*FOLFIRINOX definitely in control as first choice for first line
but this option is too toxic in the elderly so a modified version is adopted by some
.*new IMPACT STUDY, GEMZAR-ABRAXANE is being rapidly adopted as an alternative to FOLFIRINOX for this same and very reason (Toxicity of Folfirinox)
This combination was reportedly tried in selected clinics (including Eastern Europe) in a Phase III trial, was tried against Gemzar alone
and gave Progression free survival of 5.5 months Vs 3.7 months
Overall survival 8.5 months Vs 6.7 months (Von Hoff DD et al.)
Abraxane given at 125 mg/m2 and Gemzar at 1000mg/m2 Q3/4 in the combination arm
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3rd choice of course was GEMZAR-ERLOTINIB follwed by GEMZAR ALONE.
===========================================================
NOTABLY NO TARGET THERAPY DISCUSSED WHICH NEEDS TO BE CORRECTED FAST!
Showing posts with label abraxane. Show all posts
Showing posts with label abraxane. Show all posts
Sunday, March 10, 2013
Thursday, February 21, 2013
GENES IN UVEAL MELANOMA.
This one rings a bell with me because a good friend and respected professor, wife to an intensive care Doctor, died under our care before the discovery of Ipilimumab. And how well Ipilimumab fares in this particular case of melanoma is still to be closely reviewed (DTIC was not trusted enough). At the time, the patient who had liver metastasis ended up getting an Abraxane based combination.
Researchers from Washington University have now published that the SF3B1 gene could predict a better outcome in patients with Uveal Melanoma since it is linked to far lower metastasis rate and young individuals.
3 additional genes were cited also: BAP1, GNAQ, GNA11,
1. SF3B1
===== Splicing factor 3B subunit 1
Being a splicing factor puts this gene right there in the differentiating gene as we discussed earlier. Meaning the gene pushes differentiation further up which in cellular biology has been proven to normal life and submission to normal programmed death. The ATRA story used in APL is proof in the pudding.
SB3F1 is a good prognosis gene globally. In MDS, it is known to be associated with early MDS, particularly the MDS with ring Sideroblast. This fact is noticeable and warrants a speculative comment. That is when you talk of Sideroblast, you incriminate disturbances in Iron Metabolism in or around the Mitochondria. What does create similar iron disturbance? Well, Inflammatory processes do. This is confirmed by the link of Splicing Factors to production of Inflammatory proteins and therefore participation in connective tissue disease. Remember, early MDS can respond to Immune based therapeutic interventions. So, SB3F1 seems to be an Early event. To affect differentiation, it must lead to proteins that interact with later Splicing factors and impose a trend away from Apoptosis and migration. The literature suggests that it is an "evolutionary", that it has an impact on cellular evolution. The SB3F1 has been seen also in Breast cancer with similar prognosis indications.
The notion that one of the proteins resulting from various splicing factors could be Autoantigenic brings another dimension to bear! That an abnormality at SB3F1 could in effect produce Autoantigen making the cell susceptible to Autoimmune death, another way that would limit its chances of spreading. Remember, Melanoma is often susceptible to Interferon and now T cell CTLA-4 related agents (such as Ipilimumab).
SB3F1, an early Mutation, influencing other late splicers and therefore "evolutionary", and rising autoimmunity!
(In MDS, SB3F1 is also associated with high Hb, Platelet counts, all the good stuff of better prognosis). It has been noted in CLL, MDS and Breast cancer, and now Uveal Melanoma.
Presence of TET2, an angel of proliferation, will stop the good prognosis acting of SB3F1. And so will the presence of Mutations in P53, EZH, ETV6, RUNX-1, and ASXL! (check it out!) it's all in the literature...
2. BAP-1
--------------
Members of the polycomb-group proteins (PcG) of highly conserved transcriptional repressors required for long-term silencing of genes that regulate cell fate determination, stem cell pluripotency, and other developmental processes.[3]" (wikepedia
In cancer, BAP1 can function both as a Tumor suppressor and as a Metastasis suppressor.
BAP1 mutations were identified in a small number of breast and lung cancer cell lines,[1] but BAP1 was first shown to act as a tumor suppressor in cultured cells, where its deubiquitinase (UCH) domain and Nuclear localization sequences were required for BAP1 to suppress cell growth.[9] In 2010, Exome sequencing identified inactivating mutations in BAP1 in 47% of Uveal melanomas, and BAP1 mutation was strongly associated with metastasis.[10] These mutations included multiple Nonsense mutations and splice site mutations throughout the gene. missense mutations were only found within the UCH and ULD domains, further supporting the requirement for BAP1 catalytic function. This study also identified a Germline mutation in one of the uveal melanoma patients, suggesting that, besides being a Metastasis suppressor, BAP1 could predispose certain people to more aggressive uveal melanoma tumors. Shortly thereafter, BAP1 mutations were identified in aggressive Mesotheliomas with similar mutations as seen in melanomas,[11] and have also been reported in renal cell carcinomas.[12]
Two studies used Genome sequencing independently to identify Germline mutations in BAP1 in families with Genetic predispositions to mesothelioma[13] and melanocytic skin tumors[14] Further studies have identified germline BAP1 mutations associated with other cancers.[15] These studies suggest that germline mutation of BAP1 results in a Tumor Predisposition Syndrome linking BAP1 to many more cancers. (wikipedia)
In lung cancer, it is associated with no lymph node involvement and therefore of Good prognosis.
