Development of an NTSR1-Targeted Radiotherapeutic for Colorectal Cancer

开发针对结直肠癌的 NTSR1 靶向放射疗法

• 批准号: 10591477
• 负责人: Jered C Garrison
• 金额: $ 32.15万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591477
• 关键词: Address; Anatomy; Binding; Biodistribution; Biological; Biology; Cancer Etiology; Caspase; Cessation of life; Chemicals; Clinical; Colon Carcinoma; Colorectal Cancer; Cysteine Proteinase Inhibitors; Data; Development; Diagnosis; Disease; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Effectiveness; Evaluation; Exclusion; Exhibits; External Beam Radiation Therapy; Fluorouracil; Goals; Grant; HT29 Cells; Health; Human; In Vitro; Investigational Drugs; Kidney; Label; Laboratories; Lead; Malignant Neoplasms; Maximum Tolerated Dose; Membrane; Metabolic Clearance Rate; Modeling; Molecular Weight; Neurotensin Receptors; New Drug Approvals; Operative Surgical Procedures; Pathway interactions; Peptide Hydrolases; Performance; Property; Protease Inhibitor; Proteomics; Radiation Dose Unit; Radiation Tolerance; Radiation therapy; Radiation-Sensitizing Agents; Radionuclide therapy; Research Design; Residual Neoplasm; Skin Cancer; Structure; Structure-Activity Relationship; Technology; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Treatment Efficacy; Tumor Markers; Xenograft procedure; adduct; analog; chemotherapy; clinical translation; colon cancer patients; colorectal cancer treatment; comparative efficacy; design; dosimetry; effective therapy; efficacy study; extracellular; improved; in vitro testing; in vivo; inhibitor; innovation; meetings; metastatic colorectal; microautoradiography; mouse model; novel strategies; overexpression; patient derived xenograft model; patient population; protein expression; receptor; residence; standard of care; targeted agent; targeted radiotherapeutic; targeted treatment; therapeutic evaluation; therapeutically effective; tumor

Objective: More effective treatment options are needed across all clinical stages of colorectal cancer (CRC), from eliminating residual disease after surgery, improving surgical candidacy and developing more effective treatment options for metastatic disease. Targeted radionuclide therapy (TRT), which targets tumor-specific biomarkers, has been one appealing approach in the pursuit of effective cancer therapeutics. The development of low-molecular-weight TRT agents is particularly attractive due to their rapid targeting and non-target clearance properties. However, for many investigated low-molecular-weight TRT agents, the short residence time in tumors due to inherently high clearance rates of the agents and their metabolites inhibits clinical translation. The purpose of this proposal is to design a CRC therapeutic agent capable of targeting the neurotensin receptor subtype 1 (NTSR1), a receptor found to be overexpressed in large segments of the CRC patient population. Specifically, by incorporating irreversible cysteine protease trapping agents (CPTAs) into the structure of NTSR1-targeted agents (NTSR1TAs), we seek to design TRTs that are capable of forming high molecular weight intracellular adducts. Through this retention mechanism, the 177Lu-labeled, CPTA-incorporated, NTSR1TAs (177Lu-CPTA- NTSR1TAs) will exhibit substantial increases in radiation dose delivery leading to enhanced therapeutic efficacy. Also, as part of this grant, we seek to gain a clearer understanding of the in vivo adduct binding partners, adduct half-lives and tissue/cellular localization associated with this trapping mechanism. Specific Aims: (1) Synthesis and Initial Biological Performance of 177Lu-CPTA-NTSR1-targeted Agents; (2) Examine In Vivo Adduct Protease Profiles, Adduct Half-lives and Tissue Distribution; and (3) Therapeutic Evaluation of Optimized 177Lu-CPTA-NTSR1-targeted Agents Study Design: The first aim of this proposal is to examine pathways to further improve the design of CRC residualizing 177Lu-CPTA-NTSR1TAs by 1) refining the construct to reduce T/K radiation dose ratios; 2) exploring the impact of CPTAs with varying selectivities; and 3) examining different cysteine protease inhibitor classes. After synthesis, initial assessments regarding the in vitro and in vivo performance of the177Lu-CPTA-NTSR1TAs will be performed. In the second aim, a more detailed biological evaluation will be carried out in which adduct- binding partners are identified and quantified, tissue protease expression levels ascertained, adduct half-lives are estimated and cellular distribution (percent intracellular, membrane or extracellular) determined. Lastly, lead TRT candidates will be examined in advanced CRC mouse models to determine the best candidates to move forward to the maximum tolerated dose and therapeutic efficacy studies. At the end of this project, we anticipate being able to identify a candidate to advance towards FDA investigational new drug approval.

目的：在结直肠癌（CRC）的所有临床阶段都需要更有效的治疗选择， 从手术后消除残留疾病，改善手术候选资格并发展更有效 转移性疾病的治疗选择。靶向放射性核素治疗（TRT），该治疗靶向肿瘤特异性 生物标志物是追求有效癌症治疗剂的一种吸引人的方法。发展 低分子量的TRT代理由于其快速靶向和非目标间隙特别有吸引力 特性。但是，对于许多研究的低分子量TRT剂，肿瘤的停留时间很短 由于固有的高度清除率及其代谢产物抑制了临床翻译。目的 该建议的是设计能够靶向神经素受体亚型1的CRC治疗剂1 （NTSR1），一种受体在CRC患者人群的大部分中过表达的受体。具体来说， 通过将不可逆的半胱氨酸蛋白酶捕获剂（CPTA）纳入NTSR1靶向的结构 代理（NTSR1TA），我们试图设计能够形成高分子量的细胞内的TRT 加合物。通过这种保留机制，具有177lu标记的CPTA合并，NTSR1TA（177lu-cpta-- NTSR1TA）将显示出辐射剂量递送的大幅增加，从而提高治疗功效。 另外，作为这笔赠款的一部分，我们试图更清楚地了解体内加合物绑定伙伴，加合物 半衰期和组织/细胞定位与此捕获机制相关。 具体目的：（1）177lu-CPTA-NTSR1靶向剂的合成和初始生物学性能； （2） 检查体内加合蛋白酶谱，加合物半衰期和组织分布； （3）治疗 评估优化的177LU-CPTA-NTSR1靶向剂 研究设计：该提案的第一个目的是检查进一步改善CRC设计的途径 通过1）精炼构造以降低T/K辐射剂量比； 2）探索 CPTA具有不同选择性的影响； 3）检查不同的半胱氨酸蛋白酶抑制剂类别。 合成后，关于177LU-CPTA-NTSR1TA的体外和体内性能的初步评估 将执行。在第二个目标中，将进行更详细的生物学评估，其中加合物 - 结合伴侣被鉴定并定量，组织蛋白酶表达水平确定，加合物半衰期 估计并确定细胞分布（细胞内，膜或细胞外）。最后，领导 将在高级CRC鼠标模型中检查TRT候选人，以确定移动的最佳候选者 转发至最大耐受剂量和治疗功效研究。在这个项目结束时，我们预计 能够确定候选人促进FDA调查新药批准。