Dr. Gordon Li's Research
Cancer is a disease that has touched everyone’s lives. Many of us had to personally experience or witness the pain and suffering of our family, friends, or loved ones went through as they fought against this debilitating disease. One of the most lethal cancers is brain tumors. Adult brain tumors, known as glioblastoma (GBM), afflict four out of every 100,000 Americans and there are currently no cures to this disease. After being diagnosed the overall median survival time for patients treated with surgery, concomitant radiation, plus chemotherapy is only 14–15 months. Even children are not immune to brain tumors. The most common pediatric tumor, medulloblastoma (MB), does have a cure rate of 70-75%, the surviving patients are afflicted with neurocognitive impairment, endocrine dysfunction, and a severe decrease in quality of life.
Due to the severity and lethality of these diseases, identifying novel and more effective therapies is crucial to help cure diagnosed patients. My laboratory studies the biology of brain tumors with the goal of understanding at a cellular and molecular level how these cancers growth and are created. By elucidating how these brain tumors function we can identify new therapeutic targets that can provide hope to patients afflicted with these lethal diseases.
Currently we are pursuing two distinct research projects:
1.) Elucidating the role of casein kinase 2 in GBM and MB:
Casein kinase 2 (CK2) is a highly conserved pleiotropic serine/threonine kinase that has been associated with many cellular pathways that are essential in tumorigenesis including cellular proliferation, migration, and invasion. There are 3 major subunits of CK2: 2 catalytic (CK2a, CK2a’) and 1 regulatory subunit (CK2b). Through our work and others we showed that elevated CK2a expression correlated with a worse prognosis in both GBM and MB. We discovered that CK2a is a key component of GBM tumorigenesis and stem cell maintenance by regulating the transcription factor b-catenin. CK2a has also been linked to protein pathways heavily involved in both GBM and MB including the hedgehog and notch signaling pathways. Since CK2a activity plays a key role in brain tumors we have begun analyzing the efficacy of using small molecular inhibitors to CK2a to treat GBM and MB. Targeting CK2a can be especially advantages for brain tumor therapy since: a) highly specific compounds exist that may have less deleterious effects than traditional chemotherapy, b) multiple tumorigenic pathways can be targeted at once since CK2a interacts with numerous protein cascades, and c) preliminary drugs were found to cross the blood-brain-barrier which prevents many therapies from reaching the tumor.
2.) Using EGFRvIII as a target for immunotherapy
Immunotherapy is an attractive treatment modality given its potential for exquisite specificity, systemic penetrance, memory, and its favorable side effect profile. With FDA approval of novel immunotherapeutic strategies, there has been significant interest in applying this treatment modality across all cancer types. The epidermal growth factor variant III (EGFRvIII) vaccine is a GBM antigen specific peptide vaccine that has been tested in over 900 GBM patients worldwide. Exciting survival and immunological data from initial phase 2 studies prompted a randomized phase 3 trial for the treatment of newly diagnosed GBM patients (ACTIV) as well as a randomized phase 2b trial for the treatment of recurrent GBM patients (ReACT). Results of ACTIV are being analyzed and should be announced in the next few months, while the preliminary data from ReACT demonstrates overall survival benefit in patients treated with the vaccine. The vaccine is being considered for the fast track FDA approval at this time and could potentially change standard of care for GBM patients. While this is a big step forward for GBM therapy, the full potential of the vaccine is still limited by the immune microenvironment. One mechanism of tumor induced immunosuppression is through the upregulation of immune checkpoint inhibitors. Targeting checkpoint molecules such as PD-1, PD-L1, and CTLA-4 has resulted in durable responses in solid tumors such as melanoma, renal cell cancer, and lung cancer. GBM has been found to upregulate the checkpoint inhibitor PD-L1, hence a combination approach is the next logical step.
My clinical interests include improving surgical techniques for brain tumor surgery, immunotherapy for the treatment of glioblastoma, and novel uses for stereotactic radiosurgery. In the operating room, we are looking at ways of intraoperatively visualizing the tumor with fluorescence as well as minimizing brain retraction with more minimally invasive tumor resection techniques. With clinical trials I am interested in treating glioblastoma with the EGFRvIII vaccine and other combinatorial immune therapy approaches. At the Stanford Cyberknife center, our physicians are continually looking for improved ways to treat brain cancer with stereotactic radiosurgery or other non surgical devices like the focused ultrasound machine.