The reading about mechanisms of resistance of to Taxol calls for a new strategy for treatment of triple negative breast cancer; while it is true that PARP inhibitor should still be considered in BRCA positive cancers, adding AURORA inhibitors seems to offer logically the best opportunity to increase the activity of proposed first line drugs.
Indeed, triple negative breast cancer assumes that the receptors to conventional stimulants of the breast cancer cell are not functional or responsive. Therefore, increasing the role of a direct attack of either the nuclear material or the microfilament/microtubule. Taxol - Cisplatin combination achieves that! Adding Avastin and other receptor stimulators could be a riskier proposition if you assume a questionable sensitivity of receptor in general. Your best bet is an action on the Histones and further DNA destruction. The cell division is your focus here and this is re-emphasized by the importance of CDKs as described by MD Anderson researchers. As a matter of fact, the AURORA inhibitors by binding to Adenine and to the Histone appear to offer a potential and logical choice to recruit in first line to boost response rates! So, pending proof of concept, we support the idea of adding Aurora inhibitors to a Taxane-Cisplatin core combination. Some of the Aurora Kinase also target CDKs and JAK2. These will be my choice for new trials!
After the cancer has seen chemotherapy, endothelial cells have been altered, hypoxia has been triggered by closure of some of the blood vessel closure, the MTOR has been stimulated, we believe adding the MTOR makes more sense. This has been also suggested after failure of Avastin, These concepts have been publicized, It is time to move to clinical trial! (FOR THOSE WHO CAN, WE HAVE OUR HANDS TIED BY HUMAN HISTORY!)
Showing posts with label mtor. Show all posts
Showing posts with label mtor. Show all posts
Tuesday, April 30, 2013
Friday, April 5, 2013
Nomenclature of 2 important genes in Ovarian cancer !
1.RASSF1A: One of the thing cancer cell do is to Methylate some genes in order to block its path to death.
it appears this gene is a critical door to shut or disable. It not only decrease the significance of RAS and MAPK in the pathogenesis of tumor that harbor this mutation. It also remove blockage to proliferation by desensitizing the cell to the effect of P53, Cyclins. Desensitize the cell to Death Receptor 6 and its Fas connection. RASSF1a, demethylation is a valid target in ovarian cancer.
2.HNF1B: " Hepatocyte Nuclear Factor 1α (HNF1α) is an atypical homeodomain-containing transcription factor that transactivates liver-specific genes including albumin, α-1-antitrypsin and α- and β-fibrinogen. Biallelic inactivating mutations of HNF1A have been frequently identified in hepatocellular adenomas (HCA), rare benign liver tumors usually developed in women under oral contraceptives, and in rare cases of hepatocellular carcinomas developed in non-cirrhotic liver. HNF1α-mutated HCA (H-HCA) are characterized by a marked steatosis and show activation of glycolysis, lipogenesis, translational machinery and mTOR pathway. We studied the consequences of HNF1α silencing in hepatic cell lines, HepG2 and Hep3B and we reproduced most of the deregulations identified in H-HCA."
(Laura Pelletier et al)
This gene is the gene of differentiation for liver formation, it has the structure of a CBF (core binding Factor) therefore has a subunit binding the DNA, therefore silencing that portion, and another subunit having locations for enzymatic proteins or molecular structures that directly assume various functions intended by the cell (formation of Albumin, alpha Antitrypsine, and Beta Fibrinogen).
Interestingly enough, Steatosis is a prominent feature here. This structure and gene may be of interest in LIPOSARCOMA?
DOES ACTIVATION OF MTOR DEMONSTRATED HERE OPEN THE DOOR TO THE USE OF MTOR IN LIPOSARCOMA?
it appears this gene is a critical door to shut or disable. It not only decrease the significance of RAS and MAPK in the pathogenesis of tumor that harbor this mutation. It also remove blockage to proliferation by desensitizing the cell to the effect of P53, Cyclins. Desensitize the cell to Death Receptor 6 and its Fas connection. RASSF1a, demethylation is a valid target in ovarian cancer.
