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gdpawel · 03-13-2013, 03:10 PM

The PI3K pathway is an area of rapidly growing interest as new compounds target this key regulatory protein complex. Both selective and non-selective (pan PI3K) inhibitors are in clinical testing. Laboratory oncologists have reported their findings on the dual PI3K/mTOR PARP inhibitor BEZ235 (Nagourney, RA et al, Proc AACR, 2586, 2012). Using PI3K/mTOR inhibitors, they explored the activities, synergies and possible clinical utilities of these novel compounds.

Perjeta (pertuzumab) inhibits signaling at the PI3K pathway, upstream from mTOR. Afinitor (everolimus) blocks mTOR itself, thus both drugs are influencing cell signaling that channel through metabolic pathways PI3K is the membrane signal from insulin, while mTOR is an intermediate in the same pathway. Thus, these are in the truest sense of the word, breakthroughs in metabolomics.

New classes of compounds are being developed that inhibit both TORC1 and TORC2. More interesting are the compounds that influence upstream signaling, including phosphoinositol kinase (PI3K) and AKT. What we are coming to learn, however, is that these are not targets but collections of targets. Indeed, the PI3K inhibitors themselves have influence on one, two or all of the distinct classes of phosphoinositol kinases.

Most of the studies to date have used compounds that affect all the classes equally (pan-inhibitors). Pharmaceutical companies are now developing highly selective inhibitors of this fundamental pathway. In addition, duel inhibitors that target both PI3K and mTOR are in clinical trials. What we are coming to realize is the complexity of these pathways. What may prove more vexing still is their redundancy.

One well-established by-product of successful inhibition of mTOR (principally TORC1) is the upstream activity of AKT via a feedback loop. This has the undesirable affect of redoubling mTOR stimulation through the very pharmacological manipulation that was designed to inhibit it. Again, an unintended consequence of a well laid plan.

To unravel the complexities and redundancies of these processes, laboratory oncologists have utilized the primary culture platform. It enables them to examine the end result of signal inhibition and dissect disease specific profiles. Using this approach they can partner with collaborators to define the specific operative pathways in each disease entity. Biological complexity is the hallmark of life.

03-13-2013, 03:10 PM	#4
gdpawel Senior Member Join Date: Aug 2006 Location: Pennsylvania Posts: 1,080	Use Functionality to Inform Genomics The PI3K pathway is an area of rapidly growing interest as new compounds target this key regulatory protein complex. Both selective and non-selective (pan PI3K) inhibitors are in clinical testing. Laboratory oncologists have reported their findings on the dual PI3K/mTOR PARP inhibitor BEZ235 (Nagourney, RA et al, Proc AACR, 2586, 2012). Using PI3K/mTOR inhibitors, they explored the activities, synergies and possible clinical utilities of these novel compounds. Perjeta (pertuzumab) inhibits signaling at the PI3K pathway, upstream from mTOR. Afinitor (everolimus) blocks mTOR itself, thus both drugs are influencing cell signaling that channel through metabolic pathways PI3K is the membrane signal from insulin, while mTOR is an intermediate in the same pathway. Thus, these are in the truest sense of the word, breakthroughs in metabolomics. New classes of compounds are being developed that inhibit both TORC1 and TORC2. More interesting are the compounds that influence upstream signaling, including phosphoinositol kinase (PI3K) and AKT. What we are coming to learn, however, is that these are not targets but collections of targets. Indeed, the PI3K inhibitors themselves have influence on one, two or all of the distinct classes of phosphoinositol kinases. Most of the studies to date have used compounds that affect all the classes equally (pan-inhibitors). Pharmaceutical companies are now developing highly selective inhibitors of this fundamental pathway. In addition, duel inhibitors that target both PI3K and mTOR are in clinical trials. What we are coming to realize is the complexity of these pathways. What may prove more vexing still is their redundancy. One well-established by-product of successful inhibition of mTOR (principally TORC1) is the upstream activity of AKT via a feedback loop. This has the undesirable affect of redoubling mTOR stimulation through the very pharmacological manipulation that was designed to inhibit it. Again, an unintended consequence of a well laid plan. To unravel the complexities and redundancies of these processes, laboratory oncologists have utilized the primary culture platform. It enables them to examine the end result of signal inhibition and dissect disease specific profiles. Using this approach they can partner with collaborators to define the specific operative pathways in each disease entity. Biological complexity is the hallmark of life.