Periodic Reporting for period 3 - iGBMavatars (Glioblastoma Subtype Avatar models for Target Discovery and Biology)
Período documentado: 2020-07-01 hasta 2021-12-31
Glioblastoma is the most common primary brain tumor and it is still incurable. In this project, we aim to address two major challenges affect glioblastoma clinical management: (i) the tumor heterogeneity (which treatment will best fit this very patient?) and (ii) its resistance to available treatments (will the patient benefit in any way from the chosen therapy?). We are generating new glioblastoma models reflecting glioblastoma molecular subtypes at molecular level. In these models, we seek to find molecular switches that aggravate the effect of DNA damaging agents, which constitute the standard of care for glioblastoma patients. To identify drug targets favoring patients’ responses to the current standard of care, we exploit our models for state-of-art genetic screens in vivo. To best understand the GBM heterogeneity in vivo, we combine genetic and phenotypic tracing. The overall goal of this project is to identify therapeutic improvements that would enhance the response of the patients to the available treatments and to set the basis to discover more effective ones using transformative technologies.
- We have successfully generated and characterized novel glioblastoma models reflecting glioblastoma molecular subtypes at the genetic, histological and molecular level. In doing so, we have learned the main features we need to control to maximize the similarity between the patients and the models, which is now the ground for improving our models.
- We have established an anatomically accurate and reproducible platform to support our disease models with the same care that patients receive at hospitals. This will be key to identify the most effective improvement to the current standard of care.
- To study the disease from a completely novel perspective, we have invented and applied technology to investigate how the glioblastoma heterogeneity is attained and how this affects patients’ responses to therapeutics.
- Using this technology we were able to establish a causal relationship between some (mirco)environmental factors and the glioblastoma heterogeneity and to demonstrate that tumor heterogeneity critically affects responses to therapeutics. With this tool, we are currently refining the culture conditions to amplify the most common glioblastoma molecular and cellular identities.
- We have established an inducible CRISPR/Cas9 system to epigenetically suppress target genes, and we believe this is the most suitable tool to perform the proposed in vivo screens.
- We have established an anatomically accurate and reproducible platform to support our disease models with the same care that patients receive at hospitals. This will be key to identify the most effective improvement to the current standard of care.
- To study the disease from a completely novel perspective, we have invented and applied technology to investigate how the glioblastoma heterogeneity is attained and how this affects patients’ responses to therapeutics.
- Using this technology we were able to establish a causal relationship between some (mirco)environmental factors and the glioblastoma heterogeneity and to demonstrate that tumor heterogeneity critically affects responses to therapeutics. With this tool, we are currently refining the culture conditions to amplify the most common glioblastoma molecular and cellular identities.
- We have established an inducible CRISPR/Cas9 system to epigenetically suppress target genes, and we believe this is the most suitable tool to perform the proposed in vivo screens.
In the final part of the project, we will build on the exciting technological ground developed thus far and generate accurate models for large groups of glioblastoma patients and use the models to identify novel targets to improve therapy and learn the barriers that prevented us to succeed until now.