2.HNF1B: " Hepatocyte Nuclear Factor 1α (HNF1α) is an atypical homeodomain-containing transcription factor that transactivates liver-specific genes including albumin, α-1-antitrypsin and α- and β-fibrinogen. Biallelic inactivating mutations of HNF1A have been frequently identified in hepatocellular adenomas (HCA), rare benign liver tumors usually developed in women under oral contraceptives, and in rare cases of hepatocellular carcinomas developed in non-cirrhotic liver. HNF1α-mutated HCA (H-HCA) are characterized by a marked steatosis and show activation of glycolysis, lipogenesis, translational machinery and mTOR pathway. We studied the consequences of HNF1α silencing in hepatic cell lines, HepG2 and Hep3B and we reproduced most of the deregulations identified in H-HCA."
(Laura Pelletier et al)
This gene is the gene of differentiation for liver formation, it has the structure of a CBF (core binding Factor) therefore has a subunit binding the DNA, therefore silencing that portion, and another subunit having locations for enzymatic proteins or molecular structures that directly assume various functions intended by the cell (formation of Albumin, alpha Antitrypsine, and Beta Fibrinogen).
Interestingly enough, Steatosis is a prominent feature here. This structure and gene may be of interest in LIPOSARCOMA?
DOES ACTIVATION OF MTOR DEMONSTRATED HERE OPEN THE DOOR TO THE USE OF MTOR IN LIPOSARCOMA?
Sunday, March 17, 2013
PANCREATIC CANCER GENE (CONTINUED)
1' KRT20: keratin related gene, most likely of an early expression in neoplastic transformation
more predictive and diagnostic than of less therapeutic potential.
2-TEM 7: The blood vessels of Tumors seems to have an exclusive marker called Tumor Endothelial Marker or TEM. Target therapy directed at this stuff may lead tumor to anoxic death by closing these vessels, at least that the wish of researchers, will follow their efforts!
Certainly this used as serologic marker or radiologically, can locate metastatic lesions.
3-MAP2K4" direct activator of the MAPK/c-JUNK through MAP8& 14. (Not the standard MAPK1)
but it also interact with an anchor called Filamin Though FLNC, filamin is actin binding protein, raising the issue of whether or not it is using this tract to quickly influence the Nucleus or whether it allows it to phosphorylate things right there! we know its expression is, like the MTOR stimulated path, preserving survival! Does this open the door to MTOR Inhibitor in Pancreatic cancer? Does expression of this pathway, an opportunity to introduce MTOR inhibitors?
4-BAT-26
please read this:
"BAT-26, an indicator of the replication error phenotype in colorectal cancers and cell lines" by
9-ERBB2
10-GAS
11-TM4SF5
more predictive and diagnostic than of less therapeutic potential.
2-TEM 7: The blood vessels of Tumors seems to have an exclusive marker called Tumor Endothelial Marker or TEM. Target therapy directed at this stuff may lead tumor to anoxic death by closing these vessels, at least that the wish of researchers, will follow their efforts!
Certainly this used as serologic marker or radiologically, can locate metastatic lesions.
3-MAP2K4" direct activator of the MAPK/c-JUNK through MAP8& 14. (Not the standard MAPK1)
but it also interact with an anchor called Filamin Though FLNC, filamin is actin binding protein, raising the issue of whether or not it is using this tract to quickly influence the Nucleus or whether it allows it to phosphorylate things right there! we know its expression is, like the MTOR stimulated path, preserving survival! Does this open the door to MTOR Inhibitor in Pancreatic cancer? Does expression of this pathway, an opportunity to introduce MTOR inhibitors?
4-BAT-26
please read this:
"BAT-26, an indicator of the replication error phenotype in colorectal cancers and cell lines" by
BAT 26 IS THEREFORE AN INDICATOR OF MICRO-SATELLITE INSTABILITY STATUS IN CANCER.
