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方案， 从消除术后残留疾病，提高手术成功率，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)，靶向肿瘤特异性 生物标记物，一直是追求有效的癌症治疗方法的一个吸引人的方法。最新进展 低分子TRT类药物因其快速靶向和非靶向清除而特别吸引人 属性。然而，对于许多被研究的低分子TRT药物来说，在肿瘤中的短暂停留时间 由于这些药物及其代谢物固有的高清除率，抑制了临床翻译。目的 这项提议的目的是设计一种能够靶向神经降压素受体亚型1的结直肠癌治疗剂 (NTSR1)，一种在大部分结直肠癌患者群体中过度表达的受体。具体来说， 通过将不可逆半胱氨酸蛋白酶捕捉剂(CPTA)引入NTSR1靶向结构 试剂(NTSR1TA)，我们寻求设计能够在细胞内形成高分子量的TRT 加合物。通过这种保留机制，177Lu标记的、结合了CPTA的NTSR1TA(177 Lu-CPTA- NTSR1TA)将显示辐射剂量传递的大幅增加，从而提高治疗效果。 此外，作为这项资助的一部分，我们试图更清楚地了解体内加合物结合伙伴、加合物 与此捕获机制相关的半衰期和组织/细胞定位。 具体目标：(1)177Lu-CPTA-NTSR1靶向药物的合成及初步生物学性能； 体内检测加合物蛋白水解酶、加合物半衰期和组织分布；以及(3)治疗 优化的~(177)Lu-CPTA-NTSR1靶向药物的评价 研究设计：这项建议的第一个目标是研究进一步改进CRC设计的途径 通过1)改进结构以降低T/K辐射剂量比来残存177Lu-CPTA-NTSR1Tas；2)探索 具有不同选择性的CPTA的影响；以及3)检测不同类型的半胱氨酸蛋白酶抑制剂。 177Lu-CPTA-NTSR1TA合成后的体内外性能初步评价 将会被执行。在第二个目标中，将进行更详细的生物学评估，其中包括- 识别和量化结合伙伴，确定组织蛋白酶表达水平，加成半衰期 估计并确定细胞分布(细胞内、膜或细胞外的百分比)。最后，领导 TRT候选人将在高级CRC鼠标模型中进行检查，以确定最适合移动的候选人 展望最大耐受量和治疗效果研究。在这个项目结束时，我们预计 能够确定一个候选人，以推进FDA的新药研究批准。