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Law, Hin Ni

University of British Columbia

Cancer cell quiescence or dormancy is a reversible state whereby cells have undergone G0-G1 cell cycle arrest and are non-proliferating. These cells can recover the ability to self-renew with exposure to reopened or new vasculatures, and may be the founders of metastasis. One factor that may promote cancer cells to enter a dormant state is exposure to hypoxia, which not only limits cellular proliferation but also promotes drug resistance. In addition, some dormant cancer cells have been reported to express “stem-ness” markers that may provide these cells with stem cell-like characteristics to prolong survival. Thus, this thesis aims to describe work developing radioimmunoconjugates to target certain cancer stem cell and hypoxia-induced markers, specifically CD96 and carbonic anhydrase IX (CAIX), in efforts to potentially identify and eradicate dormant tumour cells, adding to the clinical arsenal against metastatic relapse and drug resistance in cancer patients. We hypothesize that leukemic stem cell- and hypoxia-specific markers can be targeted for cancer treatment and/or theranostic applications to help identify areas of tumor dormancy, aiding against drug resistance and patient relapse. Both panels of anti-CD96 and anti-CAIX radioimmunoconjugates showed specific tumour uptake in vivo for their respective target. The first aim is to evaluate radioimmunoconjugate candidates against CD96 for acute myeloid leukemia (AML) by positron emission tomography (PET) imaging, which was extensively investigated but resulted in decreasing tumour uptake over time in NRG/NSG mouse models and a loss of specific tumour uptake in the nude mouse model, suggesting a novel panel of mAbs may be required. The second aim is to screen mAbs targeting CAIX by PET imaging in renal cancer, colon cancer, and acute myeloid leukemia models, which resulted in three successful radioimmunoconjugate candidates for the solid cancers, and possible further study needed for expression of CAIX in AML. Overall, from this thesis, c2C7 emerged as a lead anti-CAIX mAb candidate that proved to have most potential as a radioimmunotherapy (RIT) agent, which warrants further therapeutic and possibly clinical studies.

Text

2023-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/80611

Interdisciplinary Oncology

University of British Columbia

UBCV

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