SBIR TOPIC 229, PHASE II: PHARMACODYNAMIC ASSAY FOR AKT FOR USE WITH PI3K/AKT/MT

SBIR 主题 229，第二阶段：AKT 与 PI3K/AKT/MT 一起使用的药效学测定

• 批准号: 8339854
• 负责人: DAVID CHIMENTO
• 金额: $ 99.9万
• 依托单位: ROCKLAND IMMUNOCHEMICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-29 至 2013-09-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8339854
• 关键词: AKT Signaling Pathway; AKT2 gene; AKT3 gene; Address; Antibodies; Antineoplastic Agents; Biological Assay; Biological Markers; Biological Models; Cancer Therapy Evaluation Program; Cells; Clinical; Data Analyses; Dose; Environment; Enzyme-Linked Immunosorbent Assay; Feedback; Freezing; Immunoassay; Individual; Malignant Neoplasms; Measures; Medicine; Methods; Modality; Modeling; Monoclonal Antibodies; PI3K/AKT; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phosphorylation; Physicians; Production; Property; Protein Isoforms; Proto-Oncogene Proteins c-akt; Protocols documentation; Reader; Reagent; Recombinant Proteins; Reporting; Research; Research Personnel; Sampling; Small Business Innovation Research Grant; Solid Neoplasm; Technology; Therapeutic; Tissues; Treatment Cost; Treatment Protocols; Validation; Xenograft procedure; base; dosage; drug candidate; human FRAP1 protein; improved; in vitro Model; mutant; novel; response; small molecule; theranostics; tumor; tumor xenograft

In response to this NCI solicitation, Rockland proposes to develop a novel method to assay the pharmacodynamic (PO) properties of anti-cancer small molecules targeting the PI3K/mTOR/AKT signaling pathway by quantitatively and independently measuring the phosphorylation of each unique AKT isoform in a validated multiplex immunoassay. The developed PD-AKT-ELISA would offer improved personalized medicine, whereby physicians would prescribe a dosage according to the pharmacodynamic effects of anti-cancer drugs on individual patients, or modify therapeutic modality based on the feedback for each individual Akt isoform. We plan to use a number of anti-cancer drug candidates in this study and to produce reagents, including monoclonal antibodies to measure inactive and active AKT isoforms suitable for a fit-for-use theranostic quantitative biomarker ELISA for AKT. The PO-AKT-ELISA and associated reagents will be produced, optimized, validated and applied to both solid tumor and soft tumor xenograft tissue. The reagents and validated assay will measure all AKT isoforms in its active and inactive states to fill a need not currently addressed by products or technologies commercially available to researchers and clinicians. The end result will be a multiplex assay that can be used by most existing immunoassay readers in both a research and high through-put clinical environment. Assay results will allow physicians to more precisely target dosages or types of drugs that modulate the PI3K/mTOR/AKT pathway, and will ultimately lower treatment costs by more accurately prescribing effective doses of anticancer drugs and potentially shortening the duration of drug treatment regimens.

为了应对这种NCI征求，Rockland提议开发一种新方法，以测定针对PI3K/MTOR/AKT信号通路的抗癌小分子的药效学（PO）特性，通过定量和独立地测量有效的Akt型倍增ImmununosaSsay中的每个独特的Akt isoform的磷酸化，通过定量和独立地测量型号的磷酸化。开发的PD-AKT-ELISA将提供改进的个性化医学，医生会根据抗癌药对个别患者的药效动力学作用开出剂量，或根据每个单个AKT同工型的反馈来修改治疗方式。我们计划在这项研究中使用许多抗癌药物候选物，并生产包括单克隆抗体在内的试剂，以测量适合使用Akt的拟合使用的theranostic theranostic定量生物标志物ELISA的非活性和活性Akt同工型。 将生产，优化，验证，并应用于实体瘤和软肿瘤异种移植组织。试剂和经过验证的测定法将测量其活跃和不活跃状态中的所有AKT同工型，以填充研究人员和临床医生在市售的产品或技术目前未解决的需求。最终结果将是一个多重分析，大多数现有的免疫测定读者都可以在研究和高贯穿临床环境中使用。测定结果将使医生能够更精确地针对调节PI3K/MTOR/AKT途径的药物的类型 药物并可能缩短药物治疗方案的持续时间。