AKT as a Biomarker of Ovarian Cancer Progression and a Target for Therapy

AKT 作为卵巢癌进展的生物标志物和治疗靶点

• 批准号: 7668734
• 负责人: Joseph R. Testa
• 金额: $ 79.98万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7668734
• 关键词: AKT inhibition; Address; Amino Acids; Antibodies; Apoptosis; Behavioral Genetics; Biological; Biological Assay; Biological Markers; Biopsy; Brain; Breast; CA-125 Antigen; Cancer Model; Cancer Patient; Cancer cell line; Carcinoma; Cell Proliferation; Cell Survival; Cells; Cellular Immunity; Cessation of life; Cetuximab; Chemicals; Chemoprevention; Chemopreventive Agent; Classification; Clinical; Clinical Data; Clinical Pharmacology; Clinical Trials; Colon; Complementary DNA; Consensus; DNA; DNA Microarray Chip; DNA Microarray format; Data; Death Rate; Detection; Development; Disease; Disease Progression; Dose; EGF gene; End Point; Enzymatic Biochemistry; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Erbitux; Etiology; Evaluation; Event; Exanthema; Excision; Fatty-acid synthase; Fractionation; Freedom; Future; G1 Arrest; Gel; Genes; Genomics; Genus Cola; Goals; Head and neck structure; High Pressure Liquid Chromatography; Human; In complete remission; Individual; Institutes; Label; Laboratories; Leeks (dietary); Lesion; Light; Location; Lung; MALDI-TOF Mass Spectrometry; MAPK Signaling Pathway Pathway; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Mass Spectrum Analysis; Measures; Messenger RNA; Microarray Analysis; Modality; Modeling; Molecular; Molecular Profiling; Molecular Target; Monitor; Monoclonal Antibody C225; Mus; Mutation; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Ovarian; Ovarian Carcinoma; Ovary; Pancreas; Participant; Pathway interactions; Patients; Pattern; Peptide Vaccines; Peptides; Peritoneal; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Platinum; Play; Post-Translational Protein Processing; Probability; Process; Prostatic Neoplasms; Protein Isoforms; Protein Overexpression; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; RNA Splicing; Rate; Reaction Time; Receptor Signaling; Recurrence; Recurrent disease; Refractory; Reporting; Reproduction spores; Research Personnel; Resistance; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Role; Safety; Sampling; Scientist; Signal Pathway; Signal Transduction; Sirolimus; Solid Neoplasm; Specimen; Subgroup; Surrogate Endpoint; System; Taxane Compound; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Time; Toxic effect; Transcriptional Regulation; Transgenic Mice; Transgenic Organisms; Tumor Biology; Tumor Tissue; Two-Dimensional Gel Electrophoresis; Tyrosine Kinase Inhibitor; United States Food and Drug Administration; Validation; Washington; Week; Woman; Xenograft Model; ZD1839 (IRESSA); base; bevacizumab; cancer therapy; chemotherapeutic agent; chemotherapy; clinically relevant; day; design; drug sensitivity; epidermal growth factor receptor VIII; frontier; genetic profiling; human FRAP1 protein; improved; in vivo; inhibitor/antagonist; insight; intravenous administration; mTOR Inhibitor; mTOR inhibition; mouse model; mutant; neoplastic cell; ovarian neoplasm; panitumumab; pre-clinical; promoter; prospective; protein protein interaction; receptor; receptor expression; research study; response; small molecule; symposium; taxane; technology development; therapeutic target; tool; trafficking; tumor; tumor immunology; tumor progression; tumorigenesis; tumorigenic

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的激活促进了肿瘤细胞的存活，增殖和侵入性，这表明AKT可能在肿瘤发生和治疗反应中起核心作用。 AKT经常在卵巢癌中激活，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，从而导致具有活化AKT的肿瘤细胞中G1停滞。脂肪酸合酶（FAS）通常在卵巢癌中过表达，并且其表达部分受AKT信号传导调节。特定药理剂对FA的酶促抑制会诱导肿瘤细胞凋亡。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标。该提案的长期目标是确定特定药理剂的MTOR或FAS抑制是否可以在卵巢癌中有效地有效，以及反应是否取决于给定肿瘤的AKT状态。具体目的是“ 1）确定AKT激活和基因组不平衡是否发生在人类卵巢癌的发展早期。免疫染色将对推定的质外塑性卵巢病变进行，以确定Akt激活的早期事件，以确定卵巢肿瘤的早期事件，以在卵巢肿瘤上进行AKT的允许在ovarian tumor tare tare tare tare tray tare tray tare tare tare tare tare tare tare tray tare train tare train and train tare的事件。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抑制与各种的潜在协同作用 卵巢癌细胞系中的化学治疗剂，有或没有AKT的本构激活。 3）确定AKT途径的药理抑制是否可以抑制卵巢肿瘤的形成。作为一种化学治疗策略，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，将使用表达活性AKT的转基因卵巢癌模型来确定雷帕霉素是否可以抑制或延迟肿瘤的形成。 4）在卵巢癌治疗中对MTOR抑制剂进行II期试验。总体而言，这些研究将产生有关AKT作为预测卵巢癌发展，进展和药物敏感性的生物标志物价值的重要见解，并确定AKT途径抑制是否可以作为卵巢癌中有效的化学预防和/或化学治疗策略。