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!
Sunday, February 10, 2013
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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February 8, 2013
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Thursday, February 7, 2013
Denosumab: The Better Option for Bone Metastases in NSCLC?
Overall Survival Improvement in Patients With Lung Cancer and Bone Metastases Treated With Denosumab versus Zoledronic Acid
Scagliotti GV, Hirsh V, Siena S, et al
J Thorac Oncol. 2012;7:1823-1829
Denosumab, a monoclonal antibody against the receptor activator of nuclear factor κB ligand (RANKL), is administered subcutaneously once every 28 days. The treatment became a feasible and arguably superior option in the wake of several trials demonstrating a significantly superior reduction in the rate of skeletal complications as compared with zoledronic acid.[1-3] In the absence of a difference in overall survival (OS) or any major differences in adverse events, combined with the notably greater cost for denosumab, I concluded in the editorial[4] that accompanied the publication of one of the studies[1] that denosumab was an appealing option but there was no mandate to consider it the standard of care.
Oncologists and patients have historically been most motivated by improvements in OS. Consequently, when a subset analysis of patients with lung cancer from the trial of denosumab vs zoledronic acid reveals a significant improvement in OS, as published by Scagliotti and colleagues, I view this as a very relevant factor to consider in our clinical management decisions.
Overall, my view is that even without the difference in OS,
denosumab offered some compelling arguments to favor it over zoledronic
acid, but with evidence supporting a 1.2-month improvement in OS -- seen
in SCLC and squamous cell NSCLC patients, 2 groups for which we have
had great difficulty offering any interventions with a survival
difference -- the cost of denosumab over zoledronic acid seems to be a
relative bargain. I'm inclined to accept the shortcomings of a
retrospective subset analysis because I would argue that these data only
move denosumab from a justifiable, compelling option to a very strong
leading consideration for my patients with bone metastases from lung
cancer. If denosumab can improve survival at a relatively low cost
compared with so many of our other interventions, the oncology community
should be more proactive about providing denosumab to appropriate
patients and not relegating it to the status of an afterthought compared
with other systemic interventions.
Abstract
J Thorac Oncol. 2012;7:1823-1829
Background
Patients with bone metastases from solid tumors typically are treated with either zoledronic acid or denosumab to reduce the risk for future skeletal metastases. However, therapy for bone metastases is usually a secondary focus, with greater emphasis placed on systemic therapies to improve survival and/or directly reduce a patient's cancer-related symptoms.Denosumab, a monoclonal antibody against the receptor activator of nuclear factor κB ligand (RANKL), is administered subcutaneously once every 28 days. The treatment became a feasible and arguably superior option in the wake of several trials demonstrating a significantly superior reduction in the rate of skeletal complications as compared with zoledronic acid.[1-3] In the absence of a difference in overall survival (OS) or any major differences in adverse events, combined with the notably greater cost for denosumab, I concluded in the editorial[4] that accompanied the publication of one of the studies[1] that denosumab was an appealing option but there was no mandate to consider it the standard of care.
Oncologists and patients have historically been most motivated by improvements in OS. Consequently, when a subset analysis of patients with lung cancer from the trial of denosumab vs zoledronic acid reveals a significant improvement in OS, as published by Scagliotti and colleagues, I view this as a very relevant factor to consider in our clinical management decisions.
Study Summary
Specifically, the broader trial enrolled 1776 patients, and the leading subtype was lung cancer, including both non-small cell lung cancer (NSCLC) (n = 702) and small cell lung cancer (SCLC) (n = 109). Denosumab when compared with zoledronic acid was associated with a statistically significant improvement in skeletal-related complications of new or progressive bone lesions that required palliative radiation, opioid pain medication, or caused a pathologic fracture. More important, denosumab was associated with a significantly superior OS by 1.2 months (8.9 vs 7.7 months; HR = 0.80). Also, an improvement in survival was seen across tumor histologies, including adenocarcinoma and squamous NSCLC, as well as SCLC, in which denosumab was associated with a difference in survival of 2.5 months (7.6 vs 5.1 months; HR = 0.81).Viewpoint
The oncology community is typically somewhat skeptical about exploratory subset analyses, which are often viewed as "fishing expeditions" for positive results that might not be borne out in prospective testing. I think it is quite fair to view the results of this subset analysis with some skepticism, but I consider these results to be more robust than many post-hoc subset analyses because of the large size of the study (having a total of 811 patients), the hard endpoint of OS, and the consistency of the results across multiple histologically defined groups of lung cancer patients.
Which patients should you test for biomarkers?
OC468600PROF-D 10/12
Information from Industry
Abstract
Latest in Hematology-Oncology
Medscape Oncology © 2013
WebMD, LLC
Cite this article: H. Jack West. Denosumab: The Better Option for Bone Metastases in NSCLC? Medscape. Jan 23, 2013.
MTOR INHIBITOR, changing Oncology practice,
I confess that after the Taxanes and Velcade, the MTOR inhibitors are one of the most powerful drugs that came to the market, inducing critical change in oncology clinical practice. It seems that if you have resistance to Hormone, the MTOR inhibitors answer the call and break the barrier, if you meet resistance to Octreotide in Neuroendocrine disease, the MTOR inhibitors emerge with an answer, if you are dealing with a refractory condition such as clear cell renal cell cancer, go to MTOR inhibitors. And the list is rapidly growing as we move forward.
When you look at the site of action, you quickly understand why. Not only do they take their momentum deep into the nucleus (FOXO 3 and crisscross with the deep MYC amplification pathways), it has also Mitochondrial effects! I believe this is why it is so effective! The MTOR inhibitors, harvesting new ways to Caspases and Apoptosis. Cure is still within reach!
