A Novel PET Imaging based Companion Diagnostic

基于 PET 成像的新型伴随诊断

基本信息

批准号：
10078029
负责人：
SUSANTA K SARKAR
金额：
$ 30万
依托单位：
CADENZAMED, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10078029
关键词：
4T1 Angiogenesis Inhibitors Binding Biodistribution Breast Cancer Model Chemistry Clinical Collaborations Cyclooctenes Cysteine Data Development Disease Outcome Drug Targeting Endothelial Growth Factors Receptor Engineering FDA approved Failure Foundations Head Healthcare Systems Human Image In Vitro Inbred BALB C Mice KDR gene Label Laboratories Legal patent Letters Licensing Measures Minority Modeling Mus N-terminal Oncology Patient Selection Patient-Focused Outcomes Patients Pharmaceutical Preparations Phase Phosphotransferases Positron-Emission Tomography Prevalence Radiolabeled Senior Scientist Signal Transduction Site Small Business Innovation Research Grant Specificity Staging Technology Transfer Testing Therapeutic Therapeutic Agents Time Tracer Tumor Angiogenesis Tumorigenicity United States National Institutes of Health VEGFA gene Vascular Endothelial Growth Factors alternative treatment anti-cancer therapeutic base cancer therapy clinical development companion diagnostics cost cost estimate design drug development efficacy evaluation efficacy study evidence base experience heparin proteoglycan improved in vivo individual patient mutant novel orthotopic breast cancer patient response patient stratification patient subsets precision medicine preclinical development receptor receptor binding specific biomarkers theranostics tumor unnecessary treatment uptake

4T1 Angiogenesis Inhibitors Binding Biodistribution Breast Cancer Model Chemistry Clinical Collaborations Cyclooctenes Cysteine Data Development Disease Outcome Drug Targeting Endothelial Growth Factors Receptor Engineering FDA approved Failure Foundations Head Healthcare Systems Human Image In Vitro Inbred BALB C Mice KDR gene Label Laboratories Legal patent Letters Licensing Measures Minority Modeling Mus N-terminal Oncology Patient Selection Patient-Focused Outcomes Patients Pharmaceutical Preparations Phase Phosphotransferases Positron-Emission Tomography Prevalence Radiolabeled Senior Scientist Signal Transduction Site Small Business Innovation Research Grant Specificity Staging Technology Transfer Testing Therapeutic Therapeutic Agents Time Tracer Tumor Angiogenesis Tumorigenicity United States National Institutes of Health VEGFA gene Vascular Endothelial Growth Factors alternative treatment anti-cancer therapeutic base cancer therapy clinical development companion diagnostics cost cost estimate design drug development efficacy evaluation efficacy study evidence base experience heparin proteoglycan improved in vivo individual patient mutant novel orthotopic breast cancer patient response patient stratification patient subsets precision medicine preclinical development receptor receptor binding specific biomarkers theranostics tumor unnecessary treatment uptake

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项目摘要

Abstract High attrition rates - particularly at the late stage of drug development – contribute to the estimated $2.0B cost of bringing a drug to the market. Furthermore, many of the drugs that reach the market benefit only a subset of patients. Currently, there is a lack of target-specific biomarkers that can better identify responsive patients. Consequently, the benefits from many mainstay treatments, including anti-angiogenic drugs, are still limited. This adds significant costs to the healthcare system by the unnecessary treatment of patients that are not likely to respond to a specific therapy. Therefore, the development of a non-invasive PET imaging-based companion diagnostic (CD) using a radio-labeled version of the therapeutic agent itself, will help stratify patients and improve disease outcomes. This is because the CD will i) provide quantitative measures of target expression in patient tumors at the time of treatment to select patients; and ii) enable the staging of therapeutic modulation, including increase/decrease of target prevalence during the treatment cycle; and iii) allow for timely switches to alternative treatment when imaging shows the failure of the ongoing therapy. We propose to test the feasibility of developing a [18 F] labeled cys-tagged vascular endothelial growth factor-3S (VEGF-3S) as a novel non-invasive PET-imaging based CD, to be used with VEGF-3S, a novel (and patented) VEGF antagonist generated through targeted disruption of 3 heparin sulfate proteoglycan (HSPG) binding residues in VEGF-A 165. The proposed CD will be based on VEGF-3S engineered with N-terminal 15- aa fusion tag containing cysteine residue (cVEGF-3S) for site-specific 18F radiolabeling. A positive [18F] cVEGF-3S PET signal from tumor sites in a patient will confirm the prevalence of VEGFRs targeted by VEGF- 3S only. Thus, VEGF-3S with the CD will have significant clinical advantages over the existing VEGF targeted drugs providing precision medicine to individual patients. We will establish the target specificity of [18F] cysVEGF-3S in this proposal which will be the quantitative milestone to progress to Phase II for IND enabling studies.

抽象的高属性率（尤其是在药物开发的后期），估计为2.0B美元将药物带入市场的成本。此外，许多到达市场的药物仅受益于患者子集。目前，缺乏特定目标的生物标志物可以更好地识别响应速度患者。因此，包括抗血管生成药物在内的许多主阶治疗的好处仍然是有限的。通过不必要的治疗患者，这为医疗系统增加了巨大的成本不太可能对特定疗法做出反应。因此，基于非侵入性宠物成像的发展伴侣诊断（CD）使用射电标记的治疗剂本身，将有助于分层患者并改善疾病预后。这是因为CD将i）提供目标定量度量治疗时患者肿瘤的表达； ii）实现治疗的分期调节，包括在治疗周期期间目标患病率的增加/降低； iii）允许当成像显示正在进行的治疗失败时，及时切换到替代治疗方法。我们建议测试开发[18 F]标记为Cys标记的血管内皮生长的可行性因子-3S（VEGF-3）作为一种新型的非侵入性宠物成像CD，可与VEGF-3一起使用（一种新颖的）（和一种新颖的CD）获得专利的）VEGF拮抗剂，通过靶向破坏3硫酸肝素蛋白聚糖（HSPG）产生 VEGF-A 165中的结合残基。拟议的CD将基于由N末端15-工程设计的VEGF-3 AA融合标签包含半胱氨酸居住地（CVEGF-3S），用于特定于位点的18F放射性标记。阳性[18F] 来自患者肿瘤部位的CVEGF-3S PET信号将确认VEGF-靶向的VEGFR的患病率仅3s。这是与CD的VEGF-3相比，与现有的VEGF有关的VEGF-3将具有明显的临床优势为个别患者提供精确药物的药物。我们将在本提案中建立[18F] cysvegf-3的目标特异性，这将是定量的在ID阶段进行研究的里程碑。