BRCA-1 Associated Protein-1 could be associated with BRAF, and 15% of clear cell Renal cancers.
This one rings a bell with me because a good friend and respected professor, wife to an intensive care Doctor, died under our care before the discovery of Ipilimumab. And how well Ipilimumab fares in this particular case of melanoma is still to be closely reviewed (DTIC was not trusted enough). At the time, the patient who had liver metastasis ended up getting an Abraxane based combination.
Researchers from Washington University have now published that the SF3B1 gene could predict a better outcome in patients with Uveal Melanoma since it is linked to far lower metastasis rate and young individuals.
3 additional genes were cited also: BAP1, GNAQ, GNA11,
1. SF3B1
===== Splicing factor 3B subunit 1
Being a splicing factor puts this gene right there in the differentiating gene as we discussed earlier. Meaning the gene pushes differentiation further up which in cellular biology has been proven to normal life and submission to normal programmed death. The ATRA story used in APL is proof in the pudding.
SB3F1 is a good prognosis gene globally. In MDS, it is known to be associated with early MDS, particularly the MDS with ring Sideroblast. This fact is noticeable and warrants a speculative comment. That is when you talk of Sideroblast, you incriminate disturbances in Iron Metabolism in or around the Mitochondria. What does create similar iron disturbance? Well, Inflammatory processes do. This is confirmed by the link of Splicing Factors to production of Inflammatory proteins and therefore participation in connective tissue disease. Remember, early MDS can respond to Immune based therapeutic interventions. So, SB3F1 seems to be an Early event. To affect differentiation, it must lead to proteins that interact with later Splicing factors and impose a trend away from Apoptosis and migration. The literature suggests that it is an "evolutionary", that it has an impact on cellular evolution. The SB3F1 has been seen also in Breast cancer with similar prognosis indications.
The notion that one of the proteins resulting from various splicing factors could be Autoantigenic brings another dimension to bear! That an abnormality at SB3F1 could in effect produce Autoantigen making the cell susceptible to Autoimmune death, another way that would limit its chances of spreading. Remember, Melanoma is often susceptible to Interferon and now T cell CTLA-4 related agents (such as Ipilimumab).
SB3F1, an early Mutation, influencing other late splicers and therefore "evolutionary", and rising autoimmunity!
(In MDS, SB3F1 is also associated with high Hb, Platelet counts, all the good stuff of better prognosis). It has been noted in CLL, MDS and Breast cancer, and now Uveal Melanoma.
Presence of TET2, an angel of proliferation, will stop the good prognosis acting of SB3F1. And so will the presence of Mutations in P53, EZH, ETV6, RUNX-1, and ASXL! (check it out!) it's all in the literature...
2. BAP-1
--------------
Members of the polycomb-group proteins (PcG) of highly conserved transcriptional repressors required for long-term silencing of genes that regulate cell fate determination, stem cell pluripotency, and other developmental processes.[3]" (wikepedia
In cancer, BAP1 can function both as a Tumor suppressor and as a Metastasis suppressor.
BAP1 mutations were identified in a small number of breast and lung cancer cell lines,[1] but BAP1 was first shown to act as a tumor suppressor in cultured cells, where its deubiquitinase (UCH) domain and Nuclear localization sequences were required for BAP1 to suppress cell growth.[9] In 2010, Exome sequencing identified inactivating mutations in BAP1 in 47% of Uveal melanomas, and BAP1 mutation was strongly associated with metastasis.[10] These mutations included multiple Nonsense mutations and splice site mutations throughout the gene. missense mutations were only found within the UCH and ULD domains, further supporting the requirement for BAP1 catalytic function. This study also identified a Germline mutation in one of the uveal melanoma patients, suggesting that, besides being a Metastasis suppressor, BAP1 could predispose certain people to more aggressive uveal melanoma tumors. Shortly thereafter, BAP1 mutations were identified in aggressive Mesotheliomas with similar mutations as seen in melanomas,[11] and have also been reported in renal cell carcinomas.[12]
Two studies used Genome sequencing independently to identify Germline mutations in BAP1 in families with Genetic predispositions to mesothelioma[13] and melanocytic skin tumors[14] Further studies have identified germline BAP1 mutations associated with other cancers.[15] These studies suggest that germline mutation of BAP1 results in a Tumor Predisposition Syndrome linking BAP1 to many more cancers. (wikipedia)
In lung cancer, it is associated with no lymph node involvement and therefore of Good prognosis.
BRCA-1 Associated Protein-1 could be associated with BRAF, and 15% of clear cell Renal cancers.