--------------------------------------------------------------------------------------------
5-ALOX12
6-TP53
7-BIRC5
8-NME19-ERBB2
10-GAS
11-TM4SF5
Monday, March 11, 2013
ADVANCES IN METASTATIC RENAL CANCER
*IL-2 (High dose) Response rate < 10% but with rare cures
* Medication approved
1. Sunitinib which was compred to Interferon to win approval
2. Avastin in combination to Interferon (not alone) was compared to interferon alone to win approval
3.Pazopanib was compared to placebo to win approval
4.Temsirolimus was compared to Interferon to win approval.
someone thought combining Interferon and Tensirolimus will give a higher response rate, well it did not. But this bring back the notion that until the MTOR is really amplified, rushing into its inhibition may not bring result. So timing suggested after failure of VEGF is critical.
5. Pazopanib was compared to Sunitinib, non inferiority proven although Pazopanib had PFS of 8.4 against a 9.5 months accomplished Sutent. The statical referee came in not statistical difference depite the hair color change of Pazopanib recipient! The hematologic toxicitywere worse with Sutent!
6.New kids on the block (Tivozanib and anti-PD1)
-Tivozanib was compared to Nexavar and came up on top in terms of PFS. OS not measure because of cross-over
ONE HAS VENTURED TO SUGGEST THAT
START WITH SUTENT
THAN AFINITOR
FOLLOWED BY AXITINIB
THAN ANTI-PD1
----------------------------------------
BUT REMEMBER THAT HISTOLOGY MAY FORCE YOU TO SKIP SUNITINIB
AND INTERFERON-BEVACIZUMAB ARE ALSO SOLID OPTIONS, AND SO REMAINS HIGH DOSE IL-2.
7-AXITINIB (AN ANTI-VEGF(s) ) WAS ALSO MATCHED WITH SORAFENIB IN THE HUTSON ET AL STUDY.AND CAME UP ON TOP FOR PFS. HOWEVER THE OBSERVERS ARE SAYING THAT IN THE LATEST PHASE III STUDY AXITINIB,ALTHOUGH ACTIVE, DID NOT MEET ITS PRIMARY END POINT.
8.EVEROLIMUS AGAINST PLACEBO WON BIG PFS, BUT NO OS!?
* Medication approved
1. Sunitinib which was compred to Interferon to win approval
2. Avastin in combination to Interferon (not alone) was compared to interferon alone to win approval
3.Pazopanib was compared to placebo to win approval
4.Temsirolimus was compared to Interferon to win approval.
someone thought combining Interferon and Tensirolimus will give a higher response rate, well it did not. But this bring back the notion that until the MTOR is really amplified, rushing into its inhibition may not bring result. So timing suggested after failure of VEGF is critical.
5. Pazopanib was compared to Sunitinib, non inferiority proven although Pazopanib had PFS of 8.4 against a 9.5 months accomplished Sutent. The statical referee came in not statistical difference depite the hair color change of Pazopanib recipient! The hematologic toxicitywere worse with Sutent!
6.New kids on the block (Tivozanib and anti-PD1)
-Tivozanib was compared to Nexavar and came up on top in terms of PFS. OS not measure because of cross-over
ONE HAS VENTURED TO SUGGEST THAT
START WITH SUTENT
THAN AFINITOR
FOLLOWED BY AXITINIB
THAN ANTI-PD1
----------------------------------------
BUT REMEMBER THAT HISTOLOGY MAY FORCE YOU TO SKIP SUNITINIB
AND INTERFERON-BEVACIZUMAB ARE ALSO SOLID OPTIONS, AND SO REMAINS HIGH DOSE IL-2.
7-AXITINIB (AN ANTI-VEGF(s) ) WAS ALSO MATCHED WITH SORAFENIB IN THE HUTSON ET AL STUDY.AND CAME UP ON TOP FOR PFS. HOWEVER THE OBSERVERS ARE SAYING THAT IN THE LATEST PHASE III STUDY AXITINIB,ALTHOUGH ACTIVE, DID NOT MEET ITS PRIMARY END POINT.
8.EVEROLIMUS AGAINST PLACEBO WON BIG PFS, BUT NO OS!?
Friday, March 8, 2013
INTERESTING DEBATES
1.NF1 Mutation is upstream from
BRAF
and MTOR
But NF-1 is Mutated in Melanoma
can infusion of protein resulting from NF-1 be used to strengthen effect of MTOR inhibitor and BRAF inhibitor by maintaining these pathways open!
