A better approach, however, may be to target Ras proteins or molecules downstream of Ras proteins through which meningioma-associated growth factors transduce their signals. These include small molecule inhibitors of the enzyme farnesyl-protein transferase (FPTase) and mevalonate pathway inhibitors that suppress those enzymes that are involved in production of farnesyl diphosphate, the substrate for FPTase. Because farnesylation is critical for converting a cytoplasmic and biologically inactive precursor Ras protein into a functional membrane-associated protein, several pharmaceutical companies are currently assessing anticancer activities of FPTase inhibitors in clinical trials.

Considering the nature of molecular alterations in meningiomas, one can hypothesize that inhibition of proteins that function downstream of the growth factor/Ras pathway by small molecule compounds can also be thera-peutically useful. For example, a novel inhibitor drug, PD 184352, was recently discovered to directly and specifically inhibit the Mek-1 kinase, a protein that acts downstream of Ras proteins to activate extracellular signal-regulated kinases Erk-1 and Erk-2. This Mek-1 inhibitor significantly suppressed the growth of human colon and ovarian xenograft tumors in mice without unacceptable side-effects [49].

It is well established that activation of the growth factor/Ras pathway causes increased turnover of the arachidonic acid metabolism, including production of prostaglandins and leukotrienes, by regulating the activity of cytosolic phospholipase A2, cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LO), respectively. Dramatically elevated concentrations of arachidonic acid, prostaglandins and leukotrienes have been reported to occur in meningiomas compared with normal brain tissue, and are believed to be important mediators of peritumoral brain edema. One can therefore speculate that inhibitors of these lipid enzymes, such as COX-2-specific and 5-LO inhibitors, may be of use to prevent or treat meningiomas and peritumoral edema. At least six cancer trials with a COX-2-specific inhibitor, celecoxib, are currently underway [50]. Boswellic acids, naturally occurring compounds isolated from the gum-resin exudate from the stem of the tree Boswellia serrata (frankincense), are potent inhibitors of 5-LO. At low micromolar, physiologically achievable concentrations, boswellic acids are cytotoxic for meningioma and glioma cells [51]. A phase I/II clinical trial to establish the effects of boswellic acids on peritumoral edema in glioblastoma patients is currently in progress (at www. clinical.html ).

Clearly, an improved understanding of the biological functions of known genes that play a critical role in meningioma development, as well as identification of novel molecular abnormalities, will provide potential targets for new therapeutic approaches that are both more effective and better tolerated than the traditional therapies.

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