Development of stem cell-based therapies for brain cancer treatment
Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, United States
Department of Cell Biology, Utrecht University, The Netherlands
MSc research advisors: Dr. Khalid Shah, Dr. Paul M.P. van Bergen en Henegouwen and Dr. Rob C. Roovers
Department of Cell Biology, Utrecht University, The Netherlands
MSc research advisors: Dr. Khalid Shah, Dr. Paul M.P. van Bergen en Henegouwen and Dr. Rob C. Roovers
Therapeutic stem cells (green) migrate towards and invade brain tumours (red) to deliver their payload.
Therapeutic stem cells secreting bi-modal Nb-TRAIL eliminate highly malignant brain tumours in vivo.
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Glioblastoma multiforme (GBM) is the most common, but also most aggressive type of brain cancer. Despite progress in treatment of other cancers, GBM remains difficult to treat with an average patient survival of 9 months upon diagnosis and a mortality rate close to 100%. One of the main issues is the blood-brain barrier that prevents the efficient delivery of drugs to the tumour. Stem cells, however, migrate towards lesions and could be used as vehicles for localised drug delivery. This study primarily focused on the epidermal growth factor receptor (EGFR), which is often deregulated in GBM, and silencing its oncogenic signalling may be a good target for GBM therapy. Stem cells secreting anti-EGFR nanobodies (Nb) were engineered and found to significantly inhibit GBM growth, but unable to eliminate the tumour. To improve therapeutic efficacy, stem cells secreting a fusion (Nb-TRAIL) between an anti-EGFR nanobody and TRAIL (Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand), which specifically induces cell death in cancer cells, were engineered. Using various in vivo imaging techniques, the pharmacokinetics and therapeutic efficacy were monitored. This stem cell-delivered bi-modal therapeutic agent with both EGFR inhibitory and apoptosis-inducing properties was found to significantly reduce tumour volumes in several GBM models, including TRAIL-resistant GBM cells and highly malignant, invasive primary GBM stem cells. Overall, the survival in mouse GBM model systems was significantly enhanced.
Another therapeutic strategy investigated for the treatment of GBM was a retrovirus-based gene therapy used to deliver tumour suppressor genes and short hairpin RNA (shRNA) genes targeting oncogenes. In addition, an inducible protein expression system for therapeutic stem cells was developed and high through put screens on the efficacy of small molecule tyrosine kinase inhibitors (smTKI) for brain cancer treatment were conducted as part of this project. |
Development of anti-cancer nanobodies
Department of Cell Biology, Utrecht University, The Netherlands
Research advisors: Dr. Rob C. Roovers and Dr. Paul M.P. van Bergen en Henegouwen
Research advisors: Dr. Rob C. Roovers and Dr. Paul M.P. van Bergen en Henegouwen
The development and progression of cancer is driven in part by cell growth promoting signalling. In many carcinomas, including lung, liver, prostate, colon and brain cancer, the epidermal growth factor receptor (EGFR) is responsible for this oncogenic signalling. EGFR signalling results not only in tumor growth, but it also prevents cancer cells from dying. The goal of this research was to use engineered antibody fragments, called Nanobodies®, to prevent EGFR signalling by competitively inhibiting the binding of the ligand to the receptor. I developed nanobodies that were specific for Domain II of the EGFR and thereby inhibited both ligand binding and receptor dimerisation, resulting in complete silencing of oncogenic EGFR signalling. Anti-EGFR nanobodies may therefore prove to be successful therapeutic molecules for cancer treatment.