2. Discriminating Redundancy in cellular language
same gene base corresponding to same Amino Acid
same receptors at membrane being sensitive by different stimuli
but when it comes to the RAS, nature and intensity need to matter and this also a function of tissue involved!
some time however the nature of the stimulus is more important particularly inside the cell where ie HP90 seems to stimulate more the CoN to achieve PTEN suppression. And you know that CoM stimulation raise Bcl2 level...we will say more in our upcoming article of langaue of the cell as it pertains to pathways!
3. PTEN is repressed by low expression of gene or mislocalization (reported PNUTS 'role) at Nuclear level or both?
BRAF
and MTOR
But NF-1 is Mutated in Melanoma
can infusion of protein resulting from NF-1 be used to strengthen effect of MTOR inhibitor and BRAF inhibitor by maintaining these pathways open!
2. Discriminating Redundancy in cellular language
same gene base corresponding to same Amino Acid
same receptors at membrane being sensitive by different stimuli
but when it comes to the RAS, nature and intensity need to matter and this also a function of tissue involved!
some time however the nature of the stimulus is more important particularly inside the cell where ie HP90 seems to stimulate more the CoN to achieve PTEN suppression. And you know that CoM stimulation raise Bcl2 level...we will say more in our upcoming article of langaue of the cell as it pertains to pathways!
3. PTEN is repressed by low expression of gene or mislocalization (reported PNUTS 'role) at Nuclear level or both?
Tuesday, March 5, 2013
Molecules and Cancer Cells
Now that we know that the cell does not discriminate about what is the category of this molecule invading me as classified by humans, we are ready to suggest some unconventional combinations of chemotherapy drugs:
Nexavar-Metformin for hepatocarcinoma
anti-MEK- calcium channel blocker for K-ras expressing lung cancer
Antibiotic with impact on splicing molecule with the MTOR
(to be continued)
Nexavar-Metformin for hepatocarcinoma
anti-MEK- calcium channel blocker for K-ras expressing lung cancer
Antibiotic with impact on splicing molecule with the MTOR
(to be continued)
Sunday, February 24, 2013
NOMENCLATURE OF GENES TO LOOK FOR IN TRIPLE NEGATIVE BREAST CANCER
One may try to determine whether a breast cancer has bad prognosis in order to determine whether chemotherapy should be given (MammaPrint, Oncotypr DX), but more importantly, I believe, is to focus on genes of good prognosis which include driver genes against which we dispose of an answer in our Arsenal.
Currently we dispose of
1. Chemotherapy that attacks DNA and Microfilament/Microtubules, (first and second law of nature)
2. Immune Modulators such as Interferon
3. Antibody to Membrane Receptor (EGFR/VEGF) Avastin
4. Inhibitor to T-cell driven immunity (CTLA4)
5. Inhibitors to sub-membrane or first line driver Mutations KRAS, HRAS, or the RAS family
6. Inhibitors to 2nd line driver Mutations (anti MEK)
7. Inhibitor to Tertiary line driver Mutations and Mitochondrial level inhibition (MTOR, Metformin)
8. Anti-proteasome or inhibitor to cellular protein degradation (Velcade)
9. Inhibitors at Nuclear lever Include Histone Deacethylator and Acyl transferase inhibitor, check point controller inhibitors, anti-Centrosome metabolism and inhibitors of various promoters and transcription factors.
Other opportunities not included in this classification go to specific genes of proliferation, Amplification, differentiation and metastasis that have been brought forth as indicator of either response to chemotherapy or simply as "Good prognosis" genes. These will include the BRCA since a response to PARP inhibitors and Cisplatin based combinations should be anticipated.
Multikinase inhibitors such as Dasatinib (SRC+ BCR/ABL but also STAT5) and Arsenic Trioxide should be included
LBK1: could predict early disease (inhibitor controlling initiation of metastasis)
DDR2: could predict anti MEK sensitivity
MEKK-1 sensitivity to Cisplatin
TFF1-could predict sensitivity to estrogen despite negative Estrogen
DYRK2, favorable in lung cancer
c-JUN amplification and over expression of 8q23-24 could predict response to interferon/Interleukin
EGFR, VEGF, ALK, and other Driver Mutations would match those discussed By DR Kris in lung cancer.
