Doctor of Philosophy
Cancer remains a serious clinical problem and in order to continue to improve patient health outcomes, novel treatment strategies must continue to be developed. Platinum chemotherapies remain as one of the most widely successful classes of cancer therapeutic, with over 50% of cancer patients receiving a platinate at some point over the span of their treatment. However, intrinsic and extrinsic resistances limit their effectiveness, long term efficacy, and broad applicability to multiple cancer subtypes. Therefore, the development of new agents and strategies which can overcome these limitations are crucial for patient health. To this end a novel class of polynuclear platinum agents was developed, structurally distinct from cisplatin based platinates with respect to size, charge, and chemical conformation. Proof of principle was shown by the clinical agent BBR3464 (Triplatin) advancing to Phase II clinical trials, which were later halted due to suboptimal pharmacokinetic profile. Strategies to improve the therapeutic index of Triplatin, as well as to further understand its unique structure based modes of action have been ongoing.
Glycosaminoglycans such as heparan sulfate (HS) and chondroitin sulfate (CS) may be thought of as extracellular DNA due to their highly negatively charged sulfate clusters, helical conformation which they adopt at physiological conditions, and their ability to serve as a signaling molecule through the binding to multiple ligands. The polynuclear platinum complexes (PPCs) are a novel class of highly cationic chemotherapeutic with the emerging property of glycan targeting. Through their unique structures and distinct modes of binding to DNA (the phosphate clamp), PPCs are also possessed of the ability to bind to and interact with glycosaminoglycans on the cell suface, which are typically linked to a core proteoglycan bound within the cell membrane. Functional consequences of glycosaminoglycan binding include the internalization of PPCs with high efficiency, the perturbation of GAG structure and blocking of its binding to ligands through an interaction termed metalloshielding, and the protection of GAG components of the cell and extracellular matrix from degradation by modifying enzymes. The interaction with glycosaminoglycans also serves as the initial point of contact between PPC and target cell, and thus may serve as a limiting or exploitable factor in the pharmacology of Triplatin.
This thesis focuses on strategies utilizing the newly emerging phenomenon of metalloshielding for potential therapeutic benefit in the context of cancer. It is shown that triple-negative breast cancer and ovarian cancer cell lines with dysregulated levels of GAGs have enhanced rates of accumulation of Triplatin both in vitro and in vivo. Methods to measure GAGs via IHC are utilized to assay the levels of HS in patient derived xenografts of TNBC. The development of later generation derivatives of Triplatin was then used to study the multifunctional nature of PPCs in the absence of cytotoxic effects. The generality of metalloglycomics was then expanded to other metals, through the use of cobalt coordination complexes which demonstrated GAG binding properties. Finally, a newly discovered phenomenon involving enhanced GAG levels on the surface of irradiated cancer cell exosomes was shown to be a druggable interaction in vitro, as metal GAG binding drugs were able to block their induction of an inflammatory response in bone marrow derived macrophages. All of this taken together shows that through metalloglycomics, there remain a plethora of approaches for the continued clinical development of Triplatin and for the design of metal based therapeutic strategies of the future.
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