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AZ funded Non clinical PhD Studentship in Unravelling and predicting toxicity of Antibody Drug Conjugates in the Lung using Genome-wide Multi-omics and CRISPR-Cas9

University of Cambridge - Wellcome Trust/Cancer Research UK Gurdon Institute

Qualification Type: PhD
Location: Cambridge
Funding for: UK Students, EU Students, International Students
Funding amount: £21,500 per annum
Hours: Full Time
Placed On: 1st December 2023
Closes: 8th January 2024
Reference: PR39642

Applications are invited for 4-year PhD studentship based in the Department of Physiology, Development and Neuroscience (PDN) and the MRC Toxicology unit at University of Cambridge and the new AstraZeneca Discovery Centre at Cambridge. The student will be working on a collaborative project jointly supervised by Dr. Mennella in in the MRC Toxicology Unit and Dr. Emma Rawlins in Department of PDN, University of Cambridge and Dr. Jennifer Tan, Dr. Benedicte Recolin, Dr. Kelly Evans and Dr. Catherine Betts at AstraZeneca and will have the opportunity to work across the two sites. The project, entitled "Unravelling and predicting toxicity of Antibody Drug Conjugates in the lung using genome-wide multi-omics and CRISPR-Cas9" aims at leveraging knowledge in airway biology and Omics technologies to understand why Antibody Drug Conjugates, a promising new drug modality with high efficacy against lethal cancers can cause adverse response limiting their use.

Antibody-drug conjugates (ADCs) are promising oncology agents targeting both solid tumours and haematological malignancies with high target specificity and killing efficiency. ADCs consists of a small molecule cytotoxin (payload) attached to a monoclonal antibody (mAb) carrier. Recently, a handful of blockbuster ADCs have been approved by the FDA and currently over 400 drugs are in the pipeline, rapidly transforming healthcare. However, clinical toxicities limit their full potential. In particular, pulmonary toxicities, (i.e. Interstitial Lung Disease (ILD)), which can be potentially fatal, has been reported in the clinic e.g. ILD has been reported for T-Dxd, an ADC consisting of anti-Her2 antibody/anti- topoisomerase 1 inhibitor conjugate (15.8% with 2% fatal rate). Importantly, to date, no biomarker and/or screening assay is available for safety screening and assessment. Mechanisms underlying ADC-induced lung toxicities are believed to be complex, mediated primarily through ADC uptake by alveolar macrophages, which may crosstalk with epithelial cells, leading to scarring and remodeling. The underlying molecular cascade remains unknown. To maximize the full potential of ADC therapeutics, urgent new information is required to understand off-target toxicities of ADCs and how different components of the ADCs may be modified to mitigate their toxicity (antibody, linker, payload). The project proposes a data-driven approach using multi-omics and CRISPR-Cas9 screening using airway models to investigate the molecular mechanisms underpinning ADC lung toxicity.

Applicants should have or expect to obtain a first or upper second-class degree from a UK university, or an equivalent standard from an overseas university, in a relevant subject such as Cell Biology, Molecular Biology and Biochemistry. Interest in bioinformatics and omics data analysis is preferred but not required. These positions are open to UK citizens or overseas students who meet the UK residency requirements or can augment the funds to cover the extra costs associated with international student fees through scholarships or funding schemes. Full details of the University's entrance requirements and scholarships are specified on the following link: www.postgraduate.study.cam.ac.uk

Full funding covering Maintenance fees at £21,500 per annum and the University Composition Fee is provided for the studentship, effective from 1st October 2024.

Deadline for applications is 8th January 2024 and interviews will be held in January.

Please send a covering letter that describes your previous research experience and motivation for the project, your CV with your University grades, your academic transcripts and the contact details of two academic referees who have agreed to act on your behalf to Dr. Vito Mennella via email (vm430@cam.ac.uk).

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