Relevant Thesis-Based Degree Programs
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Graduate Student Supervision
Doctoral Student Supervision
Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
Development of novel stable GRPR-targeting radiopharmaceuticals with low pancreas uptake for cancer diagnosis and therapy (2025)
Gastrin-releasing peptide receptor (GRPR) is overexpressed in multiple cancers, making it a promising target for diagnosis and therapy. However, most clinically evaluated GRPR-targeted radiopharmaceuticals show high accumulation in the pancreas and limited metabolic stability, which may restrict their diagnostic and therapeutic applications. This dissertation focuses on developing radiolabeled GRPR-targeting ligands with reduced pancreas uptake and improved metabolic stability to enhance diagnostic and therapeutic efficacy for GRPR-expressing tumors. Inspired by a series of GRPR antagonists published by Schally’s group, we first developed four radiolabeled GRPR antagonists based on the Bombesin(7-14) sequence and three radiolabeled GRPR agonists by restoring the reduced peptide bond between residues 13-14 (Leu¹³ψThz¹⁴) in the Bombesin(7-14) sequence with a normal amide bond. The antagonist Ga-TacsBOMB2 and agonist Ga-TacBOMB2 showed good tumor uptake and minimal pancreas uptake. Then we modified our lead agonist and antagonist candidates (TacBOMB2 and TacsBOMB2) with unnatural amino acid substitution to strengthen the bonds at the potential cleavage sites of neutral endopeptidase (NEP) to improve the stability. Our findings indicate that the Tle¹⁰ and NMe-His¹² substitutions markedly improve the stability of the GRPR agonist TacBOMB2 without affecting its binding affinity. Though, with no significant improvement in stability, NMe-Gly¹¹ substitution was shown to improve the tumor uptake and provide a better tumor-to-background contrast ratios for Ga-TacsBOMB5 derived from TacsBOMB2. Then we labeled our lead candidates with ¹⁷⁷Lu for further evaluations. However, shorter tumor retention and lower absorbed radiation doses in PC-3 tumor xenograft were observed for all our ¹⁷⁷Lu-labeled GRPR-targeted ligands compared with the clinically validated Lu-RM2, indicating further optimizations are still needed to prolong the tumor retention for therapeutic applications. To avoid the oxidation of Thz, we replaced the Thz¹⁴ with Pro¹⁴ to potentially prolong the shelf-life of our top GRPR-targeted radiopharmaceuticals. GRPR antagonist, Ga-ProBOMB5 (DOTA-Pip-Bombesin(6-14)), showed great tumor uptake, minimal accumulation in pancreas, and excellent tumor-to-background contrast ratios among all the novel GRPR-targeted tracers in this dissertation. Our results are encouraging to support clinical translation of Ga-ProBOMB5 as a diagnostic radiotracer for detecting GRPR-expressing lesions, particularly the lesions in or adjacent to the pancreas.
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Fibroblast activation protein-targeted radioligands for cancer imaging and therapy (2025)
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 benzoquinoline-based Ga-/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.
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Master's Student Supervision
Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
Development of bispecific prostate-specific membrane antigen/fibroblast activation protein (PSMA/FAP) - targeting radiotracers for prostate cancer imaging (2024)
Oncology practice is rapidly shifting toward personalize cancer diagnosis and treatment by utilizing targeted therapies or probes against the specific molecular drivers of tumors in individual patients. Molecular imaging has been playing a major role in personalized cancer management, including detection, staging, and treatment response assessment. However, tumor heterogeneity limits the utility of monospecific radiotracers in prostate cancer diagnosis and therapy. Utilizing heterodimeric radiotracers to target different proteins overexpressed in tumor has been shown to be a promising strategy to overcome these limitations and improve lesion detection. Previous studies evinced that prostate-specific membrane antigen (PSMA) and fibroblast activation protein (FAP) are overexpressed in prostate cancer, and their expressions are associated with poor prognosis. Therefore, both PSMA and FAP are promising biomarkers of prostate cancer and many PSMA- and FAP-targeting radioligands have been developed for imaging and therapy. Despite many effective PSMA-targeting radiotherapeutic agents being developed, patients with low to no PSMA expression are not eligible for these PSMA-targeted radioligand therapies and have very limited treatment options. Since FAP and PSMA are concomitantly expressed in prostate cancer, the use of bispecific PSMA/FAP-targeting radioligands is expected to increase lesion detection sensitivity in this patient cohort.We hypothesize that the bispecific PSMA/FAP-targeting radiotracers will have comparable or even higher tumor uptake than the monospecific radiotracers. In this thesis, we synthesized several bispecific PSMA/FAP-targeting radiotracers, evaluated their binding affinity in vitro using cell-based competitive binding assays, imaging potential and biodistribution in tumor-bearing mice, and compared their data with the monospecific PSMA- and FAP- targeting radiotracers. Here, we also describe the work of developing pyridine-based FAP-targeted pharmacophore which we hypothesized to be more hydrophilic than the quinoline-based pharmacophore, resulting in higher tumor-to-background contrast ratio of the derived radiotracers. Lastly, we synthesized two bispecific PSMA/FAP-targeting tracers containing the pyridine-based FAP-targeted pharmacophore. Overall, this research demonstrates the feasibility of designing PSMA/FAP-targeting radiotracers and how linker selection, length, pharmacophore selection and modification, and hydrophilicity of the compounds affect the binding affinity, tumor uptake, tumor-to-background contrast ratio of the bispecific PSMA/FAP-targeting radiotracers. This can give insights on parameters to consider in designing PSMA/FAP bispecific radiotracers.
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Development and evaluation of radioimaging agents targeting prostate-specific membrane antigen (2023)
Prostate-specific membrane antigen (PSMA) is a transmembrane protein with an extracellular catalytic site that hydrolyzes N-acetylaspartate glutamate. It is associated with many solid cancers, and most notably prostate cancer as per its namesake. Moreover, PSMA expression correlates with prostate specific antigen expression and Gleason score which means the detected PSMA expression can be utilized to diagnose and stage prostate cancer patients. PSMA expression also has prognostic and predicative values which can further inform prostate cancer management and precision medicine. Its large extracellular domain makes it an ideal drug target for antibody and small molecule development. Antibodies are larger and have longer blood residence time and are expensive to develop, while small molecules have faster clearance and penetrance making them the ideal vector for further uses. Many lysine-urea-glutamate-based PSMA inhibitors targeting the folate enzymatic site such as DCFPyL and Tc- EDDA/HYNIC-iPSMA have been developed and evaluated in clinical and pre-clinical settings. However, a common problem for glutamate-based tracers is their high non-specific kidney and salivary gland uptake which can be problematic in detecting metastatic lesions and can cause side-effects like xerostomia when translating imaging-based radiopharmaceuticals into therapeutic ones.Hence, there remains a need to further optimize and increase the specificity and affinity of PSMA-targeting radiopharmaceuticals. We present a peptide-chemistry based synthesis of novel PSMA-targeting radiopharmaceuticals which is further evaluated for their in vitro and in vivo characterization based on parameters including binding affinity, hydrophilicity, labelling yield and purity, stability, biodistribution and tracer uptake, and tumour-to-background ratio inLNCaP cell and tumour xenograft models. Here, we report several successful candidates labelled with technetium-99m and fluorine-18 for SPECT and PET imaging, respectively, with ideal pharmacodynamic and pharmacokinetic properties for further pre-clinical evaluation.
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