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!
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