If the statins (lovastatin, simvastatin, atorvastatin etc., inhibitors of HMGCoA reductase) have offered little benefit in the treatment of cancer, they are regarded almost as wonder drugs in the prevention of atherosclerosis and stroke. Polyisoprene (squalene) formation

is a key step in the formation of cholesterol and the membrane anchors (farnesyl and geranylgeranyl) that link the Ras GTPases to the plasma membrane (see page 105).

advantage that the kinase is less likely to escape inhibition. The general trend now is to shift attention away from single, highly selective inhibitors towards broader spectrum compounds or to cocktails of specific inhibitors acting

in different ways. These approaches open up a range of new therapeutic promise but also the possibility of unacceptable adverse effects.

Other signal transduction components targeted for therapeutic intervention

There are many other components of signal transduction pathways that might be regarded as possible targets for drug therapy. The Ras-MAP kinase pathway has been studied extensively and its components, H-, K- and N-Ras, B-Raf, and MEK1, have been identified as human oncogenes. In particular, it has been suggested that because Ras-mediated cell transformation demands membrane attachment (through polyisoprenoid chains: see page 105), prevention of this post translational modification might stop cancer growth.52 However, none of the drugs developed for this purpose have shown any benefit in the cancer field, and in many cases mutated Ras escapes their effect. Inhibitors of B-Raf share the same misfortune though the jury is still out for the inhibitors of MEK. Three highly selective MEK inhibitors have recently reached the stage of clinical trials.53,54 These differ from many other kinase inhibitors in that they do not compete with ATP but bind close to the catalytic cleft, thereby impeding access of the activation segment of ERK (the unique substrate of MEK) (Figure 23.10).

Inhibitors targeting enzymes of the PI 3-kinase pathway (PI 3-kinase, PKB, and mTOR) that controls protein synthesis, cell cycle progression and, importantly, cell survival, also show some promise.55 Another possible target is Hsp90,56 involved in protein folding. It is highly expressed in tumours and appears to play a role in the activation and localization of kinases such as Raf, Cdk4/6, v-Src, or PKB. Some of the compounds developed to inhibit protein kinases are listed in Table 23.3.

Towards a different approach in testing cancer drugs?

The general opinion is that with the single exception of imatinib, signal transduction blockers have yet to realize a real breakthrough in cancer treatment. Whereas the limiting factor to advances in this field used to be the definition of drug targets, today it seems to be the design of appropriate and effective clinical trials. We have many compounds, all based on good scientific rationales, all seemingly safe and which offer promising effects in in vitro (cell culture) and in vivo (mouse xenograft) studies.

for general clinical application, these markers remain useful in order to verify whether or not tumours are responding.57 The design of clinical trials should provide the opportunity to assess retrospectively why a particular compound failed to give the expected result in a particular patient.53 Unfortunately,

the pressure exerted both by patients and by the industry to advance new blockbuster drugs limits the scale and value of such retrospective analytical approaches.58

For more information about clinical trials we suggest: http://www. cancer.gov/clinicaltrials/ learning