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.

Applications are invited for 4-year PhD studentship based in the Department of Physiology, Development and Neuroscience and the MRC Toxicology unit in the School of Biological Sciences at U. 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 Physiology, Development and Neuroscience in the School of Biological Sciences at U. 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. This is an important area of applied research that has generated much excitement in both academia and industry.

Project Abstract:

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. In recent years, 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. However, 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.

Candidate:

We are looking for a highly motivated and enthusiastic individual capable of thinking and working independently. Applicants should have or shortly 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 (home fees) or are able to 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: https://www.postgraduate.study.cam.ac.uk/

Funding

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

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

Please quote reference PR39642 on your application and in any correspondence about this vacancy.

How to apply: 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 names and contact details of two academic referees who have agreed to act on your behalf to Dr Vito Mennella via email ([email protected] ). For important queries related to the PhD studentship contact Dr Vito Mennella, [email protected] .

The University actively supports equality, diversity and inclusion and encourages applications from all sections of society.

The University has a responsibility to ensure that all employees are eligible to live and work in the UK.

Student support and training

As a graduate student at Cambridge, you will have access to a wide range of training opportunities and benefit from close supervision provided by a primary and secondary PhD supervisor as well as a personal mentor. During their PhD, there is no taught or examined coursework, but students are encouraged to attend the wide variety of lectures and training courses available to them across the Institute and wider University. This includes a centrally run Statistics course and the University Core Skills Training Programme, which includes sessions on Time Management, Presentation and Performance and Scientific Writing. Students at the Institute will be members of the University's Postgraduate School of Life Sciences (PSLS) who offer a wide variety of core skills and professional development training. Visit the Researcher Development page on the PSLS website for more information. In addition, the student can also take advantage of training courses and seminars in therapeutic sciences offered by Cambridge Academy of Therapeutic Sciences. All students are expected to attend all internal and external seminars held within the Department of Physiology, Development and Neuroscience and the MRC Toxicology Unit. Students will also be encouraged to attend and present at the annual AstraZeneca students symposium.

Diversity and Inclusion

The University actively supports equality, diversity and inclusion and encourages applications from all sections of society. We place major emphasis on the importance of team work and an enjoyable work environment as a foundation for performing internationally leading research. This will allow the student to acquire cutting edge research methodologies in a supportive environment, where they can focus on making the best possible scientific progress.