Supervisors and Projects

Investigating the Therapeutic Efficacy of a First-in-Class MDM2 Dimerisation Inhibitor Against MDM2-MDMX Driven Neuroblastoma

Supervisors

George Baillie, School of Cardiovascular & Metabolic Health, University of Glasgow 

John J Cole, School of Immunology & Infection, University of Glasgow 

Industry Partner: Disruptyx Therapeutics Ltd (DRx)

 

Summary

MDM2 is a proto-oncogene which plays an essential role in negatively regulating the tumour suppressor p53 (TP53 gene). p53 is crucial for inducing cell cycle arrest and apoptosis in response to cellular stress. Utilising DRx-098D-R, this project will look to develop a precision medicine approach to treating MDM2 ± MDMX driven neuroblastoma. DRx-098D-R is a first-inclass cell-penetrating peptide capable of selectively binding MDM2, disrupting formation of the MDM2-MDM2 and MDM2-MDMX complex, and subsequently blocking its E3 ligase activity. DRx098D-R potently inhibits cancer cell proliferation, in-part through upregulation of pro-apoptotic signaling pathway(s). Crucially, DRx-098D-R anti-proliferative activity occurs independent of TP53 mutational status, highlighting a role for DRx-098D-R in TP53 wild-type and TP53 mutant cancers.

Current MDM2 inhibitors (e.g., Idasanutlin, ALRN-6294, etc.) solely regulate TP53-dependent signaling associated with MDM2, making them appropriate therapeutic options for TP53 wildtype cancers. However, these therapies are in-effective against cancers that harbour a loss of function TP53 mutation – observed in treatment resistant high-risk neuroblastoma. Overexpression/amplification of MDM2 is frequently identified in high-risk neuroblastoma tumours, correlating with poor patient prognosis. Thus, novel approaches to inhibiting MDM2/MDMX activity in both TP53 wild-type and TP53 mutant cancer represent an attractive therapeutic approach to treating MDM2 amplified/overexpressed high-risk neuroblastoma. DRx-098D-R represents such a novel approach.

Utilising a rationally selected heterogenous panel of human-derived neuroblastoma cell lines, this PhD project will:

(1) Assess the therapeutic efficacy of DRx-098D-R (2D/3D) against TP53 wild-type and mutant neuroblastoma.

(2) Investigate the ability of DRx-098D-R to enhance (i) standard of care chemotherapeutics, (ii) targeted therapeutics.

(3) Compare DRx-098D-R against current sub-optimal MDM2 inhibitor Idasanutlin.

(4) Identify key genetic/transcriptomic/proteomic biomarkers that correlate with DRx098D-R treatment sensitivity/resistance.

(5) Elucidate DRx-098D-R mechanism of action through monitoring specific alterations in MDM2/MDMX associated signalling pathway(s) (p53-dependent and p53-independent).

(6) Combine data from bioinformatic data basis with data generated from (1) – (5) and subsequently select specific biomarkers that will shape future pre-clinical/clinical study design and patient stratification.