I confess that after the Taxanes and Velcade, the MTOR inhibitors are one of the most powerful drugs that came to the market, inducing critical change in oncology clinical practice. It seems that if you have resistance to Hormone, the MTOR inhibitors answer the call and break the barrier, if you meet resistance to Octreotide in Neuroendocrine disease, the MTOR inhibitors emerge with an answer, if you are dealing with a refractory condition such as clear cell renal cell cancer, go to MTOR inhibitors. And the list is rapidly growing as we move forward.
When you look at the site of action, you quickly understand why. Not only do they take their momentum deep into the nucleus (FOXO 3 and crisscross with the deep MYC amplification pathways), it has also Mitochondrial effects! I believe this is why it is so effective! The MTOR inhibitors, harvesting new ways to Caspases and Apoptosis. Cure is still within reach!
In advanced prostate cancer
TREAT FIRST-LINE WITH PROVENGE TO
EXTEND SURVIVAL
Pivotal trial results
The PROVENGE pivotal trial was designed to demonstrate an overall survival benefit
The pivotal trial was a Phase 3, randomized, double-blind, controlled study1
- Primary endpoint—Overall survival
- Secondary endpoint—Time to objective disease progression
Trial Design1
*Eligible patients were hormone refractory and had
metastatic disease in the soft tissue and/or bone with evidence of
progression; 18% had received prior chemotherapy (including docetaxel).
†Control was nonactivated, autologous, peripheral blood mononuclear cells.
‡Progression=radiographic evidence of disease progression.
§Autologous, peripheral blood mononuclear cells that were cryopreserved at the time of control generation and subsequently activated.
†Control was nonactivated, autologous, peripheral blood mononuclear cells.
‡Progression=radiographic evidence of disease progression.
§Autologous, peripheral blood mononuclear cells that were cryopreserved at the time of control generation and subsequently activated.
64% of patients in the control group, following progression, crossed over to a nonrandomized open-label protocol to receive an investigational autologous immunotherapy made from cryopreserved cells1
- Treatment in the open-label protocol was at the physician's discretion
PROVENGE extends median survival beyond 2 years
PROVENGE reduced the risk of death by 22.5% vs the control group (P=0.032)1
Overall Survival Benefit of PROVENGE1,2
Data originally published in The New England Journal of Medicine:
Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study
Investigators. Sipuleucel-T immunotherapy for castration-resistant
prostate cancer. N Engl J Med. 2010;363:411-422.
Average time to subsequent therapy with docetaxel in the IMPACT trial was approximately 1 year.1
Average time to subsequent therapy with docetaxel in the IMPACT trial was approximately 1 year.1
PROVENGE provides a sustained survival benefit and a durable immune response
PROVENGE provided a survival benefit every year studied3
Overall Survival Benefit for PROVENGE3
||(Percent PROVENGE-percent control)/percent control.
| Percentage of Patients Alive: ITT Population (95% CI)3 | ||||
|---|---|---|---|---|
| 1 year | 2 years | 3 years | 4 years | |
| PROVENGE | 81.1% (76.9, 85.3) n=274 |
52.1% (46.4, 57.7) n=129 |
31.7% (25.7, 37.8) n=49 |
20.5% (14.0, 26.9) n=14 |
| Control | 72.4% (65.6, 79.1) n=123 |
41.2% (33.5, 49.9) n=55 |
23.0% (15.5, 30.5) n=19 |
16.0% (8.5, 23.4) n=4 |
ITT=intent-to-treat.
PROVENGE provided a durable immune response3
- A sustained immune response to PROVENGE was seen out to 26 weeks in the pivotal study (the last time point measured)
PROVENGE provides a safety profile you and your patients can manage
Only 1.5% of patients treated with PROVENGE in the pivotal trial discontinued treatment due to adverse events3
92% of patients in the PROVENGE group in the pivotal trial received all 3 infusions3
The most common adverse events (≥15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache3
PROVENGE is not cleared by the liver or the kidneys and does not require dose adjustments or monitoring of liver/kidney functions
PROVENGE does not require concomitant steroids
Autologous use
- PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases.
Serious adverse events
- In controlled clinical trials, serious adverse events reported in the PROVENGE group include acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group.
Common adverse events
- The most common adverse events (incidence ≥15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache.
NEXT ARTICLE
NCCN Category 1 recommendation and patient selection
NCCN Category 1 recommendation and patient selectionINDICATION
PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.Please see the Full Prescribing Information.
References
- Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.
- PROVENGE [package insert]. Dendreon Corporation; June 2011.
- Data on file. Dendreon Corporation.
- ==========================================================
- THIS NOTE COME FROM THE MANUFACTURER, NOT CRBCM, JUST FOR YOUR FYI
DON'T SAY I DID NOT MAKE YOU AWARE
The
Indiana State Department of Health, the Tippecanoe County Health
Department and Purdue University are investigating a positive case of
typhoid fever in a food handler
at Purdue University.
Anyone
who ate at the Boiler Bistro, John Purdue Room, or the coffee shop,
Lavazza, at Marriott Hall on the Purdue campus from January 23-25 2013
may be at risk. Health
officials advise these individuals to see a healthcare provider right
away if they start to experience symptoms such as a high fever (103° to
104° F), weakness, stomach pains, headache, nausea, vomiting,
constipation or diarrhea, or loss of appetite. In some
cases, a rash of flat, rose-colored spots may appear. Symptoms usually
begin within 8-14 days after exposure, but could potentially appear for
up to 30 days.
