AKT as a Biomarker of Ovarian Cancer Progression and a Target for Therapeutic Int

AKT 作为卵巢癌进展的生物标志物和治疗整合的靶点

• 批准号: 6958701
• 负责人: Joseph R. Testa
• 金额: $ 10.38万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-22 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6958701
• 关键词: biological signal transduction; biomarker; carcinoma; cell growth regulation; chemoprevention; clinical research; enzyme activity; enzyme mechanism; fatty acid synthase; gene expression; genetically modified animals; human subject; laboratory mouse; metastasis; neoplastic growth; neoplastic process; oncogenes; ovary neoplasms; phosphatidylinositol 3 kinase; tissue /cell culture

Activation of AKT promotes tumor cell survival, proliferation and invasiveness, suggesting that AKT may play a central role in tumorigenesis and therapeutic response. AKT is frequently activated in ovarian cancer and may occur early in tumor progression. Rapamycin targets AKT signaling via inhibition of mTOR, leading to G1 arrest in tumor cells with activated AKT. Fatty acid synthase (FAS) is often overexpressed in ovarian carcinomas, and its expression is regulated in part by AKT signaling. Enzymatic inhibition of FAS by specific pharmacologic agents induces apoptosis in tumor cells. Collectively, these data suggest that mTOR and FAS are promising targets for the treatment of ovarian cancer patients. The long-term objective of this proposal is to determine if mTOR or FAS inhibition by specific pharmacologic agents can be therapeutically efficacious in ovarian carcinomas, and whether response is dependent on the AKT status of a given tumor. The specific aims are" 1) Determine whether AKT activation and genomic imbalances occur early in the progression of human ovarian cancer. Immunostaining will be performed on putative preneoplastic ovarian lesions to determine if activation of AKT is an early event in ovarian tumorigenesis. To place AKT activation in the context of a model of ovarian tumor progression, array-CGH, an invaluable new tool that permits high-resolution analysis of genomic imbalances, will also be used to identify early somatic genetic changes in these same specimens. 2) Identify potential synergy between FAS inhibition or mTOR inhibition and various chemotherapeutic agents in ovarian cancer cell lines with or without constitutive activation of AKT. 3) Determine whether pharmacologic inhibition of AKT pathways can repress ovarian tumor formation. As a chemotherapeutic strategy, xenograft models of human ovarian cancer will be used to assay anti-tumorigenic effects of mTOR and FAS inhibitors. As a chemoprevention strategy, a transgenic ovarian cancer model expressing active AKT will be used to determine if rapamycin can inhibit or delay tumor formation. 4) Conduct a phase II trial of an mTOR inhibitor in the treatment of ovarian cancer. Overall, these studies will yield important insights regarding the value of AKT as a biomarker for predicting ovarian cancer development, progression and drug sensitivity and will ascertain whether AKT pathway inhibition can serve as an effective chemopreventive and/or chemotherapeutic strategy in ovarian cancer.

AKT 的激活促进肿瘤细胞存活、增殖和侵袭，表明 AKT 可能在肿瘤发生和治疗反应中发挥核心作用。 AKT 在卵巢癌中经常被激活，并且可能发生在肿瘤进展的早期。雷帕霉素通过抑制 mTOR 来靶向 AKT 信号传导，导致 AKT 激活的肿瘤细胞发生 G1 期停滞。脂肪酸合酶 (FAS) 在卵巢癌中通常过度表达，其表达部分受到 AKT 信号传导的调节。特定药物对 FAS 的酶抑制可诱导肿瘤细胞凋亡。总的来说，这些数据表明 mTOR 和 FAS 是治疗卵巢癌患者的有希望的靶点。该提案的长期目标是确定特定药物对 mTOR 或 FAS 的抑制是否对卵巢癌有效，以及反应是否取决于特定肿瘤的 AKT 状态。具体目标是“ 1) 确定 AKT 激活和基因组失衡是否发生在人类卵巢癌进展的早期。将对假定的癌前卵巢病变进行免疫染色，以确定 AKT 的激活是否是卵巢肿瘤发生的早期事件。 array-CGH 是一种非常有价值的新工具，可以对卵巢肿瘤进展模型进行高分辨率分析 基因组失衡，也将用于识别这些相同的早期体细胞遗传变化 标本。 2) 确定 FAS 抑制或 mTOR 抑制与各种药物之间的潜在协同作用 具有或不具有 AKT 组成型激活的卵巢癌细胞系中的化疗药物。 3) 确定AKT途径的药理抑制是否可以抑制卵巢肿瘤的形成。作为一种化疗策略，人类卵巢癌的异种移植模型将用于测定 mTOR 和 FAS 抑制剂的抗肿瘤作用。作为一种化学预防策略，表达活性 AKT 的转基因卵巢癌模型将用于确定雷帕霉素是否可以抑制或延缓肿瘤形成。 4) 进行mTOR抑制剂治疗卵巢癌的II期试验。总体而言，这些研究将得出关于 AKT 作为预测卵巢癌发生、进展和药物敏感性的生物标志物的价值的重要见解，并将确定 AKT 通路抑制是否可以作为卵巢癌的有效化学预防和/或化疗策略。