The HIV challenge has many interesting aspects when it comes to pathophysiology and genetic based studies. It goes without saying that the disease is bad and has caused many deplorable deaths. But for scientists it has provided significant opportunity for advances as it has shed light on several aspects of this disease:
1. Viral infection: the takeover of the Human genome to the benefit of the life of the Virus
2. Sexually transmitted diseases and difficulties in controlling this line of infections, particularly in poor populations
3. Impact of hormone (Testosterone and corticoids which tend to worsen the disease such as in Kaposi Sarcoma)
4. Revealing weaknesses in the structure of our Immune systems for the decrease of CD4, to the development of lymphoproliferative disorders, to the development of opportunistic infections, to the increased risk of AIDS related lymphomas (ARL) in patients expressing Stromal cell derived Factor 1 ( and decrease risk in those having a deletion in Chemokine Receptor CCR5)
5. On the genetic front, Mutations, suppression and translocations of the c-MYC, P53, and Bcl6...
6. The disease causes the body to be swamped with Cytokines ( IL-1,6,10)
7. The disease has shown us the importance of duration of exposure as various diseases develop the longer you stay under the curb of low CD4 (less than 100) with certain diseases being seen only at certain CD4 counts.
8. New biomarkers are now defined CD30 (heightened risk of progression of ARL)
and new diagnosis (CD138, VS38c for Plasmablastic lymphoma)
9. Early introduction of Etoposide in the treatment plan seems to be important with the resurgence of the EPOCH regimen rather than CHOP; Etoposide seems to control those Epigenetic events better!
10. Eminence of Macrophages in the inflammatory process as they drive the EGFR
and the use of Anti-VEGF in KS. An angiosarcoma...(where is Avastin?)
You name HIV, the syndrome does it. The push for us is to go back to the genetic bases of this disease!
Showing posts with label anti-vegf. Show all posts
Showing posts with label anti-vegf. Show all posts
Saturday, November 9, 2013
Monday, March 11, 2013
INHIBITION OF MTOR
from R T Kurmasheva, et al
"Thus, inhibition of mTOR may have direct effects on cancer cell proliferation and survival, indirect effects via inhibition of HIF-1α, thus reducing tumour-elicited VEGF, direct effects on vascular endothelial cells, or vascular smooth muscle cells (Humar et al, 2002; Majumder et al, 2004). For example, induction of HIF-1α and VEGF by the CML-associated oncogene, BCR-ABL, is mTOR-dependent (Mayerhofer et al, 2002), and in vitro, rapamycin inhibited VEGF production in primary cultures from BCR-ABL transformed, imatinib resistant, CML (Mayerhofer et al, 2005). The role for mTOR in VEGF production is supported by regulation of HIF-1α by mTOR signalling and increased VEGF in cells deficient in the TSC that negatively regulates mTOR via Rheb (Hudson et al, 2002). However, other studies support a role mainly for PI3K and to a lesser extent mTOR being required for insulin-induced HIF-1α expression (Treins et al, 2002). Our studies indicate that rapamycin treatment has little effect on hypoxia-driven VEGF production in most rhabdomyosarcoma or neuroblastoma cell lines (Kurmasheva et al, submitted). Thus, in these cells it is unlikely that rapamycin would block tumour-derived VEGF, although it may directly block the response of vascular endothelial or other stromal cells in tumour tissue. Potentially, in vivo resistance to mTOR inhibition could be elicited by secretion of angiogenic factors that signal to stromal cells via mTOR-independent pathways to increase proliferation or motility of vascular cells."
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Yesterday we saw that Anti-VEGF drug induced alteration of vascular endothelium that could eventually bring Hypoxia into the cell, today we add evidence that the Hypoxia may induce HIF expression bringing MTOR overexpression into the battle leading to cancer cellular survival. THIS INDICATES THAT WHILE CONTINUING AVASTIN, INTRODUCING MTOR INHIBITOR AT THIS POINT MAY BRING A NEW STRATEGY TO REVERSE AVASTIN RESISTANCE, MEANING WHEN PLACENTAL GROWTH FACTOR OVER EXPRESSION IS HIGH (A MARKER OF AVASTIN FAILURE) , IT WOULD BE AN APPROPRIATE TIME TO BRING IN THE MTOR WITHOUT STOPPING AVASTIN. REMEMBER STOPPING AVASTIN HAS DEVASTATING REBOUND OF CANCER. AVASTIN HERE SERVES AS A PRIME FOR MTOR!
"Thus, inhibition of mTOR may have direct effects on cancer cell proliferation and survival, indirect effects via inhibition of HIF-1α, thus reducing tumour-elicited VEGF, direct effects on vascular endothelial cells, or vascular smooth muscle cells (Humar et al, 2002; Majumder et al, 2004). For example, induction of HIF-1α and VEGF by the CML-associated oncogene, BCR-ABL, is mTOR-dependent (Mayerhofer et al, 2002), and in vitro, rapamycin inhibited VEGF production in primary cultures from BCR-ABL transformed, imatinib resistant, CML (Mayerhofer et al, 2005). The role for mTOR in VEGF production is supported by regulation of HIF-1α by mTOR signalling and increased VEGF in cells deficient in the TSC that negatively regulates mTOR via Rheb (Hudson et al, 2002). However, other studies support a role mainly for PI3K and to a lesser extent mTOR being required for insulin-induced HIF-1α expression (Treins et al, 2002). Our studies indicate that rapamycin treatment has little effect on hypoxia-driven VEGF production in most rhabdomyosarcoma or neuroblastoma cell lines (Kurmasheva et al, submitted). Thus, in these cells it is unlikely that rapamycin would block tumour-derived VEGF, although it may directly block the response of vascular endothelial or other stromal cells in tumour tissue. Potentially, in vivo resistance to mTOR inhibition could be elicited by secretion of angiogenic factors that signal to stromal cells via mTOR-independent pathways to increase proliferation or motility of vascular cells."