Health
care providers are encouraged to ask those who present with these
symptoms about potential exposure and consider testing for typhoid
fever. Stool and blood are
appropriate specimens for testing. Suspect cases should be reported
immediately to your local health department.
People are at risk of typhoid fever if they eat food or drink beverages that have been handled by someone who infected with
Salmonella Typhi or if sewage contaminated with the bacteria gets
into the water used for drinking or washing food. Typhoid fever is more
common in areas where hand washing is less frequent and water can be
contaminated with sewage.
Typhoid fever is a life-threatening illness caused by the bacterium
Salmonella Typhi. In the United States, approximately 400 cases
of typhoid fever occur each year with 75 percent of these acquired while
traveling internationally. Typhoid fever is still common in the
developing world, where it affects about 21.5 million
persons each year. The case being investigated recently traveled
internationally and this is where the infection was acquired.
For questions, please contact Sarah Slette, ISDH Enteric Epidemiologist, at 317-234-2808 or
sslette@isdh.in.gov.
William C. VanNess II, MD
State Health Commissioner
ROLE OF UNDERSTANDING THE "LAWS OF NATURE" IN CELLULAR BIOLOGY.
Although cells pathways have now been described, harvesting this information with no discrimination will not lead to a cure in a timely fashion. There is a perception that combining therapeutic agents will always be better than using one agent. Extremists have even believed that throwing to the patient a kitchen sink of medications could yield better results. And time and again these approaches failed to show an improvement of survival.
One of the most memorable example is the CHOP story which led to keeping CHOP as standard of care for lymphoma over at least 2 decades. The CHOP reign ended with the Arrival of Rituxan, a target therapy.
What we have learned over the years is that there could be minimal or no improvement in attacking the cell by focusing on one pathways. Attacking the cell on different steps of the pathway works only if that Pathway has the DRIVER mutation. Otherwise the cell will easily escape the attack using its inter-connections, loopholes, redundancy and heterozygosity mechanism. The NF-kB would allow adaptative transformation.
For a clear clear improvement in effect, combined drug should affect 2 different pathways as they relate to different laws of Nature:
1. DNA Break (compromising cell division) include P53 arrest
2. Microtubule Break (compromising Mitosis, cell division, cell migration, and Embryogenesis) lead directly to Caspase in the Mitochondia
3. Receptors (impairment of signal generation and amplification and Angiogenesis) Growth factors, cyclins, anti VGEF, FGFR,
4. Impairment of Amplification (blocking signal amplification, includes Proteasome inhibitor which dampen signal transduction by harvesting an overall feedback-negative effect of ubiquitinated compounds )
5. Impairment of Differentiation (RAS)
6. Immune Modulation
7. Opening Hidden traps to Apoptosis or program cell death (FOXO3, histone deacetylase)
8. Impairing Migration to block Metastasis and cellular sensing of its environment lead to Anoikis.
Most combination fail because they focus on 1 of the 8 aspects.
Taxol carboplatin has been good to us because of the Microtubule and DNA. This combination works better in standard rate of cell division. In higher rate, breaking the DNA faster with Etopside-Cisplatin prove to be beneficial (small cell lung cancer, c-MYC is the amplifier like in Burkitt). But it is until you involve the Mirotubule that you see benefit such as in Gastric cancers. Adding 5-FU based product did not show benefit particularly in Gastric cancer.
CAF in Breast cancer was incremental because of DNA breakage but also because of the Adriamycin effect of cellular membrane which disturb the Microtubule at this location.
DRUGS AFFECTING one each path generally surprised us
1 here are CISPLATIN, etoposide,Oxaliplatin
2. Taxanes
3. Avastin, Erbitux
4. Velcade, Afinitor, Cabozantinib
5. anti-BRAF, anti-Hedgehog, Ibrutinib
6. Interferon, Rituxan
7. M-tor, Dasatinib
8. Anti-Integrins
significant combinations should cross these 8 lines! And choice should be based on
1. Solid Vs Hematologic disease
2. Knowledge of Driver Mutations if any
3. Knowledge of driver pathways if any
4. knowledge of Resistance mechanism if any
5. knowledge of preponderant specific Receptor
6. Importance of Cyclins and growth factors
7. Exclusive Seeding niche if any
Although cells pathways have now been described, harvesting this information with no discrimination will not lead to a cure in a timely fashion. There is a perception that combining therapeutic agents will always be better than using one agent. Extremists have even believed that throwing to the patient a kitchen sink of medications could yield better results. And time and again these approaches failed to show an improvement of survival.
One of the most memorable example is the CHOP story which led to keeping CHOP as standard of care for lymphoma over at least 2 decades. The CHOP reign ended with the Arrival of Rituxan, a target therapy.
What we have learned over the years is that there could be minimal or no improvement in attacking the cell by focusing on one pathways. Attacking the cell on different steps of the pathway works only if that Pathway has the DRIVER mutation. Otherwise the cell will easily escape the attack using its inter-connections, loopholes, redundancy and heterozygosity mechanism. The NF-kB would allow adaptative transformation.
For a clear clear improvement in effect, combined drug should affect 2 different pathways as they relate to different laws of Nature:
1. DNA Break (compromising cell division) include P53 arrest
2. Microtubule Break (compromising Mitosis, cell division, cell migration, and Embryogenesis) lead directly to Caspase in the Mitochondia
3. Receptors (impairment of signal generation and amplification and Angiogenesis) Growth factors, cyclins, anti VGEF, FGFR,
4. Impairment of Amplification (blocking signal amplification, includes Proteasome inhibitor which dampen signal transduction by harvesting an overall feedback-negative effect of ubiquitinated compounds )
5. Impairment of Differentiation (RAS)
6. Immune Modulation
7. Opening Hidden traps to Apoptosis or program cell death (FOXO3, histone deacetylase)
8. Impairing Migration to block Metastasis and cellular sensing of its environment lead to Anoikis.
Most combination fail because they focus on 1 of the 8 aspects.
Taxol carboplatin has been good to us because of the Microtubule and DNA. This combination works better in standard rate of cell division. In higher rate, breaking the DNA faster with Etopside-Cisplatin prove to be beneficial (small cell lung cancer, c-MYC is the amplifier like in Burkitt). But it is until you involve the Mirotubule that you see benefit such as in Gastric cancers. Adding 5-FU based product did not show benefit particularly in Gastric cancer.
CAF in Breast cancer was incremental because of DNA breakage but also because of the Adriamycin effect of cellular membrane which disturb the Microtubule at this location.
DRUGS AFFECTING one each path generally surprised us
1 here are CISPLATIN, etoposide,Oxaliplatin
2. Taxanes
3. Avastin, Erbitux
4. Velcade, Afinitor, Cabozantinib
5. anti-BRAF, anti-Hedgehog, Ibrutinib
6. Interferon, Rituxan
7. M-tor, Dasatinib
8. Anti-Integrins
significant combinations should cross these 8 lines! And choice should be based on
1. Solid Vs Hematologic disease
2. Knowledge of Driver Mutations if any
3. Knowledge of driver pathways if any
4. knowledge of Resistance mechanism if any
5. knowledge of preponderant specific Receptor
6. Importance of Cyclins and growth factors
7. Exclusive Seeding niche if any
CABOZANTINE COULD BE THE ANSWER IN PAPILLARY RENAL CANCER AND ANGIOSARCOMA.
Based on the fact that Cabozantine is an inhibitor of RET, MET,VEGF 1through 3, KIT, TRKB, FLT and TIE-2. It needs to be tried in papillary renal cancer, angiosarcoma, and VHL were amplification of MET is important. in VHL however, proof of concept studies should be done when Cabozantine is combine to MTOR or Velcade.
Cabozantine and Velcade would have an exclusive role in Myeloma
cabozantine and MTOR would have an exclusive role in Clear Cell Renal cancer
A role in Pheochromocytoma is anticipated!
Based on the fact that Cabozantine is an inhibitor of RET, MET,VEGF 1through 3, KIT, TRKB, FLT and TIE-2. It needs to be tried in papillary renal cancer, angiosarcoma, and VHL were amplification of MET is important. in VHL however, proof of concept studies should be done when Cabozantine is combine to MTOR or Velcade.
Cabozantine and Velcade would have an exclusive role in Myeloma
cabozantine and MTOR would have an exclusive role in Clear Cell Renal cancer
A role in Pheochromocytoma is anticipated!
NEWS from ASCO
1.The kitchen sink thrown to the patient when it comes to combination chemotherapy, sometimes, works!
It was the case for FOLFOXIRI in Colon cancers, and sometime Pancreatic cancers. In Myeloma, DR Palumbo from the Italian Gimena reportedly suggested the Bortezomib, Melphalan,Prednisone and Thalidomide, (BMPT) followed by 2 years of maintenance BT was better than BMP alone.
Median progression free survival 35.3 months Vs 24.8 months.
5 Year Survival (OS) 61% Vs 51%.
2.patients with history of 30 pack year and still smoking, or have quit within 15 years, 55-74 years of age. can now be offered low dose Cat scan (CT) instead of a Chest X-ray. This new National Cancer Society standard is based review of the literature since 1996, and the new National Lung Screening study (NLST) suggesting a 20% reduction in Mortality between the 2 groups.
3. MCL1, MYC,JAK2, PIM1,BRCA would be the gene mostly involved in Triple negative Breast cancer. Some common pathways also listed (Researcher from Vanderbilt suggested)
4.Ibrutinib ?becoming an important option in Mantle cell. with a 70% response rate as compared with 30% achieved by other drugs in relapsed/refractory cases. Target therapy is in!
5. Telintra, Ezatiostat was granted Orphan drug status by the FDA for treatment of Myelodysplastic Syndrome.
1.The kitchen sink thrown to the patient when it comes to combination chemotherapy, sometimes, works!
It was the case for FOLFOXIRI in Colon cancers, and sometime Pancreatic cancers. In Myeloma, DR Palumbo from the Italian Gimena reportedly suggested the Bortezomib, Melphalan,Prednisone and Thalidomide, (BMPT) followed by 2 years of maintenance BT was better than BMP alone.
Median progression free survival 35.3 months Vs 24.8 months.
5 Year Survival (OS) 61% Vs 51%.
2.patients with history of 30 pack year and still smoking, or have quit within 15 years, 55-74 years of age. can now be offered low dose Cat scan (CT) instead of a Chest X-ray. This new National Cancer Society standard is based review of the literature since 1996, and the new National Lung Screening study (NLST) suggesting a 20% reduction in Mortality between the 2 groups.
3. MCL1, MYC,JAK2, PIM1,BRCA would be the gene mostly involved in Triple negative Breast cancer. Some common pathways also listed (Researcher from Vanderbilt suggested)
4.Ibrutinib ?becoming an important option in Mantle cell. with a 70% response rate as compared with 30% achieved by other drugs in relapsed/refractory cases. Target therapy is in!
5. Telintra, Ezatiostat was granted Orphan drug status by the FDA for treatment of Myelodysplastic Syndrome.
Wednesday, February 6, 2013
AMERICAN DIABETES ASSOCIATION AND THE EUROPEAN ASSOCIATION FOR THE STUDY OF DIABETES UPDATED THE ALGORITHM FOR DIABETES TREATMENT IN 2012.
