Award Title: Apelin Antagonists For The Treatment Of Glioblastoma
Funder: Cancer Research UK

Abstract: Background Despite invasive surgery followed by radiation and chemotherapy, Grade IV glioblastoma multiforme (GBM) remains the most lethal primary tumour of the central nervous system. To effectively treat this disease, evidence is emerging that attention needs to shift to novel approaches to remove the factors responsible for maintaining tumour growth. GBM malignancy is closely associated with vascularisation and the interaction between glioblastoma-initiating cells, that are similar to neural stem cells, and endothelial cells, where the peptide Apelin, our therapeutic target, is highly expressed. Apelin activates a g protein-coupled receptor and has been implicated as a local mediator of GBM growth (a sustaining endocrine factor). To investigate the role of Apelin in GBM, we have discovered novel antagonists, which selectively block the Apelin receptor. In orthotopic in-vivo models of glioblastoma the antagonists arrest growth of GBM tumours and significantly reduce tumour size. They are synergistic with the current therapy temozolomide and in studies have shown no toxicity.  Aims To progress towards a clinical study, we will:  1. Further optimise our novel apelin antagonists for efficacy, safety and metabolic stability 2. Measure important pharmacokinetic and pharmacodynamic properties 3. Validate their therapeutic utility in a second species, where we will measure vascularisation, metabolism and image the GBM upon treatment. 4. Identify a lead compound suitable for progression to pre-clinical evaluation and first in human studies.  Methods Compounds are designed (based on knowledge gained from 300 analogs previously synthesized and evaluated in-vitro/in-vivo) utilizing molecular dynamics and structure activity/property calculations. Solid phase peptide synthesis uses standard Fmoc chemistry. Pharmacology studies using human tissue samples, human/rat receptors and in-vivo models will be used to measure affinity, selectivity, receptor bias, PK/PD, safety pharmacology and haemodynamics. Nuclear spin hyperpolarization allows magnetic resonance imaging of injected hyperpolarized 13C labelled cell substrates in-vivo and the kinetics of their metabolic conversion into other cell metabolites. We will use this technique to detect tumour progression and response to treatment of GBM using patient derived xenografts implanted orthotopically in nude rats. T2-weighted MRI will be used to follow changes in tumour size, imaging with hyperpolarized [1-13C]pyruvate to evaluate changes in tumour metabolism and dynamic contrast agent-enhanced MRI changes in tumour perfusion following treatment with apelin antagonists.  How the results of this research will be used This will validate a completely new approach to the treatment of GBM. Engagement with CRUK Centre for Drug Development will enable progress into first in human studies.

Lay Abstract: Background Despite invasive surgery followed by radiation and chemotherapy, Grade IV glioblastoma multiforme (GBM) remains the most lethal primary tumour of the central nervous system. To effectively treat this disease, evidence is emerging that attention needs to shift to novel approaches to remove the factors responsible for maintaining tumour growth. GBM malignancy is closely associated with vascularisation and the interaction between glioblastoma-initiating cells, that are similar to neural stem cells, and endothelial cells, where the peptide Apelin, our therapeutic target, is highly expressed. Apelin activates a g protein-coupled receptor and has been implicated as a local mediator of GBM growth (a sustaining endocrine factor). To investigate the role of Apelin in GBM, we have discovered novel antagonists, which selectively block the Apelin receptor. In orthotopic in-vivo models of glioblastoma the antagonists arrest growth of GBM tumours and significantly reduce tumour size. They are synergistic with the current therapy temozolomide and in studies have shown no toxicity.  Aims To progress towards a clinical study, we will:  1. Further optimise our novel apelin antagonists for efficacy, safety and metabolic stability 2. Measure important pharmacokinetic and pharmacodynamic properties 3. Validate their therapeutic utility in a second species, where we will measure vascularisation, metabolism and image the GBM upon treatment. 4. Identify a lead compound suitable for progression to pre-clinical evaluation and first in human studies.  Methods Compounds are designed (based on knowledge gained from 300 analogs previously synthesized and evaluated in-vitro/in-vivo) utilizing molecular dynamics and structure activity/property calculations. Solid phase peptide synthesis uses standard Fmoc chemistry. Pharmacology studies using human tissue samples, human/rat receptors and in-vivo models will be used to measure affinity, selectivity, receptor bias, PK/PD, safety pharmacology and haemodynamics. Nuclear spin hyperpolarization allows magnetic resonance imaging of injected hyperpolarized 13C labelled cell substrates in-vivo and the kinetics of their metabolic conversion into other cell metabolites. We will use this technique to detect tumour progression and response to treatment of GBM using patient derived xenografts implanted orthotopically in nude rats. T2-weighted MRI will be used to follow changes in tumour size, imaging with hyperpolarized [1-13C]pyruvate to evaluate changes in tumour metabolism and dynamic contrast agent-enhanced MRI changes in tumour perfusion following treatment with apelin antagonists.  How the results of this research will be used This will validate a completely new approach to the treatment of GBM. Engagement with CRUK Centre for Drug Development will enable progress into first in human studies.

Research Activity Codes: 5.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS