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ICT staff awarded funding from BCN

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ICT staff have been awarded funding from Breast Cancer Now with the focus of investigating two ways of selectively bioactivating ultrapotent duocarmycins in tumour tissue, which potentially could be to the benefit of patients with breast cancer.

The duocarmycins are members of a family of ultrapotent antitumour antibiotics that have been the subject of extensive investigations due to their mode of action and potential in the design of new anticancer therapeutics. The natural products and their analogues exert their effects through a sequence selective alkylation of duplex DNA in the minor groove at the N3 position of adenine. The duocarmycins is known to evade drug-resistant mechanisms, but there is unfortunately no way at present to deliver these agents selectively to tumour tissue and thereby significantly minimise the side effects associated with clinical administration of these drugs. However, two produg approaches pursued by staff at ICT that target MMP or CYP450 enzymes expressed in breast cancer may provide an opportunity for selective therapy with clinical potential.

Specifically the two projects are:

Project 1: Development of a novel, targeted cytotoxic treatment for breast cancer (£191,037)

Investigator team: Robert Falconer (PI), Paul M. Loadman, Steven D. Shnyder, Klaus Pors & Chris Twelves (Leeds)

Several matrix metalloproteinases (MMP) play pivotal roles in tumourigenesis and tumour malignancy. Known roles include regulation of tumour cell growth, migration, differentiation, and ultimately metastasis. However, the elevated expression and proteolytic activity of MMPs can be exploited in drug design. This project is focussed of the development of duocarmycin peptide conjugates that can be selectively cleaved by MMPs, thereby providing a delivery vehicle of ultrapotent duocarmycins to selectively treat breast cancer tissue.

The anticipated start date is September 2018. Further information about the research and how to apply for the PostDoc position, please click on the link below: https://jobs.bradford.ac.uk/Vacancy.aspx?ref=HR0058948

Project 2: Duocarmycin prodrugs to treat breast cancer: single-agent and combination therapy efficacy in 2D and 3D cancer models (£91,424)

Investigator team: Klaus Pors (PI), Paul M. Loadman, Steven Shnyder, Andrew Hanby (Leeds), Stewart Martin (Nottingham)

The purpose of this study is to understand if cytochrome P450 enzymes frequently expressed in breast cancer patients can be utilised as targets for selective bioactivation of duocarmycin bioprecursors. Specifically, the project seeks to determine the efficacy of duocarmycins as single-agents or in combination with radiotherapy. 2D and 3D breast cancer models will be analysed for CYP1A1 and CYP1B1 expression and new duocarmycin bioprecursors will be assessed for capacity to destroy breast cancer cells. Additionally, duocarmycins will be evaluated with radiotherapy or precision medicine to understand if such combination treatment will increase the effectiveness of currently used treatment modalities.

The anticipated start date is September 2018. This PhD will be based at ICT and is fully funded, including study fees (for home and EU students), bench fees, and a stipend to meet living costs. Applications (cover letter and CV) are now being accepted. For further enquiries about the available PhD position, please contact Dr Klaus Pors by email: k.pors1@bradford.ac.uk

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