(to be continued!)
Currently we dispose of
1. Chemotherapy that attacks DNA and Microfilament/Microtubules, (first and second law of nature)
2. Immune Modulators such as Interferon
3. Antibody to Membrane Receptor (EGFR/VEGF) Avastin
4. Inhibitor to T-cell driven immunity (CTLA4)
5. Inhibitors to sub-membrane or first line driver Mutations KRAS, HRAS, or the RAS family
6. Inhibitors to 2nd line driver Mutations (anti MEK)
7. Inhibitor to Tertiary line driver Mutations and Mitochondrial level inhibition (MTOR, Metformin)
8. Anti-proteasome or inhibitor to cellular protein degradation (Velcade)
9. Inhibitors at Nuclear lever Include Histone Deacethylator and Acyl transferase inhibitor, check point controller inhibitors, anti-Centrosome metabolism and inhibitors of various promoters and transcription factors.
Other opportunities not included in this classification go to specific genes of proliferation, Amplification, differentiation and metastasis that have been brought forth as indicator of either response to chemotherapy or simply as "Good prognosis" genes. These will include the BRCA since a response to PARP inhibitors and Cisplatin based combinations should be anticipated.
Multikinase inhibitors such as Dasatinib (SRC+ BCR/ABL but also STAT5) and Arsenic Trioxide should be included
LBK1: could predict early disease (inhibitor controlling initiation of metastasis)
DDR2: could predict anti MEK sensitivity
MEKK-1 sensitivity to Cisplatin
TFF1-could predict sensitivity to estrogen despite negative Estrogen
DYRK2, favorable in lung cancer
c-JUN amplification and over expression of 8q23-24 could predict response to interferon/Interleukin
EGFR, VEGF, ALK, and other Driver Mutations would match those discussed By DR Kris in lung cancer.
(to be continued!)
Friday, February 22, 2013
NEXT TO THE MTOR,
We are getting closer to the cure every day, we are clearly at the door of the cure acquiring process,
just learning the language spoken by the cell. Already it seems we are overwhelmed by what we find.
There are things we are learning though, and fast:
1. That forces within the cell can be followed through laws of nature, as grouped here: THAT AMPLIFICATION, PROLIFERATION AND DIFFERENTIATION ARE GOVERNED BY SETS OF GENES AND HAVE VARIOUS LEVELS OF EXPRESSION.
2. That treatment strategies can be made following different steps in pathways
3. That Death traps are located at the membrane, cytoplasm, mitochondria and Nucleus
4. That downstream targets inhibition can overcome resistance to earlier target inhibition
5. That Inactivation and down-regulation of gene expression appears to be more important in Oncogenesis
6. That most of the time MAPK amplification results from the down regulation of PI3K/PTEN
7. That MTOR inhibition is deeper than EGFR/VEGF and PI3k inhibition
8. That VELCADE or antiproteasome will disturb all the pathways of which products need Ubiquitination for degradation
9. That Velcade may worsen VHL depedent syndromes
10. Then, even deeper, that MTOR, are Histone de-acyl- transferases
BUT WHAT WE HAVE NOT TALKED ABOUT ENOUGH IS THE POSSIBILITY OF CURE HIDDEN EVEN DEEPER IN THE DIFFERENTIATION.: HERE ARE HIDDEN THE SO- CALLED "PATHWAYS OF SECONDARY METABOLISM" AND SURPRISE SURPRISE THAT THE ROLE OF ANTIBIOTICS RE-EMERGES!
HERE, WE LOOK FOR DIMBOA PATHWAYS AND DNA REPLICATION
ASSOCIATION WITH STRESS (FOS, C-JUN)
ASSOCIATION WITH P450
ASSOCIATION WITH UDPG GLUCOSYL TRANSFERASES AND SOME DIOXYGENASE
WE NEED TO EXPLORE ANTIBIOTICS COMING FROM FUNGI.
