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

IGF::OT::IGF 对抑制人类膀胱癌（PI3K、EGFR）两个主要途径的药物/方案的评估以及降低其毒性的方案

• 批准号: 9151999
• 负责人: CLINTON GRUBBS
• 金额: $ 67.91万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-24 至 2017-09-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9151999
• 关键词: Adverse effects; Biological Markers; Breast Cancer Model; Data; Diarrhea; Dose; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Evaluation; Exanthema; Gene Expression Profiling; Human; Incidence; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Microscopic; Mutation; Naproxen; Nitrosamines; Non-Steroidal Anti-Inflammatory Agents; PI3K/AKT; PIK3CG gene; PTEN gene; Pathway interactions; Prevention; Proteins; Proto-Oncogene Proteins c-akt; Protocols documentation; RNA; Rattus; Recurrence; Reducing Agents; Schedule; Stomach; Subgroup; Testing; Toxic effect; Tyrosine Kinase Inhibitor; in vivo Model; inhibitor/antagonist; lapatinib; novel; overexpression

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.

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）。实际上，基因表达分析（显示四种不同的膀胱癌亚型）发现，在RNA和蛋白质水平上的四个亚型中的两个（代表总癌症的60-65％）过表达是一致的变化。其他两个亚组与P | 3K/AKT途径的变化有关。但是，这两种途径中的任何一种抑制剂都倾向于引起急性皮疹和明显的腹泻，从而使这些抑制剂在预防环境中难以使用。我们最近在大鼠乳腺癌模型中评估了Lapatinib和变构AKT（MK2206）抑制剂的每周剂量，并发现每周给药非常有效。此外，我们发现每周在最后一个剂量的羟基丁基（丁基）硝基胺（OH-BBN）的剂量后，Lapatinib也是有效的。最后，我们观察到，将每日剂量的拉帕替尼与低剂量的NSAID萘普生相结合是降低膀胱癌发病率的最有效方案。人们认为，通过每周使用拉帕替尼和NSAID的间歇性给药，与这些药物相关的毒性（拉帕替尼，皮疹和腹泻； NSAID，胃毒性）应大大降低。调查每周剂量使用的吸引力 酪氨酸激酶抑制剂（E.9。，EGFR，PL3K和AKT）的是，在人类中，有明确的数据具有EGFR1抑制剂Erlotinib，每周给药可强烈降低与日常剂量相关的痤疮状皮疹。此外，由于Akt抑制剂MK2206的毒性也与急性皮疹有关，因此有理由期望与该药物的每周剂量同样会降低这种副作用。