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

AKT的激活促进肿瘤细胞的存活、增殖和侵袭，表明AKT可能在肿瘤发生和治疗反应中起核心作用。AKT在卵巢癌中经常被激活，并且可能在肿瘤进展的早期发生。雷帕霉素通过抑制mTOR靶向AKT信号传导，导致具有活化AKT的肿瘤细胞中的G1停滞。脂肪酸合成酶（FAS）在卵巢癌中经常过表达，其表达部分受AKT信号调节。特定药理学试剂对FAS的酶抑制诱导肿瘤细胞凋亡。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理学药物对mTOR或FAS的抑制是否在卵巢癌中具有治疗有效性，以及应答是否依赖于给定肿瘤的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。将对假定的肿瘤前卵巢病变进行免疫染色，以确定AKT激活是否是卵巢肿瘤发生的早期事件。为了将AKT激活置于卵巢肿瘤进展模型的背景下，阵列CGH是一种非常宝贵的新工具，它允许高分辨率分析AKT激活， 基因组不平衡，也将用于确定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 在有或没有AKT组成型活化的卵巢癌细胞系中，使用化疗剂。3)确定药物抑制AKT通路是否可以抑制卵巢肿瘤的形成。作为化疗策略，将使用人卵巢癌的异种移植模型来测定mTOR和FAS抑制剂的抗肿瘤发生作用。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迟肿瘤形成。4)进行mTOR抑制剂治疗卵巢癌的II期试验。总的来说，这些研究将产生关于AKT作为预测卵巢癌发展、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/或化学治疗策略。

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.