UCSF Brain Tumor SPORE

UCSF Brain Tumor SPORE

Specialized Programs of Research Excellence (SPOREs), designated and funded by the National Cancer Institute since 1992, are intended to promote translational research focused on an organ-specific human cancer.

This year, UCSF is one of six institutions to be awarded a SPORE grant for improving the detection, diagnosis, and treatment of brain tumors. We are the only institution to have been continuously funded since brain tumor SPOREs were first established in 2002.

Our current SPORE grant supports four translational research projects, all focused on improving the diagnosis and treatment of brain tumors:

 

Blood Immunomethylomic Markers of Outcome in Glioblastoma Patients

One of the most vexing characteristics of glioblastoma (GBM) is the way it creates an obstructive, immune-suppressive tumor environment in both children and adults. By developing and testing a powerful method for immune profiling, discovered at UCSF, which is based on unique immune cell DNA methylation fingerprints, this project aims to help clinicians and patients better understand prognoses, avoid unnecessary interventions, and improve risk stratification for future clinical trials.

Led by John Wiencke, PhD, Annette Molinaro, PhD and Jennifer Clarke, MD, the research team will

  • Assess immune status in patients with newly diagnosed GBM from initial diagnosis through surgery, radiation and chemotherapy
  • Evaluate the prognostic value of methylation-generated immune profiles and other factors in GBM patient survival and progression
  • Test how this information influences clinical decision making

 

Monitoring Metabolism in GBM Using Hyperpolarized C-13 Imaging and H-1 MRSI

Hyperpolarized C-13 pyruvate imaging provides information about dynamic changes in tumor metabolism and has delivered promising results in pre-clinical and patient studies of glioblastoma (GBM). This type of metabolic imaging could be used to more accurately detect and characterize a tumor, monitor its response to treatment, and adjust treatment accordingly. For example, hyperpolarized C-13 imaging may help clinicians rapidly determine how well a treatment is working, by tracking early changes in metabolism at the tumor site. 

Understanding how this approach can be combined with more established steady state H-1 MR spectroscopic imaging (MRSI) and conventional anatomic imaging is critical for improving patient care.

Led by Sarah Nelson, PhD and Susan Chang, MD, the objective of this project is to combine hyperpolarized C-13 imaging and H-1 MRSI data to detect differences in dynamic and steady state metabolism in an effort to improve evaluation of treatment response in patients with GBM. The research team will

  • Determine whether these imaging approaches improve the definition of residual tumor in patients with newly diagnosed GBM
  • Assess whether H-1 and C-13 imaging can be used to identify recurrent tumor versus treatment-related effects
  • Test whether data obtained via metabolic imaging can be used as an early indicator of tumor response following treatment of recurrent GBM

 

A New Therapeutic Target for TERT Promoter Mutant Glioma

More than 80 percent of glioblastoma and oligodendroglioma contain mutations in the TERT promoter region. These mutations play a role in overcoming the body’s natural barriers to cancer cell proliferation by reactivating TERT expression.

We recently discovered that the GABP transcription factor uniquely binds to the mutant TERT promoter and drives TERT reactivation in TERT-promoter-mutant glioma and other cancers. This offers promise for a powerful new therapeutic target.

Led by Joseph Costello, PhD and Mitchel Berger, MD, this project aims to develop GABP as a therapeutic target to reverse the immortality of those tumors with TERT promoter mutations. Specifically, this research team will

  • Determine whether the mutant TERT promoter is uniformly present throughout each tumor
  • Assess whether modulation of GABP will lead to tumor cell death while sparing normal cells

 

Targeting 4EBP1 on GBM

This project aims to develop a new class of drugs for clinical use as a precision medicine approach to treating patients with glioblastoma (GBM).

In both published and preliminary data, the team has identified the 4EBP1, an mTOR target, as a robust biomarker for therapeutic response. These findings also re-establish mTOR as a central target in GBM treatment; previous failure of existing drugs has been traced to incomplete and/or nondurable inhibition of mTORC1. Since then, the research team has identified and tested a new class of 4EBP1 inhibitors that potently block 4EBP1 in GBM in vivo, leading to robust improvement in survival in preclinical models of GBM.

Led by William Weiss, MD, PhD, and Nicholas Butowski, MD, this research team will develop this class of drugs for clinical use, by

  • Defining the optimal glioma sub-population for clinical trials using inhibitors of 4EBP1
  • Optimizing the efficacy of 4EBP1 inhibitors for clinical development
  • Designing and conducting a phase IB clinical trial with the clinical agent Rev1 in pathway-activated recurrent GBM