Chemical and biological investigations of new vanadium compounds: determining their potential in the treatment of cancer

Globally, the treatment of cancer is a substantial economic burden and the effects of cancer have a detrimental impact on the lives of patients and their families, potentially leading to further physical and mental illnesses. The current clinically used metal-based compounds (e.g. cisplatin, oxaliplatin and carboplatin) work by targeting DNA, however, they do not distinguish between cancerous and normal cells. They lead to adverse side effects, including renal failure, neurotoxicity and nausea. Many of the tumours become resistant to these platinum drugs, therefore, there is an urgent need for new drugs which selectively target and eradicate the cancerous cells, whilst minimising the associated side effects.

The PI's recently published work highlighted new vanadium drugs which are more active than the clinically used platinum drugs and more selective for cancerous cells. Importantly, the ligands can be modified to incorporate a wide range of functionalities and allow us to determine structure-activity relationships. Also, the complexation of these ligands with vanadium will use our own literature methods, which will allow effective and efficient establishment of compound libraries. The proposed research will also investigate the drugs' distribution and accumulation within cells, and provide insights to the cellular targets and modes of actions. Furthermore, the drugs' activities will be measured in 3D cell culture models, as their environment is closer in nature to real-life tumours. This will enable the PI to identify more suitable and selective drugs, which can be taken towards clinical trials. Overall, this cheap and straight-forward drug design, coupled with in depth "tumour-like" studies, will provide new alternatives to cost-effective and targeted treatment.

Cancer is one of the leading causes of death worldwide, responsible for 9.6 million deaths in 2018 alone (World Cancer Report, 2018). The Cancer Research UK reported that the likelihood of being diagnosed with cancer at some point in a person's lifetime has risen from 1 in 3 (2011) to 1 in 2 (2017). By 2020, the Cancer and Oncology Drug market is expected to garner $111.9 billion (www.alliedmarketresearch.com), with the cost of a new cancer drug increasing by 40% in the last decade. Cancer also has detrimental physical and mental side-effects for the patients and their families, with up to 49% of patients shown to be suffering from multimorbidity (mentalhealth.org.uk, 2017). Currently, platinum-based therapeutics are used in the clinical setting, however, such compounds can be associated with approximately 40 different side-effects, including nephrotoxicity (cisplatin), myelosuppression (carboplatin) and neurotoxicity (oxaliplatin) (Oun, 2018). Additionally, the range of cancers which can be treated with platinum-based therapy is limited, due to an increase in cancer cell resistance. This highlights the urgent need for new drug development. Non-platinum based compounds are being designed which have lower toxicity towards normal cell types and different modes of action to circumvent the issues with resistance.

This proposal is focused on the design and synthesis of cost effective vanadium-based compounds which will have higher selectivity towards cancerous cells and hence reduce the side-effects. This can have a direct positive impact towards the patient's quality of life during treatment. Due to the hypoxic nature of the tumours, these compounds will be screened against 3D cell culture models, in which the centre of the cell globule is hypoxic, thus providing a more realistic tumour microenvironment. The ability of these compounds to change their oxidation state under such hypoxic conditions will be measured, and their chemical structure will be fine-tuned to increase their cytotoxicity towards these hard to treat hypoxic cells. The cellular uptake, accumulation and modes of action of these vanadium compounds will be determined as well. Since vanadium is a cheap and abundant metal, this work can address the current economic burden associated with other precious metal-based drugs.

This interdisciplinary research will have important impact on the scientific community, in particular the fields of synthetic organic and inorganic chemistry, electrochemistry and chemical biology. The results will be disseminated in high impact peer-reviewed journals, and with attendance to national and international conferences, the networking and knowledge sharing will be greatly enhanced. The work has the potential to generate intellectual property and the applicant will seek advice from the research and innovation services at UEA. It will have an impact for the public due to its direct applicability towards anti-cancer treatment and in particular it will lead to important educational research-led teaching through student projects and placements. I will apply for summer grants from the RSC, the biochemical society and Wellcome Trust, whilst also taking on students from our connections with the Nuffield Foundation. As this work has significant societal impact, the applicant will attend public engagement workshops and build collaborations with the host institute's links at the Norwich and Norfolk University Hospital (NNUH). The NNUH is part of one of Europe's largest collaborative research networks with four other world-class institutes, of which three are funded by the BBSRC, and will give advice on public engagement and future clinical trials. It is essential that these results are disseminated to researchers, students and the public from both specific and general interest groups, and this will be key for innovation and national competitiveness.