The new algorithm suggest
1. lifestyle modification (diet and physical exercice)
2. Metformin; REDUCE RELEASE OF GLUCOSE BY THE LIEVR, NO WEIGHT GAIN
3.Sulfonylureas (Glimepiride,Glipizide (Glucotrol), Glyburide(Micronase) are secretaogogue complicated by hypoglycemia and weight gain
4.Thiazolidinediones(glitazones) (Actos and Avandia) Avandia has Heart attack concerns and is of limited use in the US..Weight and fluid retention are of concern
5.GLP-1 Receptor Agonist: Glucagon like peptide increases secretion of Insulin by the pancreas, decreases Glucagon, increase sens of satiety and therefore weight loss.
5.DPP-4 Inhibitor, blocks GLP-1 degradation, and therefore behave as inhibitor of GLP1
6.Insulin
other meglitinides (to be taken 30 min before the meal because they are short acting "Sulfonylureas like", alpha Glucosidase Inhibitors (slow degradation of larger carbohydrates to slow the spike of Glucose in the blood) ,Colesevelam (Anticholesterol that slow down absorption of glucose in the gut), Bromocriptine (effect on circadian control of hormones) and pramlintide (Amilin like, regulate gllucose after meal). (to be continued)
The new algorithm suggest
1. lifestyle modification (diet and physical exercice)
2. Metformin; REDUCE RELEASE OF GLUCOSE BY THE LIEVR, NO WEIGHT GAIN
3.Sulfonylureas (Glimepiride,Glipizide (Glucotrol), Glyburide(Micronase) are secretaogogue complicated by hypoglycemia and weight gain
4.Thiazolidinediones(glitazones) (Actos and Avandia) Avandia has Heart attack concerns and is of limited use in the US..Weight and fluid retention are of concern
5.GLP-1 Receptor Agonist: Glucagon like peptide increases secretion of Insulin by the pancreas, decreases Glucagon, increase sens of satiety and therefore weight loss.
5.DPP-4 Inhibitor, blocks GLP-1 degradation, and therefore behave as inhibitor of GLP1
6.Insulin
other meglitinides (to be taken 30 min before the meal because they are short acting "Sulfonylureas like", alpha Glucosidase Inhibitors (slow degradation of larger carbohydrates to slow the spike of Glucose in the blood) ,Colesevelam (Anticholesterol that slow down absorption of glucose in the gut), Bromocriptine (effect on circadian control of hormones) and pramlintide (Amilin like, regulate gllucose after meal). (to be continued)
RENAL CANCER PREVENTION (CHRONIC USE OF DECONGESTANT -AFRIN- COULD DECREASE RENAL CANCER.) and so does a CPAP mask for patients with Sleep Apnea
Renal cell cancer risk is associated to smoking and Obesity (hypertension is a corollary risk we claim). These 2 conditions lead to Hypoxia generally through sleep Apnea which in turn leads to a relative increase of Hemoglobin. The rise of Hemoglobin increases the portion of Desaturated hemoglobin. After many years of such exposure desaturated Heme enhances Phosphorylation at Tyr-530 of the SRC leading to its deactivation. In some individuals with the right MEK, suppression pf the SRC could lead to persistent amplification at the MEK which is a versatile activator of almost all signals, but particularly VEGF receptor. This in turn usually lead to papillary cancers. Amplification of signal transduction started at the MEK (which amplifies almost all major known pathways) will lead to increased ubiquitination and proteasome destruction of the HYPOXIA-inducible factor (following the Von Hippel-Lindau model. This will lead to clear cell cancer. Associated desaturated Heme and hypoxia at the mitochondria will participate in the transformation (and possibly the Atypia/clear cell transformation). The preponderance and center piece role of MEK amplification and subsequent VGEF/PDGF will justify the "bloody" nature of kidney cancers, and vessel involvement in these diseases (MEK is the driver Mutation in papillary cancers). IT ALSO EXPLAINS WHY SUTENT, NEXAVAR WORKS. AND MITOCHONDRIAL DISTURBANCES AND SECONDARY AMPLIFICATION OF AKT, THE MTOR INHIBITORS WORK IN RENAL CANCERS (MTOR participates more in clear cells) (proof of concept pending)
In Western society, obesity is increasing, and so is Sleep Apnea. Also, we live in closed homes (in some regions such as Texas and Louisiana, Mosquitoes are not helping) the level of dust participates in the increased level of allergic Rhinitis/ upper respiratory ailments. It is not unusual to sleep and wake with closed Nostrils. In obese individuals, this compounds the hypoxic episodes and worsened and prolonged hypoxia. And we are back to depression of SRC, activation of MEK---akt, MAPK and so forth.
Keeping your nostrils open at night appears to be a critical strategy in preventing renal cancer, particularly in patients with breathing issues. Lung cancer may be reduced for non smokers, but I wont touch that speculation, but do remember the role of VEGF in non-smoker lung cancers!
The involvement of PDGF which is by the way affected by Sutent seems to open a window in the frequency of strokes and heart attacks at night! That's another debate to have...!
MTOR inhibitor in combination with Anti-VGEF/ MEK could have a significant role in non smoker lung cancer.?
Velcade could have a role in VHL prevention ? and in Pheochromocytoma?
Avastin and Mtor inhibitor could treat Leiomysarcoma of the Uterus if you follow this logic!
A FREED CPRIT AND THE NIH COULD HELP!
In Western society, obesity is increasing, and so is Sleep Apnea. Also, we live in closed homes (in some regions such as Texas and Louisiana, Mosquitoes are not helping) the level of dust participates in the increased level of allergic Rhinitis/ upper respiratory ailments. It is not unusual to sleep and wake with closed Nostrils. In obese individuals, this compounds the hypoxic episodes and worsened and prolonged hypoxia. And we are back to depression of SRC, activation of MEK---akt, MAPK and so forth.
Keeping your nostrils open at night appears to be a critical strategy in preventing renal cancer, particularly in patients with breathing issues. Lung cancer may be reduced for non smokers, but I wont touch that speculation, but do remember the role of VEGF in non-smoker lung cancers!
The involvement of PDGF which is by the way affected by Sutent seems to open a window in the frequency of strokes and heart attacks at night! That's another debate to have...!
MTOR inhibitor in combination with Anti-VGEF/ MEK could have a significant role in non smoker lung cancer.?
Velcade could have a role in VHL prevention ? and in Pheochromocytoma?
Avastin and Mtor inhibitor could treat Leiomysarcoma of the Uterus if you follow this logic!
A FREED CPRIT AND THE NIH COULD HELP!
Tuesday, February 5, 2013
NEW DEVELOPMENTS
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THE CLEAN-UP AT CPRIT SHOULD BE EASY NOW!
I read again the good independent audit of CPRIT's operation and organization. In a way, this is good, what happened to CPRIT.
The experiment/trial at CPRIT is over. An evaluation is in. The powers will look at it and frame it better. From the bad will come the good. CPRIT will sharpen its image and work. This, however, will not occur until a clean-up is completed. Once again, I believe the task at the end should be easier than one would think. The new leaders at CPRIT will have a clear map for their work thanks to this audit. Act on each recommendation, with honesty and leadership, and a solid dose of vision for the cure, and you put CPRIT back to work in no time, and elevate it to how grand it should be.
There is a key to success: A CLEAN-UP!
THOSE WHO SLEPT, SHRINK THE VISION, THE POLITICIZED CPRIT NEED TO BE REMOVED. NO NEW "BIDON (FALSE)" FOUNDATIONS OR NETWORK OR INCUBATED COMPANIES. NO NEW INFORMATION GATHERING OR REFERRAL SERVICES CLOGGING THE SYSTEM WITH NON PRODUCING ENTITIES (WE HAVE THE GOOD OLD YELLOW PAGES FOR THAT).
4 REGIONAL OFFICES with power to approve grants for a greater Texas, and dilute the fight among the universities. I can't say this enough: 42% of funds to one single university is the worst thing done by CPRIT! You and I agree on this very point. CPRIT funds are coming from all Texans, not just Houstonians. These funds need to be redistributed accordingly to serve the cancer needs of all Texans.
Nobody knows how the cure will come, but an early attempt of a formulation must be made to
guide the research. Prevention must be centered around Regional Survivorship centers, and all companies moving to Texas should not end up in only one town. (Gridlock of Houston is not what you want anymore, I was there for 1 month doing home visits, I swear...!) ALL IN ALL REMEMBER EL PASO, 4TH CITY OF TEXAS, with a meager 0.2% INVESTMENT FROM CPRIT DESPITE A LOCAL UNIVERSITY PRESENT (UTEP). CRBCM spoke to university professors there at the Border Biomedical Research Center. They have no clout, political muscle in CPRIT stalling all communication, they say. But here is where CPRIT would have easily picked up the people's support...El Paso is an underserved city, and with a large low income population, prevention programs would and will have a huge impact. Richer cities like Houston will not exerience similar per capita benefits. Prevention programs have higher impact in low income areas where people are hungry for new directions and opportunities. Its like feeding a rich man Vs a poor one. The rich will send you a list of complaints on he quality of your offer, the poor will be mesmerized by a good looking loaf of bread! Send a meaningful cancer prevention program our way (EL Paso), and you will see how the people will embrace it!
7 years left, lets get back to work, FREE CPRIT, cut our losses, and give the people another chance to find the cure!
I read again the good independent audit of CPRIT's operation and organization. In a way, this is good, what happened to CPRIT.
The experiment/trial at CPRIT is over. An evaluation is in. The powers will look at it and frame it better. From the bad will come the good. CPRIT will sharpen its image and work. This, however, will not occur until a clean-up is completed. Once again, I believe the task at the end should be easier than one would think. The new leaders at CPRIT will have a clear map for their work thanks to this audit. Act on each recommendation, with honesty and leadership, and a solid dose of vision for the cure, and you put CPRIT back to work in no time, and elevate it to how grand it should be.
There is a key to success: A CLEAN-UP!
THOSE WHO SLEPT, SHRINK THE VISION, THE POLITICIZED CPRIT NEED TO BE REMOVED. NO NEW "BIDON (FALSE)" FOUNDATIONS OR NETWORK OR INCUBATED COMPANIES. NO NEW INFORMATION GATHERING OR REFERRAL SERVICES CLOGGING THE SYSTEM WITH NON PRODUCING ENTITIES (WE HAVE THE GOOD OLD YELLOW PAGES FOR THAT).
4 REGIONAL OFFICES with power to approve grants for a greater Texas, and dilute the fight among the universities. I can't say this enough: 42% of funds to one single university is the worst thing done by CPRIT! You and I agree on this very point. CPRIT funds are coming from all Texans, not just Houstonians. These funds need to be redistributed accordingly to serve the cancer needs of all Texans.
