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Bendre, Shreya

University of British Columbia

The intricate heterotypic crosstalk between cancer cells and their surrounding stromal niche helps cultivate their tumorigenic potential. Cancer-associated fibroblasts (CAFs) are pervasive elements of the tumor stroma found in various epithelial neoplasms. Cell-bound fibroblast activation protein-α (FAP-α) is a key marker that is upregulated on reactive stromal CAFs of > 90% of most investigated carcinomas. An evolving approach involves the design of targeted molecular probes that carry a radioisotope with diagnostic and/or radiotherapeutic potential based on its emission characteristics. FAP’s restrained expression in most healthy human tissues in conjunction with its CAF-bound overexpression makes it an enticing target for such a non-invasive approach. Recent development of targeted radioligands by a research group at the University of Heidelberg could be considered as one of the most striking and clinically relevant applications of FAP inhibitors (FAPIs) to date. Systemic administration of most FAPI radiotracers is associated with non-tumor specific uptake in the salivary, lacrimal and thyroid glands, skeletal muscles to name a few. Furthermore, their long-lived isotope-labeled analogues are riddled with short tumor residence time hampering therapeutic utility based on emerging clinical data. By systematically altering certain residues in the core structure of two of the clinically validated lead candidates from the FAPI series (FAPI-02 and -04), we developed a series of FAP-directed pharmacophores. This dissertation outlines their adaptation as radiopharmaceutical ligands, all the way from design to in vitro (substrate-based inhibition assays) and in vivo (stability and elaborate organ distribution analysis, PET/CT or SPECT/CT imaging) preclinical assessment. Amongst all the newly designed and investigated pharmacophores, SB04028 and SB03178 emerged as outperforming candidates. We disclose SB04028 as a novel N-(4-quinolinoyl)-D-Ala-boroPro-based pharmacophore. Its ⁶⁸Ga-labeled analogue displayed rapid and FAP-mediated tumor uptake, along with excellent tumor-to-background contrast ratios. We also disclose benzo[h]quinoline-based [⁶⁸Ga]Ga-/[¹⁷⁷Lu]Lu-SB03178 theranostic pair. ⁶⁸Ga-labeled SB03178 displayed superior tumor uptake when compared head-on to FAPI-04 radiotracer. Its ¹⁷⁷Lu-labeled equivalent demonstrated high and sustained tumor uptake, excellent tumor-to-critical organ uptake ratios resulting in a high radiation absorbed dose to the tumor and a low estimated whole-body dose to humans. These findings support their clinical development for use in a vast majority of FAP-overexpressing carcinomas.

Text

2024-06-24

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/88502

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/