Post by eliwu on Dec 15, 2011 22:04:30 GMT -5
In the July 15th issue of G&D, Dr. Suzanne Baker (St. Jude Children¡¯s Research Hospital) and colleagues report on their surprising discovery of CP-690550[/url] of PI3K signaling within the mammalian brain. This finding highlights the complexity of this clinically significant cell signaling pathway, and its relevance to the design of small molecule PI3K pathway Tasocitinib[/url], to both maximize efficacy and minimize side effects.
The INCB018424[/url] is an intricate signaling cascade that regulates cell survival and growth under normal, as well as pathological conditions. In fact, the proteasome inhibitor[/url] is mutated in more cancer patients than any other. The signaling network is balanced by the PTEN tumor suppressor Bortezomib[/url].
PTEN (Phosphatase and Tensin Homologue Deleted from Chromosome-10) is recognized as one of the most frequently mutated tumor suppressors in human Velcade[/url], and has also been associated with neurological diseases like autism. It functions primarily as a phosphatase (phosphate-group-cleaving enzyme) to antagonize PI3K signaling by dephosphorylating VX-222[/url], the lipid second messenger that signals activation of the PI3K signaling hsp90 inhibitor[/url]. Loss of PTEN results inside the upregulation of PI3K signaling, through the increased phosphorylation of PI3K effectors such as the molecule, AUY922[/url]. Thus, the PTEN/PI3K/AKT pathway represents an important target for drug discovery.
To study the role of the 17-AAG[/url] downstream effector molecule, PDK1, in mediating the effects of PTEN loss, Dr. Baker and colleagues generated a novel transgenic 17-DMAG[/url] strain deficient in both PDK1 and PTEN specifically within the brain. The researchers found that while some of the characteristic nvp-auy922[/url] abnormalities arising from PTEN loss are corrected by the concomitant deletion of PDK1, others are not: Most notably, PDK1 did not rescue the migration Igf 1r inhibitor[/url] associated with PTEN loss in neurons. PDK1-independent abnormalities in the brains of PTEN-deficient mice suggests that additional, alternate downstream SB 431542[/url] of the PI3K signal exist.
This finding underscores the consideration that, as Dr. Baker explains, ¡°LY2157299[/url] that block downstream effectors in PI3K signaling may not correct all of the defects caused by loss of PTEN sb-431542[/url].¡±
Dr. Baker¡¯s team also observed differential feedback regulation of the PI3K pathway in different CNS cell types. Clinical GDC-0449[/url] has shown that some human tumors achieve chemoresistance through the increased phosphorylation of the PI3K downstream component, AKT. Quite surprisingly, Dr. Baker and colleagues found that PDK1 Vismodegib[/url] caused a selective, dramatic increase within the phosphorylation of AKT in glial cells, but not neurons, indicating unanticipated cell-type specificity in PI3K feedback Cyclopamine[/url] inside the brain.
Further research will be needed to determine if PDK1, itself, represents a useful therapeutic target. However, this example of a cell BMS-708163[/url] response to PDK1 deletion supports the notion of personalized cancer treatment, in so far as emphasizing the relevance of tumor cell of origin and genotype to help predict which patients will respond positively to specific PI3K inhibitors.
Dr. Baker emphasizes that, likewise, ¡°There may be profound differences inside the effects of inhibitors on different types of normal cells, which could be relevant in terms of side effects induced by systemic treatment with a pathway inhibitor.¡±
The INCB018424[/url] is an intricate signaling cascade that regulates cell survival and growth under normal, as well as pathological conditions. In fact, the proteasome inhibitor[/url] is mutated in more cancer patients than any other. The signaling network is balanced by the PTEN tumor suppressor Bortezomib[/url].
PTEN (Phosphatase and Tensin Homologue Deleted from Chromosome-10) is recognized as one of the most frequently mutated tumor suppressors in human Velcade[/url], and has also been associated with neurological diseases like autism. It functions primarily as a phosphatase (phosphate-group-cleaving enzyme) to antagonize PI3K signaling by dephosphorylating VX-222[/url], the lipid second messenger that signals activation of the PI3K signaling hsp90 inhibitor[/url]. Loss of PTEN results inside the upregulation of PI3K signaling, through the increased phosphorylation of PI3K effectors such as the molecule, AUY922[/url]. Thus, the PTEN/PI3K/AKT pathway represents an important target for drug discovery.
To study the role of the 17-AAG[/url] downstream effector molecule, PDK1, in mediating the effects of PTEN loss, Dr. Baker and colleagues generated a novel transgenic 17-DMAG[/url] strain deficient in both PDK1 and PTEN specifically within the brain. The researchers found that while some of the characteristic nvp-auy922[/url] abnormalities arising from PTEN loss are corrected by the concomitant deletion of PDK1, others are not: Most notably, PDK1 did not rescue the migration Igf 1r inhibitor[/url] associated with PTEN loss in neurons. PDK1-independent abnormalities in the brains of PTEN-deficient mice suggests that additional, alternate downstream SB 431542[/url] of the PI3K signal exist.
This finding underscores the consideration that, as Dr. Baker explains, ¡°LY2157299[/url] that block downstream effectors in PI3K signaling may not correct all of the defects caused by loss of PTEN sb-431542[/url].¡±
Dr. Baker¡¯s team also observed differential feedback regulation of the PI3K pathway in different CNS cell types. Clinical GDC-0449[/url] has shown that some human tumors achieve chemoresistance through the increased phosphorylation of the PI3K downstream component, AKT. Quite surprisingly, Dr. Baker and colleagues found that PDK1 Vismodegib[/url] caused a selective, dramatic increase within the phosphorylation of AKT in glial cells, but not neurons, indicating unanticipated cell-type specificity in PI3K feedback Cyclopamine[/url] inside the brain.
Further research will be needed to determine if PDK1, itself, represents a useful therapeutic target. However, this example of a cell BMS-708163[/url] response to PDK1 deletion supports the notion of personalized cancer treatment, in so far as emphasizing the relevance of tumor cell of origin and genotype to help predict which patients will respond positively to specific PI3K inhibitors.
Dr. Baker emphasizes that, likewise, ¡°There may be profound differences inside the effects of inhibitors on different types of normal cells, which could be relevant in terms of side effects induced by systemic treatment with a pathway inhibitor.¡±