Glioblastoma multiforme (GBM) is the most common and deadly malignant primary brain tumour in adults. Despite current standard of care, which combines surgical resection, chemotherapy and radiotherapy, tumour regrowth and patient relapse remain inevitable. On average, patients face disease relapse at 7–9 months postdiagnosis and succumb to disease progression with a median survival of only 15 months. Poor patient survival correlates with high degree of intratumoral heterogeneity and increased frequency of brain tumour initiating cells (BTICs), which are also implicated in the development of treatment resistance in many malignancies, including GBM.

 

Recent genomic profiling of GBM has shown that clonal evolution within a solid tumour may progress through (and possibly be driven by) cancer treatment, such that GBM recurrence may no longer resemble the genetic landscape of the original primary tumour. Furthermore, cellular intratumoral heterogeneity (ITH) associated with clonal evolution complicates biomarker discovery and treatment personalization and underlies treatment failure. Thus, modeling clonal heterogeneity and evolution to understand cancer progression is critical for the development of effective therapeutic approaches.

 

The overall objective of this research program is to identify new therapeutic targets that drive clonal evolution in treatment-refractory GBM, develop novel and empirical immunotherapeutic paradigms, and undertake preclinical evaluation of candidate therapeutic antibodies using our unique in vivo model of human GBM recurrence.

 

We aim to build translational pipeline from initial target discovery, through target validation and mechanistic exploration, to building new biotherapeutics against novel cancer targets, and preclinical testing in our patient-derived xenograft model of treatment-resistant GBM. A promising lead panel of biotherapeutic modalities will ultimately be translated into early clinical development, generating targeted therapies and hope for future GBM patients.