As part of the Brain Tumor Center (BTC), our primary focus is on Glioblastoma (GBM), the most prevalent and aggressive brain cancer in adults. Despite intensive multimodal therapy, GBM remains a formidable challenge, necessitating new, effective, and safer therapies to enhance patient outcomes. GBM is notoriously heterogeneous, featuring multiple molecularly distinct subclones of glioblastoma stem cells (GSCs). These GSCs exhibit varied growth patterns and treatment responses, contributing significantly to treatment resistance and tumor recurrence. Therefore, they are key targets for therapeutic intervention.
Project 1: The Glioblastoma State
The therapeutic targeting of GSCs is impeded by a limited understanding of their specific master regulators, which are distinct from those in normal brain cells. Thus, a systematic exploration of the GSC-specific core regulatory program is essential. This will enhance our grasp of GSC biology and pave the way for the development of targeted GSC therapies, maximizing efficacy while minimizing toxicity. We utilize NETZEN to uncover candidate GSC-specific gene regulatory networks. Our research has identified a cluster of 5 interrelated master subnetworks, functionally categorized into stemness and cancer pathways. These networks are crucial for initiating and maintaining GSC fate and represent promising targets for GSC-focused therapy.
Project 2: “Heating Up” GBM with TTFields and Mechanism of Resistance to TTFields
Tumor Treating Fields (TTFields) have received FDA approval for use alongside adjuvant temozolomide chemotherapy in treating newly diagnosed GBM. The integration of TTFields has significantly improved overall survival rates. TTFields, low-intensity alternating electric fields, are believed to disrupt the assembly of mitotic macromolecules, leading to compromised chromosomal segregation and stability. Our laboratory is concentrating on two aspects of TTFields: firstly, their ability to trigger anti-tumor immunity through the activation of type-1 interferon pathways in the STING and AIM2 inflammasomes, alongside promoting immunogenic cell death. Secondly, we are exploring the mechanisms by which cells develop resistance to TTFields-induced cell killing. Following the successful Phase II clinical trial ‘2-THE-TOP’, our ongoing work is centered on a comprehensive analysis of tumor and peripheral immune profiles. Through this, we aim to address several questions: the synergistic effects of TTFields and immune checkpoint inhibitors, the development of resistance by GBM cells to this novel cancer treatment modality, and the identification of predictive markers for tailored treatment strategies.
(Adapted from Chen et al, JCI 2022)
Other Research Projects: