University of California San Francisco
Helen Diller Family Comprehensive Cancer Center

Scientific Accomplishments

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

Reactivation of the TERT gene extends cancer cells’ telomeres, thereby stabilizing their chromosomes and allowing them to replicate and survive longer than normal cells. TERT reactivation has been linked to highly recurrent mutations in the gene’s promoter region, which are found in approximately 85% of glioblastoma and oligodendroglioma tumors, as well as many other cancers. A team of investigators led by Costello identified the transcription factor GABP as selectively binding to the mutated promoter sequences; GABP does not recognize the normal promoter sequence and does not activate TERT expression in normal cells. The study, published in Science, also  showed that GABP recognizes and binds to the mutant promoter in tumor cells from four cancer types: glioblastoma, melanoma, hepatocellular carcinoma, and bladder carcinoma. This identified GABP as a possible therapeutic target, and future work will determine if its inhibition can decrease TERT expression or result in selective cancer cell death.


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.