IGF::OT::IGF EVALUATION OF AGENTS/PROTOCOLS THAT INHIBIT TWO MAJOR PATHWAYS INVOLVED IN HUMAN URINARY BLADDER CANCER(PI3K, EGFR) AND PROTOCOLS TO REDUCE THEIR TOXICITY

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Urinary bladder cancer, which is the fifth most common cancer in humans, is actually the most expensive cancer to treat because of high rates of recurrence.Two major altered pathways in the preponderance of human urinary bladder cancer have been identified: the EGFR pathway (EGFR 1,2,3 or ErbB 1 ,2,3) and the PI3K/AKT pathway (mutations in Pl3K, loss of PTEN, and amplification of AKT). In fact, gene expression analysis (which showed four different subtypes of bladder cancer) found that in two of the four subtypes (representing 60-65% of total cancers) overexpression of EGFR2 at the RNA and protein level was a consistent change. The other two subgroups were associated with alterations in the P|3K/AKT pathway. However, inhibitors of either of these pathways tend to cause an acneiform rash and significant diarrhea, making these inhibitors difficult to employ in a prevention setting. We have recently evaluated weekly dosing of both lapatinib and an allosteric AKT (MK2206) inhibitor in a rat mammary cancer model, and found that weekly dosing was highly effective. Furthermore, we found that lapatinib was also effective when administered weekly beginning up to two months after the last dose of hydroxybutyl(butyl)nitrosamine (OH-BBN), when microscopic urinary bladder cancers already existed. Finally, we observed that combining daily doses of lapatinib with a low dose of the NSAID naproxen was the most effective protocol in reducing bladder cancer incidence. lt is felt that by employing weekly dosing with lapatinib and intermittent dosing of an NSAID, the toxicities associated with these agents (lapatinib, rash and diarrhea; NSAID, gastric toxicity) should be greatly reduced. The appeal of investigating the use of weekly dosing of tyrosine kinase inhibitors (e.9., EGFR, Pl3K and AKT) is that in humans there is clear data with the EGFR1 inhibitor Erlotinib that weekly dosing strongly decreases the acneiform rash associated with daily dosing. Furthermore, since an acneiform rash is also associated with the toxicity of the AKT inhibitor MK2206 there is reason to expect that weekly dosing with this agent will similarly reduce this side effect.