Identification and development of novel therapeutic options to treat primary diagnosed and recurrent glioblastoma

Glioblastoma (GBM) is the most aggressive primary brain cancer in adults, with limited treatment options available. Tumor recurrence eventually develops in all patients and consequently, there is an urgent need for targeted therapies that can be used in the recurrent setting of the disease. XPO1 is a novel target in cancer and has been clinically validated by the first-in-class XPO1 inhibitor selinexor (XPOVIO®) which is approved by the FDA (July 2019) for the treatment of relapsed multiple myeloma. XPO1 inhibition has also been shown to be promising in GBM. I will evaluate a novel XPO1 inhibitor, JVH11, for its potential in GBM therapy. 
GBM is characterized by intra- and interpatient heterogeneity, which necessitates combination and tailored therapy for successful treatment. Therefore, I will also search for novel therapeutic targets that act synergistically to JVH11 by genome-wide CRISPR screening on primary diagnosed and recurrent patient-derived cell lines. Moreover, the heterogeneity makes GBM difficult to study and requires single cell analysis. To address this, I will deploy a novel CRISPR approach that can be applied in heterogeneous cell populations at single cell resolution. 
In conclusion, this project will offer crucial data for the development of JVH11 as an anti-GBM drug, while providing potential synergistic targets to further enhance its activity in either a newly diagnosed or recurrent setting.