Overcoming Glioma Resistance Through Lethal Autophagic Flux Control – A Multidisciplinary Approach
Prof Ben Loos
Overcoming glioma resistance through lethal autophagic flux control – a multidisciplinary approach.
The 2016 Nobel prize for medicine/physiology was awarded for the discovery of the cellular protein degradation and quality control process termed autophagy. Although we have learnt a lot about its molecular regulation, much focus is recently centered around clinical translation and autophagy manipulation, for the purpose of achieving cell death control. This project is aimed to overcome glioma resistance by manipulating autophagic activity to the extreme, achieving lethal autophagy selectively in gliomas. It requires the precise control and manipulation of the autophagy pathway, with sensitive probes that allow to measure and quantify autophagic activity.
A powerful team of world class experts, with expertise in cellular physiology, molecular sciences, glioma surgery, highest end microscopy, nanomedicine and chemistry, theoretical physics, mathematical modelling and complexity studies as well as SNAP-tag protein targeting technologies have been brought together to challenge the major problem of glioma resistance. The project embraces state-of-the-artobjectives that are addressed through well defined clusters each with major sub-projects that will address:
1. In vitro high throughput screening of autophagy modulators (inducers and inhibitors), 2. Novel polymer bio-conjugate and prodrug development to induce lysosomal dysfunction and thereby autophagy inhibition, 3. Cell death control, 4. Modelling and predicting resistance and 5. In Vivo and Ex vivo biopsy/neurosphere treatment application and model verification. It is hypothesised that cell death onset is dependent on autophagic flux properties inherent to the tumour and its metabolic make up, and dependent on the treatment intervention. It is moreover hypothesized that cell death onset can be maximized by fine tuning treatment intervention in a temporal manner that maximizes autophagy induction to a lethal autophagic flux level, followed by maximal autophagy inhibition, concomitantly with chemotherapeutic intervention. High end imaging techniques will enable to achieve the characterization, quantification and manipulation of autophagic flux in a precise manner, which will allow the control of cell death onset. Three powerful model systems will be employed to build a ‘chain of knowledge’ of drug screening, molecular characterization, modelling, prediction and implementation. This approach will push the data not only far beyond a scientific understanding of disease mechanisms, but will also inform prevention and treatment strategies relevant for Africa. This project, which is locally highly relevant, will contribute to the building of scientific knowledge, unique technical capability and human capacity in a tremendous fashion. It is scalable, the approach feasible and the first of this kind in Africa.