LET ME COME TO THE CHASE OF BX1, BX2, AS THEY ARE TIED TO U11, U12, AND CHROMOSOME 4. THIS IS THE NEW BATTLEGROUND!
RESEARCHERS, PLEASE GO BACK TO WORK!
We are getting closer to the cure every day, we are clearly at the door of the cure acquiring process,
just learning the language spoken by the cell. Already it seems we are overwhelmed by what we find.
There are things we are learning though, and fast:
1. That forces within the cell can be followed through laws of nature, as grouped here: THAT AMPLIFICATION, PROLIFERATION AND DIFFERENTIATION ARE GOVERNED BY SETS OF GENES AND HAVE VARIOUS LEVELS OF EXPRESSION.
2. That treatment strategies can be made following different steps in pathways
3. That Death traps are located at the membrane, cytoplasm, mitochondria and Nucleus
4. That downstream targets inhibition can overcome resistance to earlier target inhibition
5. That Inactivation and down-regulation of gene expression appears to be more important in Oncogenesis
6. That most of the time MAPK amplification results from the down regulation of PI3K/PTEN
7. That MTOR inhibition is deeper than EGFR/VEGF and PI3k inhibition
8. That VELCADE or antiproteasome will disturb all the pathways of which products need Ubiquitination for degradation
9. That Velcade may worsen VHL depedent syndromes
10. Then, even deeper, that MTOR, are Histone de-acyl- transferases
BUT WHAT WE HAVE NOT TALKED ABOUT ENOUGH IS THE POSSIBILITY OF CURE HIDDEN EVEN DEEPER IN THE DIFFERENTIATION.: HERE ARE HIDDEN THE SO- CALLED "PATHWAYS OF SECONDARY METABOLISM" AND SURPRISE SURPRISE THAT THE ROLE OF ANTIBIOTICS RE-EMERGES!
HERE, WE LOOK FOR DIMBOA PATHWAYS AND DNA REPLICATION
ASSOCIATION WITH STRESS (FOS, C-JUN)
ASSOCIATION WITH P450
ASSOCIATION WITH UDPG GLUCOSYL TRANSFERASES AND SOME DIOXYGENASE
WE NEED TO EXPLORE ANTIBIOTICS COMING FROM FUNGI.
LET ME COME TO THE CHASE OF BX1, BX2, AS THEY ARE TIED TO U11, U12, AND CHROMOSOME 4. THIS IS THE NEW BATTLEGROUND!
RESEARCHERS, PLEASE GO BACK TO WORK!
Monday, February 4, 2013
CELLULAR LANGUAGE (II)
In Cellular Language I published recently that we tried to emphasize that big functions of the cell start up with an on-and-off switch. The Tic and The Tan like in MORSE language, the 1and 0 of the computer. While this is true, there are many other simple things at the molecular level that are just as simple, but full of physiologic and scientific implications.
1.ON and OFF switch:
--------------------------
Events that lead to cancer are sometimes an exaggeration of a signal. The K-RAS (there exist many RAS (es) as we discussed in differentiation) has a switch called the Sons of the Sevenless which can stay on, sending signals down the cell continuously. Activated RAS will light on 3 signal pathways:
-MAP kinase (through RAF)--->FOS, JUN (stress), MYC (the dangerous leading to Burkitt)-TF
-RAL/CDC42 (important in the movement of the membrane, Metastasis)
-PI3K (leading to affect on AKT/MTOR) FOXO downstream hiding the PUMA-remember)
Mutations at the RAS itself can also cause it to stay on, as opposed to knocking it out.
Remember, Mutations of RAS occur in 80% of Pancreatic cancers and 50% of colon cancer.
Therefore, a simple switch can kill you with one of the most devastating diseases.
2. Change of shape:
---------------------
To confuse and look smart, your scientist calls this post-translational conformation to emphasize that this change has occurred later because of the nteraction with another molecule (in general).