------------------------------------------------------------------------------
Yesterday we saw that Anti-VEGF drug induced alteration of vascular endothelium that could eventually bring Hypoxia into the cell, today we add evidence that the Hypoxia may induce HIF expression bringing MTOR overexpression into the battle leading to cancer cellular survival. THIS INDICATES THAT WHILE CONTINUING AVASTIN, INTRODUCING MTOR INHIBITOR AT THIS POINT MAY BRING A NEW STRATEGY TO REVERSE AVASTIN RESISTANCE, MEANING WHEN PLACENTAL GROWTH FACTOR OVER EXPRESSION IS HIGH (A MARKER OF AVASTIN FAILURE) , IT WOULD BE AN APPROPRIATE TIME TO BRING IN THE MTOR WITHOUT STOPPING AVASTIN. REMEMBER STOPPING AVASTIN HAS DEVASTATING REBOUND OF CANCER. AVASTIN HERE SERVES AS A PRIME FOR MTOR!
Friday, February 22, 2013
ANTI-MEK ARE BETTER ANTI-VEGF
Based on what we know now, it is easy to see that in those diseases where Avastin has failed FDA approval, Anti-MEK will do better. MEK is down stream and MEK is involved in much more, including VEGF expression. MEK is part of the MEK/MAPK pathways, it is the door to Mesenchymal transformation (that is it the door to epithelial-mesenchymal transition), and therefore to angiogenesis, and to metastatic spread.
Anti-MEK also removes the negative inhibitory effect of the PTEN driven forces of the PI3K/MTOR pathways.
Metastatic Colon Cancer is the Primary target!
Only the MTOR inhibitors add to these drugs
Inability of Doxorubicin to add to DTIC in Melanoma is due to amplification of these 2 pathways.
Anti-MEK and MTOR combination will do far better in Melanoma and Pancreatic cancers, mark my words. We just need to brace ourselves to a new set of side effects.
Based on what we know now, it is easy to see that in those diseases where Avastin has failed FDA approval, Anti-MEK will do better. MEK is down stream and MEK is involved in much more, including VEGF expression. MEK is part of the MEK/MAPK pathways, it is the door to Mesenchymal transformation (that is it the door to epithelial-mesenchymal transition), and therefore to angiogenesis, and to metastatic spread.
Anti-MEK also removes the negative inhibitory effect of the PTEN driven forces of the PI3K/MTOR pathways.
PTEN inhibits insulin-stimulated MEK/MAPK activation andcell growth by blocking IRS-1 phosphorylation and IRS-1/Grb-2/Sos complex formation in a breast cancer model
- (Liang-Ping Weng1 at al.) The involvement of the Sons of the Sevenless could signify a large implication on the RAS pathway. And Anti-MEK were used as Medication to be used in lung cancer displaying amplification of the K-RAS
Metastatic Colon Cancer is the Primary target!
Only the MTOR inhibitors add to these drugs
Inability of Doxorubicin to add to DTIC in Melanoma is due to amplification of these 2 pathways.
Anti-MEK and MTOR combination will do far better in Melanoma and Pancreatic cancers, mark my words. We just need to brace ourselves to a new set of side effects.
Saturday, February 16, 2013
DRUGS IN THE PIPELINE PER "ONCOLOGY LIVE"
1. POMALIDOMIDE APPROVED FOR CML (EVEN T315I POSITIVE), A.L.L. PHILADELPHIA POSITIVE
2.T-DM 1 FOR HER-2 POSITIVE BREAST CANCERS.
3.APF530 FOR ACUTE AND DELAYED CHEMOTHERAPY INDUCED VOMITING
4 LYMPHOSEEK, TECHNETIUM, WILL SEEK SENTINEL NODES
5. CHEMOSAT FOR OCULAR MELANOMA METASTATIC TP THE LIVER, MELPHALAN BASED
6. TIVOZANIB ANTI-VEGF FOR METASTATIC RENAL CANCERS
7 AFATINIB FOR ADVANCED LUNG CANCER EGFR, ERB4 INHIBITOR
8. DABRAFENIB ANTI-BRAF IN MELANOMA
9. TRAMETINIB -ANTI MEK FOR ADVANCED MELANOMA
10 RADIUM-223 DICHLORIDE ALPHA PARTICLE EMISSION, IN BONE METASTASIS IN PROSTATE CANCER
2.T-DM 1 FOR HER-2 POSITIVE BREAST CANCERS.
3.APF530 FOR ACUTE AND DELAYED CHEMOTHERAPY INDUCED VOMITING
4 LYMPHOSEEK, TECHNETIUM, WILL SEEK SENTINEL NODES
5. CHEMOSAT FOR OCULAR MELANOMA METASTATIC TP THE LIVER, MELPHALAN BASED
6. TIVOZANIB ANTI-VEGF FOR METASTATIC RENAL CANCERS
7 AFATINIB FOR ADVANCED LUNG CANCER EGFR, ERB4 INHIBITOR
8. DABRAFENIB ANTI-BRAF IN MELANOMA
9. TRAMETINIB -ANTI MEK FOR ADVANCED MELANOMA
10 RADIUM-223 DICHLORIDE ALPHA PARTICLE EMISSION, IN BONE METASTASIS IN PROSTATE CANCER
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