Immuno-chemotherapeutic Metal Complexes for Cancer Stem Cell-Directed Therapy

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Cancer is one of the leading global healthcare challenges and has a high impact on society. Despite significant advancements in cancer care, fatal incidences of tumour recurrence are still common. Cancer relapse is strongly linked to the existence of cancer stem cells (CSCs), a sub-population of cancer cells that can evade current therapeutic regimens and activate tumour regrowth and metastasis. Currently there are no drugs (single or combinations) that can remove CSCs of any tissue type. The identification of chemical agents with therapeutic potential, including for cancer treatment, is of high importance for research in chemical biology and medicinal chemistry. Traditionally organic molecules have dominated research in this area, and thus relatively little is known about the therapeutic properties of metal-containing compounds. Even less information is known about the immunotherapeutic potential of inorganic compounds. The chemical diversity offered by metal complexes provides a platform to explore areas of biologically relevant chemical space that cannot be achieved by purely organic compounds. The versatility of metal complexes, which arises from the choice of metal, oxidation state, redox state, number and type of ligands, coordination geometry, magnetic and optical properties, can be harnessed to develop new agents to overcome immediate challenges in diseases including cancer. This proposal will combine fundamental inorganic chemistry and immunotherapy to develop all-in-one immuno-chemotherapeutic metal complexes to safely and selectively remove tumour cells through cytotoxic effects, and reactivate dormant immune response against residual CSCs. Specifically, we will develop copper(II) complexes that can induce immunogenic cell death (ICD) of CSCs by reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, hence acting as an anti-CSC vaccine. The outcomes of the project could ultimately lead to new strategies to achieve extended tumour remission. This is a highly multidisciplinary project that will forge new directions in medicinal inorganic chemistry, and will address key limitations in current CSC-directed therapeutic approaches.