Development of an NTSR1-Targeted Radiotherapeutic for Colorectal Cancer

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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.