Glucocorticoids remain a crucial component of T-ALL chemotherapy regimens, and primary refractory disease and relapse are frequently associated with marked glucocorticoid resistance. This project will investigate mutations in the glucocorticoid receptor gene (NR3C1) in relapsed T-ALL samples, and whether low-level mutated clones are present at diagnosis and have been therefore selected by steroid-containing chemotherapy regimens. Moreover, using a combination of ChIP-seq and next generation sequencing, it will investigate the hypothesis that epigenetic alteration and/or somatic mutations occur at enhancers of pro-apoptotic genes that abrogate binding of glucocorticoid receptors to glucocorticoid-response elements. It will also study the response to glucocorticoids in IL7 receptor mutant T-ALL that is associated with hyperactivation of the JAK-STAT pathway, and whether this can be modulated with JAK inhibitors.
Elucidating the molecular mechanisms of glucocorticoid resistance in T-ALL can provide new insights into identifying those patients who have a high risk of refractory disease or relapse, informing treatment decisions and enabling the development of new therapeutic strategies to overcome such resistance.
For informal enquiries please contact Dr Marc Mansour: [email protected]
Physicians who are GMC-registered, meet UCL general admissions criteria, and qualify as UK/EU fee payers. These three year PhD studentships, funded by Cancer Research UK, includes a competitive clinical training salary, consumables funding, a travel allowance, and tuition fees (home/EU rate) paid in full.
To apply please e-mail the following pieces of information to [email protected]
and provide the project number(s)* in the subject line.
1. A CV highlighting your academic achievement, clinical training, and research interest/experience, as well as stating your nationality and usual country of residence
2. A short summary (<500 words) detailing how your research interests and academic background matches the project
3. Contact details for two referees
*One application per candidate please. Although you may list more than one project per application, your short summary will need to specify how your background/interests fit each project.
Application Deadline: Applications accepted until 5.00pm 12th February 2015
Initial receipt of your application will be acknowledged. Short-listing and interviews to be done in February/March 2016. Queries about the application procedure or recruitment process should be directed to: [email protected]