Nobody knows how the cure will come, but an early attempt of a formulation must be made to
guide the research. Prevention must be centered around Regional Survivorship centers, and all companies moving to Texas should not end up in only one town. (Gridlock of Houston is not what you want anymore, I was there for 1 month doing home visits, I swear...!) ALL IN ALL REMEMBER EL PASO, 4TH CITY OF TEXAS, with a meager 0.2% INVESTMENT FROM CPRIT DESPITE A LOCAL UNIVERSITY PRESENT (UTEP). CRBCM spoke to university professors there at the Border Biomedical Research Center. They have no clout, political muscle in CPRIT stalling all communication, they say. But here is where CPRIT would have easily picked up the people's support...El Paso is an underserved city, and with a large low income population, prevention programs would and will have a huge impact. Richer cities like Houston will not exerience similar per capita benefits. Prevention programs have higher impact in low income areas where people are hungry for new directions and opportunities. Its like feeding a rich man Vs a poor one. The rich will send you a list of complaints on he quality of your offer, the poor will be mesmerized by a good looking loaf of bread! Send a meaningful cancer prevention program our way (EL Paso), and you will see how the people will embrace it!
7 years left, lets get back to work, FREE CPRIT, cut our losses, and give the people another chance to find the cure!
BETTER IMAGING FOR BREAST CANCER: TOMOSYNTHESIS
*Tomosynthesis gives "200 one-millimeter-thick images for an average sized breast, compared to 4 images in a regular 2-D digital mammogram" leading to 41 to 61% increase of cancer detection compared to standard 2-D digital mammography. It also reduces the return for additional imaging, according to a report by Donna Plecha, MD, Director of the Dept. of Radiology at UH, Case Western School of Medicine.
*Thomas Bachelot et al. submitted results of a phase II study related to use of Capecitabine and Lepatinib as first line therapy for patients with Brain metastasis from HER-2 positive Breast cancer. 45 patients enrolled, Median follow-up 21 months. 65.9% of patients had a partial response noted.
*Another Disparity: Although white Americans have twice as high an incidence of Bladder cancers, at similar grade and stage of disease, Black Americans do have a higher mortality!". There is a 5 fold relative risk for those who smoked 20cigarettes/day for over 40 years, compared, of course, to non smokers.
*Marginal Zone Lymphoma.includes:
-MALT
-Nodal type
-Primary splenic type which can have villious cells that can be confused with Hairy cell morphologically on peripheral blood.
has CD20+, CD5-, CD10-, CD23-
In extranodal cases, 60% have Trisomy 3 and t(11;18) which produce fusion API2and MLT, and will mark resistance to Antibiotics
API2 is an inhibitor of Apoptosis
MALT1 (procaspase) bind to Bcl-10 leading to activation of NF-bK which ultimately impair Apoptosis
Associated to Sjogren disease in some cases, in the stomach, associated with H.Pylori
Rituxan as a single agent, local RT,
*Thomas Bachelot et al. submitted results of a phase II study related to use of Capecitabine and Lepatinib as first line therapy for patients with Brain metastasis from HER-2 positive Breast cancer. 45 patients enrolled, Median follow-up 21 months. 65.9% of patients had a partial response noted.
*Another Disparity: Although white Americans have twice as high an incidence of Bladder cancers, at similar grade and stage of disease, Black Americans do have a higher mortality!". There is a 5 fold relative risk for those who smoked 20cigarettes/day for over 40 years, compared, of course, to non smokers.
*Marginal Zone Lymphoma.includes:
-MALT
-Nodal type
-Primary splenic type which can have villious cells that can be confused with Hairy cell morphologically on peripheral blood.
has CD20+, CD5-, CD10-, CD23-
In extranodal cases, 60% have Trisomy 3 and t(11;18) which produce fusion API2and MLT, and will mark resistance to Antibiotics
API2 is an inhibitor of Apoptosis
MALT1 (procaspase) bind to Bcl-10 leading to activation of NF-bK which ultimately impair Apoptosis
Associated to Sjogren disease in some cases, in the stomach, associated with H.Pylori
Rituxan as a single agent, local RT,
NOMENCLATURE OF GENES AND PATHWAYS INVOLVED IN BUTEIN INHIBITIONS: IKK and Sirtuin
IKK:
The subunit to be inhibited for the activation of the Nuclear factor and pathway NF-kB which has versatile transforming capacity to combat, escape and resist various attackers including infection and chemotherapy. Inhibition here reduces the cell capacity to adapt. It appears that the Transcription factor NFkB is sitting there in the Cytosol totally inactive, touch the IKK through phosphorylation, wakes the NFkB which spring into motion and unleashes its power. One of the best described pathway flow is TNF posphorylation of IKK which detaches and goes on to being ubiquitinated and degraded through the Proteasome. detachment of the IKK lead to a free NFkB kinase which enter the nucleus to unleash all kinds of genes of defense. DO REMEMBER that upstream NFkB go through MEK (also involved in Angiogenesis) to reach MAP3K and you can see how through networking of these pathways the phenomena gets global.
Sirtuin:
This compound is SIRT1, it is activated by BUTEIN
Butein actually activate SIRT1 and may induce aging in the cell. Remember Butein by activating Sirtuin will have a role in Diabetes, Gout, Alzheimer dementia, and Amyloid related disease. Butein, a versatile anti-inflammatory drug with effect on NAD (Nicotinamid), and may be a Histone De-acetylase inhibitor. This stuff has potential!
