Targeting p53 for colon cancer treatment & prevention

描述(申请人提供)：最近发现和开发了激活p53的小分子，为结肠癌的治疗和预防打开了新的可能性，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MDM2抑制剂Nultin-3激活，使这些肿瘤对这种化合物敏感。我们认为，在癌变的特定阶段刺激P53活性将有助于抑制结肠癌的发展。为了验证这一假设，我们将确定MDM2抑制剂Nutlin-3是否可以在小鼠AOM模型中诱导结肠肿瘤停滞或消退(目标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(使用体外培养格式；目标2)。最后，我们将确定表观遗传调控的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途径的饮食因素敏感(目标3)。这些探索性研究的长期目标是：1)建立p53/MDM2作为结肠癌预防药物的靶点；2)确定MDM2抑制剂最有效的致癌阶段；3)确定ARF在使转化细胞对激活p53的药物增敏方面的作用。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不完全切除无柄息肉和漏诊小腺瘤。我们的目标是开发安全有效的药理或饮食制剂，与目前的治疗方法结合使用，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.