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

为了响应这一NCI征集，罗克兰提出开发一种新方法，通过在经验证的多重免疫测定中定量和独立地测量每种独特AKT亚型的磷酸化，来测定靶向PI 3 K/mTOR/AKT信号传导途径的抗癌小分子的药效学（PO）特性。所开发的PD-AKT-ELISA将提供改进的个性化药物，由此医生将根据抗癌药物对个体患者的药效学作用开出剂量，或基于每个个体Akt亚型的反馈修改治疗方式。我们计划在这项研究中使用一些抗癌候选药物，并生产试剂，包括单克隆抗体，以测量适用于AKT治疗诊断定量生物标志物ELISA的非活性和活性AKT亚型。 将生产、优化、验证PO-AKT-ELISA和相关试剂，并将其应用于实体瘤和软肿瘤异种移植组织。试剂和经验证的检测试剂盒将测量活性和非活性状态下的所有AKT亚型，以满足研究人员和临床医生目前无法通过市售产品或技术解决的需求。最终的结果将是一个多重检测，可以使用大多数现有的免疫分析阅读器在研究和高通量临床环境。分析结果将允许医生更精确地靶向调节PI 3 K/mTOR/AKT通路的药物的剂量或类型，并最终通过更准确地处方抗癌药物的有效剂量来降低治疗成本。 并可能缩短药物治疗方案的持续时间。

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.