What Exactly are the Targets of Targeted Therapy?

The term “targeted therapy” has entered common parlance. Like personalized medicine, targeted therapy is a generic description of drugs and combinations that inhibit specific cancer-related pathways. I am impressed by how quickly esoteric phenomena like the downstream signal in the insulin factor pathway have entered the lexicon of medical oncologists. With the advent of temsirolimus and everolimus, both rapamycin derivatives that target mTOR, we now have at our disposal agents that are every bit a part of the therapy repertoire. Unlike erlotinib that targets a specific tyrosine kinase, mTOR is a complex and multifaceted target.

There are actually two separate forms of mTOR, TORC1 and TORC2, and they sit at a critical point in cellular determination. Stimulated by the insulin growth pathway, cells must decide whether they will grow in size or divide. The mTOR proteins participate in this process by regulating protein synthesis and glucose uptake among other functions. In turn, the mTOR pathway is regulated by numerous other factors like AMP kinase and AKT. The current crop of mTOR inhibitors all target TORC1.

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, we have utilized the primary culture platform. It enables us to examine the end result of signal inhibition and dissect disease specific profiles. Using this approach we can partner with collaborators to define the specific operative pathways in each disease entity.

Biological complexity is the hallmark of life. We ignore it at our peril.