At the surface of the membrane, there are here and there some Molecules called INTEGRINS; these are of various types and increasing molecular diversity and are best known as Receptors. They are large complexes of molecules gathered in chunks called 'subunits'. They basically cross the thickness of the cellular membrane and, outside the cell, they sense what is going on. Integrins serve many great purposes including cell division, proliferation, migration, adhesion to each either, differentiation, sensing etc. You name it, they do it! Only division of DNA, this, they don't do. But the membrane has to be divided also to make 2 cells in cell divison. Even anti-coagulation happens here. The versatility of the integrins is linked to the variety of subunits it is composed with. Some are nature of cell specific and some are contact specific. By contact specific, I mean what molecule outside the cell it will attach to (ie fibronectin Vs GPIIb).
Suffice is to say that kinking of the Integrins causes exposure of some parts of the Integrin molecule not naturally exposed. If one looks at the skin of the joint at the back of the finger, one will see folded skin. if you forcefully bend your finger, the fold you were looking at will unfold and the bottom of the fold will come out. This is what happen to the integrin when it meets outside the cell another molecule such as TALIN.
That bending triggers the attachment of other molecules or ions (phosphorylation) to the now exposed skin, lighting up the Integrins for the cascade of events which will unfold, including the activation of SRC in Sarcoma.
The shape imposed by the bending is also Molecule specific. Despite the resemblance of SRC with the c-ABL (leukemia), their bending does not offer the same shape, and therefore, different parts of the molecule are exposed and 2 different diseases result.
CELL ADHESION- "join at the hip"
----------------------------------------
At many points the cells are joined to each other at the hips of the Talins. Say, at the hip of the Talin which linked to one Integrin, there is a PLUS SIGN at Cell A, and at the next TALIN attached to the Integrin of cell B, there is a NEGATIVE sign. These 2 integrins will be attached, and cell adhesion is achieved. Simple as that!
Wheels of cellular migration,
-----------------------------,
Cells can roll over other cells by progressively attaching Talin to Talins and breaking the talin-talins (integrin-integrin) behind, engulfing the integrins and using them again in the forthcoming attachment like a wheel touching the ground. The cell is that smart at the membrane.
More simple things to come...
Hiding the PUMA behind the FOXO to have a death TRAP (Apoptsosis) in case the FOXO is compromised!
Just simple, but effective tricks ...
1.ON and OFF switch:
--------------------------
Events that lead to cancer are sometimes an exaggeration of a signal. The K-RAS (there exist many RAS (es) as we discussed in differentiation) has a switch called the Sons of the Sevenless which can stay on, sending signals down the cell continuously. Activated RAS will light on 3 signal pathways:
-MAP kinase (through RAF)--->FOS, JUN (stress), MYC (the dangerous leading to Burkitt)-TF
-RAL/CDC42 (important in the movement of the membrane, Metastasis)
-PI3K (leading to affect on AKT/MTOR) FOXO downstream hiding the PUMA-remember)
Mutations at the RAS itself can also cause it to stay on, as opposed to knocking it out.
Remember, Mutations of RAS occur in 80% of Pancreatic cancers and 50% of colon cancer.
Therefore, a simple switch can kill you with one of the most devastating diseases.
2. Change of shape:
---------------------
To confuse and look smart, your scientist calls this post-translational conformation to emphasize that this change has occurred later because of the nteraction with another molecule (in general).
At the surface of the membrane, there are here and there some Molecules called INTEGRINS; these are of various types and increasing molecular diversity and are best known as Receptors. They are large complexes of molecules gathered in chunks called 'subunits'. They basically cross the thickness of the cellular membrane and, outside the cell, they sense what is going on. Integrins serve many great purposes including cell division, proliferation, migration, adhesion to each either, differentiation, sensing etc. You name it, they do it! Only division of DNA, this, they don't do. But the membrane has to be divided also to make 2 cells in cell divison. Even anti-coagulation happens here. The versatility of the integrins is linked to the variety of subunits it is composed with. Some are nature of cell specific and some are contact specific. By contact specific, I mean what molecule outside the cell it will attach to (ie fibronectin Vs GPIIb).
