Preclinical evaluation and clinical translation of novel bispecific toxins that t

新型双特异性毒素的临床前评估和临床转化

• 批准号: 9068263
• 负责人: Antonella M Borgatti
• 金额: $ 14.77万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9068263
• 关键词: Address; Adjuvant; Animal Model; Antineoplastic Agents; Basic Science; Biological Markers; Biomedical Engineering; Blood specimen; Cancer Patient; Canis familiaris; Cells; Clinical; Clinical Research; Clinical Skills; Clinical Trials; Cytotoxic agent; Data; Development; Diagnosis; Disease; Disease Progression; Documentation; Dose; Drug Approval; EGF gene; Endothelial Cells; Environment; Epidermal Growth Factor Receptor; Exotoxins; Flow Cytometry; Foundations; Goals; Health; Hemangiosarcoma; Human; Imaging Device; Interdisciplinary Study; Investigational New Drug Application; Knowledge; Laboratory Animal Models; Laboratory Animals; Lead; Ligands; Malignant Neoplasms; Measurement; Medical; Mentors; Metabolism; Methodology; Modeling; Monitor; Morbidity - disease rate; Names; Neoplasm Circulating Cells; Neoplasm Metastasis; Outcome; Patients; Pattern; Pharmaceutical Preparations; Phase; Predictive Value; Primary Neoplasm; Progression-Free Survivals; Protein Synthesis Inhibition; Pseudomonas; Pseudomonas aeruginosa toxA protein; Recurrence; Relapse; Reproducibility; Research; Research Infrastructure; Research Personnel; Resources; Safety; Sampling; Specificity; Staging; Structure; Surrogate Markers; Targeted Toxins; Testing; Therapeutic; Time; Tissue Microarray; Toxic effect; Toxin; Training; Translating; Translational Research; Translations; Treatment outcome; Tumor-Associated Vasculature; Urokinase Plasminogen Activator Receptor; Work; absorption; anticancer activity; base; cancer cell; career development; chemotherapy; cohort; companion animal; comparative; comparison group; design; drug development; human disease; human subject; improved; improved outcome; in vivo; innovation; killings; liquid biopsy; mortality; multidisciplinary; neoplastic cell; new therapeutic target; novel; oncology; outcome forecast; peripheral blood; phase 2 study; preclinical evaluation; prognostic; prognostic value; programs; resistance mechanism; responders and non-responders; sarcoma; skills; specific biomarkers; standard of care; targeted treatment; tool; treatment strategy; tumor

DESCRIPTION (provided by applicant): My goal is to become an independent translational researcher devoted to the development of novel targeted therapeutics for cancer patients. My background in veterinary and comparative oncology provides a unique opportunity to leverage companion animals as models to accelerate such development, and this project is designed to facilitate my transition to independence through a structured program under the guidance of an exceptional mentoring team. Mentored Research Phase: I will lead a phase I clinical study in dogs with spontaneous cancer to evaluate safety and efficacy of a bispecific ligand targeted toxin we have named "EGFuPA". This compound is designed to deliver Pseudomonas exotoxin by targeting epidermal growth factor receptors (EGFR) and urokinase receptors (uPAR) expressed by tumors and associated vasculature. I will test three independent hypotheses: (1) EGFuPA is a safe and effective adjunct to standard chemotherapy for highly metastatic, chemoresistant hemangiosarcomas in dogs, (2) measurements of circulating tumor cells (CTCs) will provide an accurate, non- invasive, real-time assessment of disease status that will correlate with progression-free survival (PFS) and overall survival (OS), and (3) targeted therapy with EGFuPA is applicable to human tumors expressing EGFR and uPAR, and CTCs can be used as a surrogate of disease in human patients with sarcomas. To extend the approach to humans, we will use banked samples and tissue microarrays to identify types of sarcomas where clinical outcomes clearly identify therapeutic gaps and which are likely to be efficiently targeted by EGFuPA. The mentoring objectives are to hone skills for translating basic findings into clinical outcomes in a novel mode (dogs with spontaneous cancer) using rigorous criteria that can support an IND application. Transition to Independence Phase: The data from the mentored phase will be used to design a phase II clinical study in dogs with spontaneously occurring sarcomas. We will evaluate EGFR and uPAR expression in primary and metastatic tumor samples and in CTCs. Dogs will receive EGFuPA as adjuvant to the accepted standard of care to establish the prognostic value of EGFR and uPAR expression patterns on PFS and OS for this treatment. Both the prognostic and the predictive value of CTC levels will be assessed. This will set the stage to validate CTCs as treatment-specific biomarkers in human sarcoma patients and accelerate the translational development and approval of this unique drug by defining Absorption, Distribution, Metabolism, Elimination, Toxicity (ADMET) criteria that would be challenging to establish using laboratory animal models or human clinical trials alone. I will complete my training and transition by preparing an IND application for this drug, and subsequently apply this training for example, taking advantage of R01 as well as R21 and R33 support mechanisms, to develop and refine innovative tools that will help accelerate cancer drug development.

描述（由申请人提供）：我的目标是成为一名独立的转化研究人员，致力于为癌症患者开发新型靶向疗法。我在兽医和比较肿瘤学方面的背景为我提供了一个独特的机会，可以利用伴侣动物作为模型来加速这种发展，该项目旨在通过在优秀指导团队的指导下通过结构化计划促进我向独立过渡。 指导研究阶段：我将领导一项针对患有自发性癌症的狗的 I 期临床研究，以评估我们命名为“EGFuPA”的双特异性配体靶向毒素的安全性和有效性。该化合物旨在通过靶向肿瘤和相关脉管系统表达的表皮生长因子受体 (EGFR) 和尿激酶受体 (uPAR) 来释放假单胞菌外毒素。我将测试三个独立的假设：(1) EGFuPA 是一种安全有效的标准化疗辅助药物，用于治疗狗的高度转移性、化疗耐药的血管肉瘤，(2) 循环肿瘤细胞 (CTC) 的测量将提供准确、非侵入性、真实的结果。 - 与无进展生存期相关的疾病状态的时间评估 (PFS) 和总生存期 (OS)，(3) EGFuPA 靶向治疗适用于表达 EGFR 和 uPAR 的人类肿瘤，CTC 可用作人类肉瘤患者的疾病替代。为了将这种方法扩展到人类，我们将使用库存样本和组织微阵列来识别肉瘤类型，其中临床结果可以清楚地确定治疗差距，并且可能会被 EGFuPA 有效靶向。指导目标是磨练技能，以使用支持 IND 申请的严格标准，以新颖的模式（患有自发性癌症的狗）将基本发现转化为临床结果。过渡到独立阶段：指导阶段的数据将用于设计针对患有自发性肉瘤的狗的 II 期临床研究。我们将评估原发性和转移性肿瘤样本以及 CTC 中的 EGFR 和 uPAR 表达。狗将接受 EGFuPA 作为公认护理标准的辅助治疗，以确定 EGFR 和 uPAR 表达模式对这种治疗的 PFS 和 OS 的预后价值。将评估 CTC 水平的预后和预测价值。这将为验证 CTC 作为人类肉瘤患者治疗特异性生物标志物奠定基础，并通过定义吸收、分布、代谢、消除、毒性 (ADMET) 标准来加速这种独特药物的转化开发和批准，而使用这些标准来建立这些标准将具有挑战性仅实验室动物模型或人体临床试验。我将通过准备该药物的 IND 申请来完成我的培训和过渡，然后应用此培训，例如利用 R01 以及 R21 和 R33 支持机制，开发和完善有助于加速癌症药物开发的创新工具。