Acute pancreatitis as a side effect of asparaginase-based treatments for Childhood ALL: mechanism and improvements

Details

The most effective drugs for childhood acute lymphoblastic leukaemia (ALL) are based on asparaginase (Raja_2012). However, in up to 17% of cases, they cause a serious, life-threatening complication – acute pancreatitis (AP), which forces treatment to be stopped. Previously, attempts have been made to mutate asparaginase (Maggi_2017); however, these changes so far have not significantly reduced the pathology.

Our studies (Peng_2016, Peng_2018) have identified the initiation mechanism of the pathology: stimulation of the protease-activated receptor 2 (PAR2), leading to calcium overload. These findings have enabled us to propose strategies to reduce the side effects of asparaginase-based drugs for ALL (Peng_2018, Petersen_2021, Gerasimenko_2023, Lewis_2024).

Currently, several inhibitors of intracellular calcium channels and/or PAR2 have been tested for this purpose. Energy supplemets (pyruvate, galactose (Peng_2018)) have been shown significant improvements. Novel mutations in asparaginase will be also tested to evaluate improvements (unpublished data). Finally, a combination of energy supplementation (Peng_2018), CRAC inhibitor (Lewis_2024), and the improved asparaginase wwill be used to reduce pathology in vitro and in vivo.

The aim of the project is to test and compare the proposed approaches to identify the most effective way to improve treatments for Childhood ALL.

Contact details for supervisor- Dr Oleg Gerasimenko

Email – GerasimenkoOV@cardiff.ac.uk

Phone Number – +44 29208 70864

How to apply:

You can apply online – consideration is automatic on applying for a PhD in Biosciences. please ensure to provide a CV, statement of purpose, referee details or full references at point of application.

Please use our online application service at https://www.cardiff.ac.uk/study/postgraduate/research/programmes/programme/biosciences-phd-mphil-md

Please specify that you are applying for this particular project, the supervisor and source of funding.

Information on the application process can be found here

http://www.cardiff.ac.uk/study/postgraduate/applying

Entry requirements-

Applicants should have obtained, or be about to obtain, a first or upper second-class UK honours degree, or the equivalent qualification gained outside the UK, Applicants with a lower second class will only be considered if they also have a Master’s degree. Academic qualifications are considered alongside significant relevant non-academic experience.

English Language-

IELTS with an overall score of 6.5 with 5.5 in all subskills, or equivalent. Please see our English Language Requirements guidance for more details.

Funding Notes

This project is suitable for self funded or externally funded students looking for a PhD position at Cardiff University.

Funding required will need to cover the Tuition fees, bench fees and Living expenses.