Number of awards
1
Start date and duration
September 2021, 4 year duration.
Overview
The survival rates for patients with relapsed T-ALL remain abysmal. Recent implementation of immunotherapy approaches are mostly not applicable to T-cell malignancies, highlighting there is a clinical need to develop other therapeutic approaches. These patients can be identified by their poor response to conventional four drug induction therapy (VXLD). Using our preclinical in vivo model incorporating induction therapy, we have identified the anti-apoptotic factor BCL2L1 as a potential target to enhance induction potency and overcome drug resistance. In vitro studies in cell lines have demonstrated that BCL2L1 inhibition affects cell fitness, and confirmed that combination with induction chemotherapy results in cell death in a synergistic fashion.
We propose to build on these promising results by testing efficacy of induction therapy and BCL2L1 inhibition in patient derived xenografts (PDX) both in vitro as well as in vivo. PDX cells will be supported by in vitro co-culture with the OP9-DL1 cell line, and treated with VXLD ± BCL2 family inhibitors. Expression of BCL2 family proteins will be determined in PDX cells both before and after exposure VXLD to detect potential shifts in pro-survival protein expression.
Several recent studies have demonstrated that chromatin status and expression of the pro-apoptotic gene BCL2L11 (BIM) is important in treatment induced cell death. Hence, BCL2L11 enhancer methylation and chromatin accessibility will be determined in all PDX samples.
Our laboratory has successfully generated a PDX biobank derived from patients with T-ALL. PDX samples will be transplanted into immunocompromised NSG mice. Upon engraftment, the mice will be treated with VXLD ± BCL2 family inhibitors.
Patients with high risk T-ALL are characterised by high MRD (minimal residual disease) after induction therapy, indicating the existence of drug resistant disease. Exploration of signalling pathways and/or apoptotic balance in MRD cells could provide a therapeutic angle to overcome drug resistance and improve outcomes.
Drug resistant residual T-ALL cells will be isolated from mice for further investigation. The MRD cells will be functionally profiled, using CyTOF mass spectrometry and BH3 profiling, to identify upregulation of survival pathways.
The ultimate aim of this studentship is to inform clinical management of patients enrolled onto the International ALLTogether trial. Within the clinical trial, JI / FWvD have approval to perform CyTOF analysis in ALL samples, allowing us to test the potential applicability of BCL2 inhibition prospectively.
Figure 1 Plan of investigation.
Sponsor
Cancer Research UK
Name of supervisor(s)
Dr Frederik W van Delft, Professor Julie Irving
For further information about this project, please contact [Email Address Removed] or [Email Address Removed].
Eligibility Criteria
The successful applicant will have experience in laboratory research, and will be highly motivated and ambitious. They must have, or expect to achieve, at least a 2:1 honour’s degree or international equivalent, in an appropriate subject (e.g. biomedical sciences, physiology, biochemistry or a related area). A further qualification such as an MSc or MRes is advantageous.
Applications are invited from UK/EU and international applicants. If English is not your first language, you must have IELTS 7 with at least 6.5 in the written component, or equivalent.
How to apply
You must apply through the University’s online postgraduate application system. To do this please ‘Create a new account’.
Only mandatory fields need to be completed. However, you will need to include the following information:
• insert the programme code 8300F* in the programme of study section
• select ‘PhD in the Faculty of Medical Sciences – Cancer Research' as the programme of study
• insert the studentship code tc021 in the studentship/partnership reference field
• attach a covering letter and CV. The covering letter must state the title of the studentship, quote the studentship reference code tc021 and state how your interests and experience relate to the project
• attach degree transcripts and certificates and, if English is not your first language, a copy of your English language qualifications.
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