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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

基本信息

批准号：
10185518
负责人：
Jered C Garrison
金额：
$ 40.85万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10185518
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 Exhibits External Beam Radiation Therapy Fluorouracil Goals Grant HT29 Cells Health Human In Vitro Intracellular Membranes Investigational Drugs Kidney Label Laboratories Lead Malignant Neoplasms Maximum Tolerated Dose 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 Cancers Residual Tumors Residual state Structure Structure-Activity Relationship Technology Therapeutic Therapeutic Agents Time Tissues Toxic effect Treatment Efficacy Tumor Markers Xenograft procedure adduct analog base chemotherapy clinical translation clinically translatable colon cancer patients colorectal cancer treatment comparative efficacy design dosimetry effective therapy efficacy study extracellular improved in vitro testing in vivo inhibitor/antagonist 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

项目摘要

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：结直肠癌（CRC）的所有临床阶段都需要更有效的治疗方案。