Sunday, November 25, 2012
SEARCHING FOR A CANCER CURE
At CRBCM we believe that CPRIT is our necessary path to Victory over Cancer.
We also know we will not get its help this time around, not because we do not deserve the help but frankly because it is distracted. Science is an objective thing. It is a race. You have the right move, the right stuff, you win, no matter where you come from. It is the Olympics without steroids.
We at CRBCM have understood one thing, in the race for the cure, harnessing the force and laws of nature has an unparalleled advantage. Forcing a cell to die can be done by telling and convincing it to die. Or blasting it and crossing our fingers and hoping it will die. Chemotherapy did this mostly the second way but its success was partial. Chemotherapy only works when it manages to finally talk the language. Indeed, some chemotherapy manages to reach the syllables of the cellular language of death.
Sorting through the maze of messages, 2 powerful set of syllables come out:
1. That if it fails to repair broken DNA and therefore does not perform GENE REPAIR, this fact will automatically activate your P53 leading to an automatic stop of the cell into its cycle division. There is no loophole to this principle unless the P53 is abnormal. Knowing this is powerful. Now we understand why Cisplatin (and to some extent Gemcitabine) is a powerful drug because it disrupts the DNA structure. We also understand that cells with rapid repair of DNA, will brush it off, literally.
2.with further proof of principle, we believe that there is a second automatic message or syllables.
Destruction of Microfilaments (and therefore secondarily Microtubules in general) during cell division, leads to an automatic release of Caspase from the Mitochondria no matter what (and this is what includes the BCL-2 protection). It is in this law that resides the strength of Taxanes. Medication that works even in resistant diseases such as Melanoma where Abraxane has a role. Taxanes' limitations appear to be in the type of microtubules attacked. Medication that attacks Microfilament of the type involved in cell divison, where the Centromere is attached, appears to send a more determinant trigger to Caspase release. This is where our interest comes in the Anti-kinesin. We believe and predict that an effective anti-kinesin drug in combination with Taxane and Cisplatin/gemzar based combination, will harness best this law. They will prove to be effective in cure because they will be effective in both treatment and maintenance settings. This is also why the combination of Gemzar and Taxol has proven to be the strongest non platinum combination.
Following this principle, we believe now at CRBCM, that target therapy not following the laws of nature will have only 20-30% response rate, meaning effective in only the cells that lack loophole mechanisms. (this also means because of phenotype heterogeneity, 70-85% of cells have potentially intrinsic loophole to any signal transduction target stimulation or blockage).
Lets keep our eyes on the ball, do not invest in stuff they are throwing at you! More to come...
At CRBCM we believe that CPRIT is our necessary path to Victory over Cancer.
We also know we will not get its help this time around, not because we do not deserve the help but frankly because it is distracted. Science is an objective thing. It is a race. You have the right move, the right stuff, you win, no matter where you come from. It is the Olympics without steroids.
We at CRBCM have understood one thing, in the race for the cure, harnessing the force and laws of nature has an unparalleled advantage. Forcing a cell to die can be done by telling and convincing it to die. Or blasting it and crossing our fingers and hoping it will die. Chemotherapy did this mostly the second way but its success was partial. Chemotherapy only works when it manages to finally talk the language. Indeed, some chemotherapy manages to reach the syllables of the cellular language of death.
Sorting through the maze of messages, 2 powerful set of syllables come out:
1. That if it fails to repair broken DNA and therefore does not perform GENE REPAIR, this fact will automatically activate your P53 leading to an automatic stop of the cell into its cycle division. There is no loophole to this principle unless the P53 is abnormal. Knowing this is powerful. Now we understand why Cisplatin (and to some extent Gemcitabine) is a powerful drug because it disrupts the DNA structure. We also understand that cells with rapid repair of DNA, will brush it off, literally.
2.with further proof of principle, we believe that there is a second automatic message or syllables.
Destruction of Microfilaments (and therefore secondarily Microtubules in general) during cell division, leads to an automatic release of Caspase from the Mitochondria no matter what (and this is what includes the BCL-2 protection). It is in this law that resides the strength of Taxanes. Medication that works even in resistant diseases such as Melanoma where Abraxane has a role. Taxanes' limitations appear to be in the type of microtubules attacked. Medication that attacks Microfilament of the type involved in cell divison, where the Centromere is attached, appears to send a more determinant trigger to Caspase release. This is where our interest comes in the Anti-kinesin. We believe and predict that an effective anti-kinesin drug in combination with Taxane and Cisplatin/gemzar based combination, will harness best this law. They will prove to be effective in cure because they will be effective in both treatment and maintenance settings. This is also why the combination of Gemzar and Taxol has proven to be the strongest non platinum combination.
Following this principle, we believe now at CRBCM, that target therapy not following the laws of nature will have only 20-30% response rate, meaning effective in only the cells that lack loophole mechanisms. (this also means because of phenotype heterogeneity, 70-85% of cells have potentially intrinsic loophole to any signal transduction target stimulation or blockage).
Lets keep our eyes on the ball, do not invest in stuff they are throwing at you! More to come...
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