The subunit to be inhibited for the activation of the Nuclear factor and pathway NF-kB which has versatile transforming capacity to combat, escape and resist various attackers including infection and chemotherapy. Inhibition here reduces the cell capacity to adapt. It appears that the Transcription factor NFkB is sitting there in the Cytosol totally inactive, touch the IKK through phosphorylation, wakes the NFkB which spring into motion and unleashes its power. One of the best described pathway flow is TNF posphorylation of IKK which detaches and goes on to being ubiquitinated and degraded through the Proteasome. detachment of the IKK lead to a free NFkB kinase which enter the nucleus to unleash all kinds of genes of defense. DO REMEMBER that upstream NFkB go through MEK (also involved in Angiogenesis) to reach MAP3K and you can see how through networking of these pathways the phenomena gets global.
Sirtuin:
This compound is SIRT1, it is activated by BUTEIN
Butein actually activate SIRT1 and may induce aging in the cell. Remember Butein by activating Sirtuin will have a role in Diabetes, Gout, Alzheimer dementia, and Amyloid related disease. Butein, a versatile anti-inflammatory drug with effect on NAD (Nicotinamid), and may be a Histone De-acetylase inhibitor. This stuff has potential!
BUTEIN, A POWERFUL INHIBITOR
As we speak with the University of Texas in El Paso, the CRBCM would like to look further into the clinical use of a potent Inhibitor in a phase I study. We believe this compound will have a significant role in Triple Negative Breast Cancer. Butein, a derivative of Charcone, a powerful anti-Oxidant and known anti-inflammatory used in ASIA, seems to have a global inhibitory effect. It is one of the 3 inhibitors of the SRC, it is a Glutathione inhibitor, Blocker of EGF, inhibitor of IKK, and of the NF-kB signal transduction pathway, cause phosphorylation of the AKT, reduction of Cyclin D1 and D2, activation of WAF1/p21 and KIP1/p27, Iron induced inhibitor of Xanthine Oxidase (love that enzyme since I first learned about Asthma).
This Butein stuff is a global inhibitor. If you add this to MTOR inhibitors, you may end up with too toxic a combination for any cancer! This would be an overwhelming attack on cells!
It has demonstrated powerful Ex-vivo activity against breast and prostate cancer cell lines, and is empirically used against Gastric cancer.
This global and versatile inhibitor, Butein, should have activity in Sarcoma since it inhibits SRC and potentially the fibroblast. Other Inhibitors of SRC, heme supported phosphorylation and CYIKYYF. (of note CDK1, PTRC and PTK2)
Gave you so many letters, lets move to gene Nomenclature please! we are still working hard at the CRBCM!
This Butein stuff is a global inhibitor. If you add this to MTOR inhibitors, you may end up with too toxic a combination for any cancer! This would be an overwhelming attack on cells!
It has demonstrated powerful Ex-vivo activity against breast and prostate cancer cell lines, and is empirically used against Gastric cancer.
This global and versatile inhibitor, Butein, should have activity in Sarcoma since it inhibits SRC and potentially the fibroblast. Other Inhibitors of SRC, heme supported phosphorylation and CYIKYYF. (of note CDK1, PTRC and PTK2)
Gave you so many letters, lets move to gene Nomenclature please! we are still working hard at the CRBCM!
Monday, February 4, 2013
CRBCM MET DR RENATO AGUILARE of the University of Texas in El Paso.
=============================
======================================================================
The Meeting was centered on potential scientific collaboration between the BBRC and the CRBCM & Greater East Cancer Center. The collaboration is called for by most grant funding source for both entities. The Biomedical research (BBRC) needs cooperation with cancer centers, and the CRBCM needs ties with the local University.
We discussed the careful handling of exchanged study tissue or fluid samples which should follow NCI protocols related to studies on human subjecst (Dr Kankonde attended appropriate NCI training and is a certified investigator like most American Oncologists) and proper handling of patient information should follow HIPPA guidleines. Under the term of the understanding, no patient name will be released to the University staff.
CRBCM also met DR GIULIO FRANCIA, PHD, Assistant professor in the Dept. of Biological Sciences at UTEP. The line of discussion was similar. Collaboration on future investigations and publications was the bulk of the discussion.
The CRBCM has 2 grant request application letters pending before the BBRC.
Details of the plans are still waiting to be finalized. The meeting was informative about the spectrum of clinical research projects at this Dept. at UTEP.
=============================
|  Feb 1 (3 days ago) | | ||
| ||||
Shown
below is the parking pass –it needs to be displayed so please print it
and follow the instructions below to avoid a ticket. A campus map is
also enclosed. My office is located in the new Biosciences Research
Bldg and I am in room 4.144
Renato J. Aguilera, Ph.D.
Professor of Biology
Deputy Director and
Director of the Cell Culture and HTS Core Facility
Border Biomedical Research Center
University of Texas at El Paso
500 W. University Dr.
El Paso, TX 79968-0519
Ph:(915)747-6852======================================================================
The Meeting was centered on potential scientific collaboration between the BBRC and the CRBCM & Greater East Cancer Center. The collaboration is called for by most grant funding source for both entities. The Biomedical research (BBRC) needs cooperation with cancer centers, and the CRBCM needs ties with the local University.
We discussed the careful handling of exchanged study tissue or fluid samples which should follow NCI protocols related to studies on human subjecst (Dr Kankonde attended appropriate NCI training and is a certified investigator like most American Oncologists) and proper handling of patient information should follow HIPPA guidleines. Under the term of the understanding, no patient name will be released to the University staff.
CRBCM also met DR GIULIO FRANCIA, PHD, Assistant professor in the Dept. of Biological Sciences at UTEP. The line of discussion was similar. Collaboration on future investigations and publications was the bulk of the discussion.
The CRBCM has 2 grant request application letters pending before the BBRC.
Details of the plans are still waiting to be finalized. The meeting was informative about the spectrum of clinical research projects at this Dept. at UTEP.
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 ...
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