- Theme 1: Understanding the Underlying Biology of Brain Cancer
- Theme 2: Predicting Patient Disease, Response, and Survival
- Theme 3: Improving the Therapy of Brain Tumors
Theme 1: Understanding the Underlying Biology of Brain Cancer
In a 2014 study published in Science, Joseph Costello, PhD and colleagues sequenced the exomes of initial low-grade and matched recurrent tumors and found that 43% of the recurrent tumors had no sign of at least half the mutations found in the original tumor. They also found that tumor recurrences in patients who had been treated with temozolomide (TMZ) that presented as malignant glioblastoma demonstrated a ‘hypermutation’ phenotype, with a 20- to 50-fold increase in the number of mutations. The hypermutated TMZ-treated glioblastomas bore a unique genetic signature: 99% of the newly acquired mutations were C>T/G>A transitions, a disproportionate change that is not seen in tumors arising through spontaneous malignancy. Both spontaneous and TMZ-induced malignant progression occurs through the PI3K-AKT-mTOR cell-signaling pathway, but the mechanism for the massively increased number of C>T/G>A transitions is unique to TMZ-treated tumors. This finding reinforces the fact that chemotherapeutic drugs can also behave as mutagenic agents, arguing for more judicious use of them in patients with low-grade tumors. This work also provides a rationale for clinical trials of immune checkpoint inhibitors in patients previously treated with TMZ who may then have increased tumor mutational load. Building on this work, neuro-oncologist Jennifer Clarke, MD, MPH designed an investigator-initiated clinical trial that combines TMZ with everolimus, an FDA-approved drug that blocks mTOR and the mutagenic pathway that leads to malignant transformation . If successful, this study will have significant implications in terms of deferring the use of radiotherapy and the adverse cognitive effects.
Theme 2: Predicting Patient Disease, Response, and Survival
Theme 3: Improving the Therapy of Brain Tumors
Neuroimaging forms the basis for all diagnosis and treatment decisions in neuro-oncology. Although improvements in anatomic MRI have also improved clinical decision-making, there remains a significant need to detect signals of response or progression faster than what can currently be achieved with standard imaging. Over the last decade, the UCSF neuroimaging group, led by Sarah Nelson, PhD, has made groundbreaking advances in the areas of metabolic and physiological imaging, most recently with 13C MRSI that is able to detect changes in metabolites produced by tumor cells. Metabolic changes may serve as novel biomarkers of response to therapy and could allow clinicians to rapidly assess early response to treatment and more quickly make critical decisions regarding changes in drug therapy. The NE Program has published studies showing that 13C MRSI can detect levels of the oncometabolite 2-hydroxyglutarate (2-HG),3 as well as monitor the conversion of α- ketoglutarate to 2-HG, which can be used to detect the presence of tumor. In 2016, the first human patient with a brain tumor underwent 13C imaging at UCSF.