Targeting AKT-Mutant Human Cancers

针对 AKT 突变的人类癌症

• 批准号: 9310405
• 负责人: David Hyman
• 金额: $ 39.21万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-05 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9310405
• 关键词: 1-Phosphatidylinositol 3-Kinase; AKT inhibition; AKT1 gene; AKT2 gene; AKT3 gene; Address; Affect; Aftercare; Alleles; Biological Markers; Biopsy Specimen; Blood; CRISPR/Cas technology; Cancer Patient; Cells; Clinical; Clinical Trials; Clonality; Codon Nucleotides; Complex; Correlative Study; Coupled; DNA Sequence Alteration; Data; Dependence; Disease Progression; Employee Strikes; Enrollment; Event; Frequencies; Genetic Determinism; Genomic approach; Genomics; Goals; Histology; Human; Incidence; Individual; Institution; Knowledge; Malignant Neoplasms; Mediating; Mediator of activation protein; Modality; Modeling; Molecular; Mutate; Mutation; Oncogenic; Oral; PIK3CA gene; PIK3CB gene; PTEN gene; Pathway interactions; Patient Selection; Patients; Phase; Phosphotransferases; Population; Protein Isoforms; Proto-Oncogene Proteins c-akt; Recurrence; Resistance; Sampling; Signal Pathway; Signal Transduction; Solid; Solid Neoplasm; Somatic Mutation; Specimen; Tail; Therapeutic; Time; Treatment Efficacy; Tumor-Derived; Validation; Work; actionable mutation; base; cancer survival; cell free DNA; clinical sequencing; computer framework; evidence base; exome sequencing; genomic profiles; improved; inhibitor/antagonist; innovation; interdisciplinary approach; kinase inhibitor; mTOR Inhibitor; mutant; novel; novel strategies; oncology; patient subsets; personalized care; precision oncology; predictive marker; programs; prospective; protein structure; response; targeted treatment; therapeutic development; therapeutic target; translational genomics; trial design; tumor; tumor heterogeneity; tumor progression

PROJECT SUMMARY/ABSTRACT Mutations that activate phosphatidylinositol 3-kinase (PI3K) pathway signaling are among the most common events in human cancer. This has spurred tremendous therapeutic development seeking approaches to rationally inhibit this pathway in diverse malignancies. Despite these activities, and notwithstanding the recent dramatic increase in our knowledge of the spectrum, type, and frequency of PI3K pathway alterations in human cancer, broadly active targeted therapies for which biomarkers of sensitivity are available to facilitate patient selection are still lacking. We must address this urgent clinical challenge to improve the survival of cancer patients. We recently combined a unique institution-wide prospective clinical sequencing initiative with an active early-phase clinical trial program to demonstrate that an oral and selective ATP-competitive pan-AKT kinase inhibitor had significant single-agent activity in a multi-histology basket study of patients with AKT1 E17K-mutant advanced solid tumors. We went on to show in preliminary correlative studies that specific genomic correlates of response and resistance to AKT inhibition in AKT-mutant cancers are varied. These findings underscore the potential for developing unique therapeutic strategies targeting tumors with distinct mutational drivers that converge on hyperactivated PI3K signaling. Yet, without an integrated clinical- translational genomic approach to reveal the mechanisms underlying the dependence of solid tumors on mutant AKT, the gap in our understanding will only widen. We propose to overcome this challenge by establishing what conditions AKT inhibitor response and resistance in pre- and post-treatment tumor specimens and longitudinally collected tumor-derived cell-free DNA from patients with AKT-mutant human cancers. We will establish the genomic determinants of AKT inhibitor sensitivity. Then, we will identify which genomic abnormalities, when acquired or selected for, mediate AKT inhibitor resistance. Finally, we will identify and both functionally and clinically validate novel low-incidence activating mutations in AKT isoforms that confer similar pathway dependence and inhibitor sensitivity, thereby expanding a predictive biomarker for patient selection. Together, these studies seek to establish mutant AKT as a rational therapeutic target, and in doing so, establish a clinical-translational genomic framework to facilitate effective, evidence-based precision oncology in AKT-mutant cancers that can be extended to other molecularly defined populations of cancer patients.

项目摘要/摘要 激活磷脂酰肌醇3-激酶（PI3K）途径信号传导的突变是最常见的 人类癌症的事件。这刺激了巨大的治疗发展寻求方法 理性地抑制这种疾病的这种途径。尽管有这些活动，尽管最近 我们对人类PI3K途径变化的频谱，类型和频率的了解显着增加 癌症，广泛活跃的靶向疗法，可用于促进患者的敏感性生物标志物 仍然缺乏选择。我们必须应对这一紧急临床挑战以改善癌症的生存 患者。我们最近将一项独特的机构范围内的前瞻性临床测序计划与 活跃的早期临床试验计划，以证明口头和选择性的ATP竞争力PAN-AKT 激酶抑制剂在AKT1患者的多历史篮子研究中具有显着的单药活性 E17K突变的晚期实体瘤。我们继续在初步的相关研究中展示了特定的 反应和对AKT抑制的反应和抗性的基因组相关性各不相同。这些 发现强调了针对具有不同的肿瘤的独特治疗策略的潜力 在过度活化的PI3K信号传导上收敛的突变驱动器。但是，没有综合临床 - 翻译基因组方法揭示了实体瘤依赖性的机制 突变的AKT，我们理解的差距只会扩大。我们建议通过 确定治疗前和治疗后肿瘤中AKT抑制剂的反应和抗性 来自Akt突变的人的标本和纵向收集的肿瘤衍生的无细胞DNA 癌症。我们将建立AKT抑制剂敏感性的基因组决定因素。然后，我们将确定哪个 基因组异常，当获得或选择用于介导Akt抑制剂的抗性。最后，我们将确定 在功能和临床上都验证了Akt同工型中的新型低收入激活突变， 赋予类似的途径依赖性和抑制剂敏感性，从而扩展了预测性生物标志物 患者选择。这些研究共同试图将突变体AKT作为合理的治疗靶点，并在 这样做，建立一个临床翻译基因组框架，以促进有效的，基于证据的精度 Akt突变癌中的肿瘤学可以扩展到其他分子定义的癌症种群 患者。