Glioblastoma (GBM) is the most common and deadliest brain cancer in adults despite intensive multimodal therapy. New, effective and safe therapies are urgently needed to improve outcomes. A hallmark of GBM is its profound heterogeneity characterized by multiple molecularly distinct subclones of glioblastoma stem cells (GSCs) that have differential growth patterns and responses to treatment. GSCs are thought to be a major contributor to treatment resistance and tumor recurrence and are a natural focus for therapeutic development.
Project 1: The Glioblastoma State
Therapeutic targeting of GSCs has been a challenge because of the dearth of knowledge of master regulators specific to GSCs and not to normal brain cells. Therefore, systematic elucidation of the GSC-specific core regulatory program will improve our understanding of GSC biology and provide an opportunity to develop novel GSC-specific therapy with maximal efficacy and minimal toxicity.
Using GeneRep and nSCORE to extract candidate GSC specific gene regulatory networks, we identify a cluster of 5 interrelated master subnetworks, which were functionally grouped into the stemness and cancer pathways and are necessary and sufficient to initiate and maintain GSC fate, and thus are attractive therapeutic GSC targets.
Project 2: Immunotherapy by Transdifferentiation
Effective therapies against GBM are extremely limited and long-term survival is rare. Immunotherapies utilizing dendritic cells (DCs) have emerged as a potentially powerful approach to achieve long-term survival in GBM but still have many shortcomings, including inadequate migration of DCs to brain tumors and the high cost of cell based therapies.
The primary objective of this project is to transdifferentiate GBM cells into DCs, thus bypassing the above limitations. This approach will be enabled by GeneRep-nSCORE that can identify master fate factors to facilitate this process that otherwise would not be possible.
Project 3: Mechanism of Action of and Resistance to TTFields in Glioblastoma
Tumor Treating Fields (TTFields) were recently approved by the FDA in combination with adjuvant temozolomide chemotherapy for newly diagnosed GBM. The addition of TTFields resulted in a significant improvement in overall survival. TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules’ assembly, leading to disrupted chromosomal segregation, integrity and stability.
Our lab focuses on the mechanism of cell killing by TTFields and how GBM cells develop resistance to this new cancer treatment modality through an integrated approach using treatment-induced resistant cells, in vitro and in vivo TTFields application, GBM patients’ samples, and systems biology.