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

膀胱癌是人类第五大常见癌症，由于复发率高，实际上也是治疗费用最高的癌症。在人类膀胱癌中，已发现两种主要的改变途径：EGFR途径(EGFR 1，2，3或ErbB1，2，3)和PI3K/AKT途径(Pl3K突变，PTEN缺失，AKT扩增)。事实上，基因表达分析(显示了四种不同的膀胱癌亚型)发现，在四种亚型中的两种(占总癌症的60%-65%)中，EGFR2在RNA和蛋白质水平的过度表达是一致的变化。另外两个亚组与P|3K/AKT通路的改变有关。然而，这两种途径的抑制剂往往会引起痤疮样皮疹和严重腹泻，使这些抑制剂难以在预防环境中使用。我们最近在一个大鼠乳腺癌模型中评估了拉帕替尼和变构AKT(MK2206)抑制剂的每周剂量，发现每周剂量是非常有效的。此外，我们发现，当微观膀胱癌已经存在时，从最后一剂羟丁基(丁基)亚硝胺(OH-BBN)后两个月开始每周给药，拉帕替尼也是有效的。最后，我们观察到，联合每日剂量的拉帕替尼和小剂量的非甾体抗炎药萘普生是降低膀胱癌发病率的最有效方案。人们认为，通过每周服用拉帕替尼和间歇服用非甾体类抗炎药，与这些药物相关的毒性(拉帕替尼、皮疹和腹泻；非类固醇抗炎药、胃毒性)应该大大减少。调查每周服药使用情况的呼声 酪氨酸激酶抑制剂(E.9，EGFR，Pl3K和AKT)的一个特点是，在人类中，有明确的数据表明，EGFR1抑制剂Erlotinib每周给药可显著减少与每日给药相关的痤疮样皮疹。此外，由于痤疮样皮疹也与AKT抑制剂MK2206的毒性有关，因此有理由预计每周服用这种药物将同样减少这种副作用。

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.