Suffice is to say that kinking of the Integrins causes exposure of some parts of the Integrin molecule not naturally exposed. If one looks at the skin of the joint at the back of the finger, one will see folded skin. if you forcefully bend your finger, the fold you were looking at will unfold and the bottom of the fold will come out. This is what happen to the integrin when it meets outside the cell another molecule such as TALIN.
That bending triggers the attachment of other molecules or ions (phosphorylation) to the now exposed skin, lighting up the Integrins for the cascade of events which will unfold, including the activation of SRC in Sarcoma.
The shape imposed by the bending is also Molecule specific. Despite the resemblance of SRC with the c-ABL (leukemia), their bending does not offer the same shape, and therefore, different parts of the molecule are exposed and 2 different diseases result.
CELL ADHESION- "join at the hip"
----------------------------------------
At many points the cells are joined to each other at the hips of the Talins. Say, at the hip of the Talin which linked to one Integrin, there is a PLUS SIGN at Cell A, and at the next TALIN attached to the Integrin of cell B, there is a NEGATIVE sign. These 2 integrins will be attached, and cell adhesion is achieved. Simple as that!
Wheels of cellular migration,
-----------------------------,
Cells can roll over other cells by progressively attaching Talin to Talins and breaking the talin-talins (integrin-integrin) behind, engulfing the integrins and using them again in the forthcoming attachment like a wheel touching the ground. The cell is that smart at the membrane.
More simple things to come...
Hiding the PUMA behind the FOXO to have a death TRAP (Apoptsosis) in case the FOXO is compromised!
Just simple, but effective tricks ...
Thursday, January 17, 2013
PUTTING THINGS TOGETHER IN TRIPLE NEGATIVE BREAST CANCER BRCA TESTING AND THE MTOR UNVEIL NEW PARADIGM SHIFT AT CRBCM
Now that we know that up to 85% of triple negative Breast cancers could have the BRCA Mutation in some cohort, it is becoming a guideline shift that this test be performed not only for prognosis, but also for therapeutic information. The presence of BRCA positivity generally imparts worse prognosis of this disease.
But knowing if it is BRCA1 positive will give it an atypical morphology as per the article from Stanford suggests:
"The luminal A subtype of breast cancer had the highest frequency of PIK3CA mutation (45%), and the basal subtype had the lowest (9%). These data are consistent with the results of prior studies, as luminal A and basal-like subtypes roughly correspond to ER-positive and triple-negative breast cancer by immunohistochemistry (IHC), respectively. Even though PIK3CA mutations are oncogenic, they are a good prognostic factor and are associated with improved survival.[12] This is important to consider when assessing patient survival in trials in patients with PIK3CA mutations."
BRCA 2 is mostly of Luminal histology and therefore will be more susceptible to PIK3CA/MTOR blockade which will explain their better prognosis. We still believe that as we move forward, the role of interferon and Mtor is still to be explored. As that in Luminal triple negative BRAC2 positive hormone manipulation with MTOR could still be tried. We still believe that EGFR inhibitor in combination to MTOR inhibitor and inhibitor of NK-kB or antiproteasome are all potential add-ons!
But knowing if it is BRCA1 positive will give it an atypical morphology as per the article from Stanford suggests:
"The luminal A subtype of breast cancer had the highest frequency of PIK3CA mutation (45%), and the basal subtype had the lowest (9%). These data are consistent with the results of prior studies, as luminal A and basal-like subtypes roughly correspond to ER-positive and triple-negative breast cancer by immunohistochemistry (IHC), respectively. Even though PIK3CA mutations are oncogenic, they are a good prognostic factor and are associated with improved survival.[12] This is important to consider when assessing patient survival in trials in patients with PIK3CA mutations."
BRCA 2 is mostly of Luminal histology and therefore will be more susceptible to PIK3CA/MTOR blockade which will explain their better prognosis. We still believe that as we move forward, the role of interferon and Mtor is still to be explored. As that in Luminal triple negative BRAC2 positive hormone manipulation with MTOR could still be tried. We still believe that EGFR inhibitor in combination to MTOR inhibitor and inhibitor of NK-kB or antiproteasome are all potential add-ons!
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