall survival. Patients were randomly assigned to 1 of 4 treatment groups, 2 of which received bevacizumab.
In an analysis conducted in 2012, topotecan plus paclitaxel was
not found to be superior to the standard therapy of cisplatin plus
paclitaxel, and the investigators and patients were notified of the
finding at that time, according to the NCI.
In the trial, bevacizumab was administered intravenously, at a dose of 15 mg/kg of body weight, in conjunction with chemotherapy and was administered 1 day every 3 weeks until disease progression or unacceptable toxicity occurred. The combination therapy resulted in more adverse events than chemotherapy alone. However, the NCI reports that the adverse effects "were consistent with side effects previously known to be associated with bevacizumab."
The GOG 240 trial was sponsored by the NCI. Genentech provided support for the trial under the Cooperative Research and Development Agreement (CRADA) with the NCI for the clinical development of bevacizumab.
This news comes from an interim analysis of the large randomized clinical trial known as Gynecologic Oncology Group (GOG) 240, and is likely to change clinical practice.
Median survival was better in women treated with chemotherapy plus bevacizumab than in those treated with chemotherapy alone (17.0 vs 13.3 months). The 3.7-month difference is "highly statistically significant," according to the NCI.
These findings "are likely to change clinical practice and provide an opportunity to improve outcome in patients with recurrent cervical cancer who have previously had very limited treatment options," said GOG study chair Krishnansu S. Tewari, MD, from the University of California, Irvine, in a press statement.
"This is welcome news, as progress has been very difficult against this cancer," said Jeff Abrams, MD, clinical director of the division of cancer treatment and diagnosis at the NCI.
The trial's data safety monitoring committee recommended that the results be made public because the study met its primary end point when it was demonstrated that overall survival improved in patients who received bevacizumab.
The full interim analysis will likely be presented at the annual meeting of the American Society of Clinical Oncology in June.
A total of 452 patients in the United States and Spain with pretreated metastatic, recurrent, or persistent cervical cancer were enrolled in the GOG 240 trial from 2009 to 2012.
The investigators are evaluating whether topotecan or cisplatin is better in combination with paclitaxel, and whether the addition of bevacizumab to either regimen improves overall survival. Patients were randomly assigned to 1 of 4 treatment groups, 2 of which received bevacizumab.
OC468900PROF-D 10/12
Information from Industry
In the trial, bevacizumab was administered intravenously, at a dose of 15 mg/kg of body weight, in conjunction with chemotherapy and was administered 1 day every 3 weeks until disease progression or unacceptable toxicity occurred. The combination therapy resulted in more adverse events than chemotherapy alone. However, the NCI reports that the adverse effects "were consistent with side effects previously known to be associated with bevacizumab."
The GOG 240 trial was sponsored by the NCI. Genentech provided support for the trial under the Cooperative Research and Development Agreement (CRADA) with the NCI for the clinical development of bevacizumab.
DEPRESSION OF GENE ACTIVITY MORE OF A SIGN OF ONCOGENESIS
We have been asked to comment one more time about further evidence that depression of gen activity is more of a sign that it has induced cancer.
When we discuss that a gene is mutated, more times then not we are describing a situation where a gene ceases its function. An example would be P53 Mutation where it stops its function, and alteration in DNA does not cause cell cycle arrest.
Another situation where P53 is wild type and normal, is the depression of MDM2 which lift inhibitory influence on P53.
Depression of PTEN is the inducer of Integrins activation and of the PI3K and MAP kinases.
Drop in STAT1 has been reported in triple negative Breast cancer
in BRCA, depression in gene repair could be the trigger
MYC depression or Mutation has been implicate in Oncogenesis although it is more of an amplifier of at least 15% of genes, and can amplify itself in Burkit and other small cell diseases
So yes gene depression is more Ominous in that regard. Most of the amplification are secondary (unles it is a driver Mutation)!
We have been asked to comment one more time about further evidence that depression of gen activity is more of a sign that it has induced cancer.
When we discuss that a gene is mutated, more times then not we are describing a situation where a gene ceases its function. An example would be P53 Mutation where it stops its function, and alteration in DNA does not cause cell cycle arrest.
Another situation where P53 is wild type and normal, is the depression of MDM2 which lift inhibitory influence on P53.
Depression of PTEN is the inducer of Integrins activation and of the PI3K and MAP kinases.
Drop in STAT1 has been reported in triple negative Breast cancer
in BRCA, depression in gene repair could be the trigger
MYC depression or Mutation has been implicate in Oncogenesis although it is more of an amplifier of at least 15% of genes, and can amplify itself in Burkit and other small cell diseases
So yes gene depression is more Ominous in that regard. Most of the amplification are secondary (unles it is a driver Mutation)!
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
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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has participated in the enduring material titled
Tailored Hematology: Challenging Community Cases in Non-Hodgkin Lymphoma
February 8, 2013
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