Targeting p53 for colon cancer treatment & prevention

描述（由申请人提供）：最近鉴定和开发的激活p53的小分子为结肠癌治疗和预防开辟了新的可能性，其中p53的突变失活通常是腺瘤-癌序列中的晚期事件。我们的初步数据表明，AOM诱导的小鼠结肠肿瘤中的p53被最近开发的Mdm 2抑制剂Nultin-3激活，使这些肿瘤对这种化合物高度敏感。我们认为，在选定的癌变阶段刺激p53活性将有助于抑制结肠癌的发展。为了检验这一假设，我们将确定Mdm 2抑制剂Nutlin-3是否可以在小鼠AOM模型中诱导结肠肿瘤的停滞或消退（Aim 1）。我们还将确定Nutlin-3是否可以选择性地激活人结肠腺瘤和小鼠异常隐窝病灶中的p53和细胞凋亡（使用离体培养形式;目的2）。最后，我们将确定表观遗传学调节的ARF基因的表达水平是否使结肠癌和腺瘤细胞对Nutlin-3或影响p53通路的饮食剂敏感（Aim 3）。这些探索性研究的长期目标是：1）确定p53/Mdm 2作为结肠癌预防剂的靶点，2）确定Mdm 2抑制剂最有效时的致癌阶段，3）确定ARF对活化p53的药物致敏转化细胞的贡献。公共卫生相关性：结肠息肉切除术是预防结肠癌的重要工具。然而，这种方法的局限性包括无蒂息肉的不完全切除和小腺瘤的漏诊。我们的目标是开发安全有效的药理学或饮食制剂，与目前的治疗实践结合使用，以抑制高危患者发生结肠癌的风险。

DESCRIPTION (provided by applicant): The recent identification and development of small molecules that activate p53 open new possibilities for colon cancer treatment and prevention where the mutational inactivation of p53 is typically a late event in the adenoma-carcinoma sequence. Our preliminary data indicate that p53 in AOM-induced mouse colon tumors is primed for activation by the recently developed Mdm2 inhibitor Nultin-3, making these tumors hypersentive to this compound. We propose that stimulating p53 activity at selected stages of carcinogenesis will serve to suppress colon cancer development. To test this hypothesis, we will determine if the Mdm2 inhibitor Nutlin-3 can induce stasis or regression of colon tumors in the mouse AOM model (Aim 1). We will also determine whether Nutlin-3 can selectively activate p53 and apoptosis in human colon adenomas and mouse aberrant crypt foci (using an ex vivo culture format; Aim 2). Finally, we will determine whether the expression levels of the epigenetically regulated ARF gene sensitizes colon cancer and adenoma cells to Nutlin-3 or dietary agents that affect the p53 pathway (Aim 3). The long term goals of these exploratory studies are to: 1) establish p53/Mdm2 as a target for colon cancer prevention agents, 2) determine the stage of carcinogenesis when Mdm2 inhibitors are most effective and 3) determine the contribution of ARF to sensitizing transformed cells to agents that activate p53. PUBLIC HEALTH RELEVANCE:Colon polypectomy is an important tool for colon cancer prevention. However, limitations to this approach include the incomplete removal of sessile polyps and the missed detection of small adenomas. Our goal is to develop safe and effective pharmacological or dietary agents, to be used in conjunction with present treatment practices, to suppress the risk of colon cancer development in high risk patients.