| Mon Nov 23, 2009 |
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Glioblastoma is the most aggressive form of brain cancer, accounting for approximately 40% of all primary malignant brain tumors. Despite optimal treatment with surgery, radiotherapy and chemotherapy, the prognosis for these patients remains poor. Adjuvant temozolomide with radiotherapy serves as the standard of care for newly-diagnosed cases. Recently, antiangiogenic therapy using bevacizumab (BV) in combination with irinotecan has emerged as a promising development in the treatment of recurrent glioblastoma. BV is a humanized monoclonal antibody directed against the vascular endothelial growth factor (VEGF). Besides its role in angiogenesis, VEGF may act in an autocrine manner to enhance cellular survival, providing a pro-survival feedback loop that may decrease the efficacy of temozolomide and/or radiation. BV treatment is expected to inhibit this feedback loop to increase cytoxicity. Therefore VEGF blockade may directly inhibit tumor growth in a paracrine/autocrine fashion. In our institution, we have undertaken a phase II trial that combines BV upfront with radiotherapy/temozolomide. Interim clinical observation has been accepted for publication. Our current proposal is to use the U87MG glioblastoma cell culture model to examine the mechanism by which BV may potentiate the efficacy of radiotherapy and temozolomide. Specific Aims:
This study will lay the groundwork for understanding the interplay among anti-VEGF, radiotherapy, and temozolomide in the treatment of glioblastoma. The long-term plan of this project is to analyze the roles of anti-VEGF as a radiosensitizer in animal models.
Radiation therapy is an important treatment modality for brain tumors, but the outcome is generally dismal. Most patients with glioblastoma succumb to the disease within a year. Increasing radiation dose increases the time to recurrence for these patients, but at the cost of increased complications. Patients receiving whole brain irradiation for metastatic tumors also suffer a high rate of neurological complications, which can be severely debilitating. Therefore, an improved understanding of the normal brain tissue response to radiation is critical to increasing the therapeutic benefit of radiation therapy. Until recently, it has been thought that the late delayed effects of radiation therapy are the irreversible result of damage at the time of radiation. However, this paradigm is shifting to one in which the immediate damage at the time of radiation is only the beginning of a cascade of events which results in late radiation injury. Recent preclinical data suggest that TNFR2 plays a radioprotective role in the brain, while TNFR1 may be involved in promoting radiation-induced demyelination. Increased understanding of the mechanism of TNFR2-mediated radioprotection and the relationships between TNF-alpha signaling and the normal brain tissue response to radiation may lead to therapeutic options that can prevent or ameliorate the side effects of radiation therapy to the brain. The specific aims of this proposal are:
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Cancers contain a small population of so-called cancer stem cells. Their frequency varies between the different types of cancer, but it is generally thought to be in the order of 1 in 10,000 cells. These cells are the only cells, able to regrow the entire tumor after debulking surgery, chemotherapy, and radiation treatment while all of their progeny lack this ability. Additionally, cancer stem cells are relatively resistant to radiation therapy and highly resistant to established chemotherapeutic agents. In order to cure a cancer, all cancer stem cells have to be eliminated, which can be achieved by complete surgical resection or if the surrounding normal tissue allows for application of a sufficient radiation dose, lethal for all cancer stem cells.
Resistance to radiation therapy (RT) is a hallmark of deadly cancers such as glioblastoma multiforme (GBM), which has a dismal 2-3% five-year survival rate. Much effort has been focused on developing novel molecular therapies that sensitize tumors to RT and improve patient survival and quality of life. Researchers in the Radiation Oncology Department at UCLA have found that a molecule called Suppressor of Cytokine Signaling (SOCS)-3, is overexpressed in radioresistant glioblastoma multiforme (GBM), and confers protection from radiation-induced cell death. Using genetically engineered cells, they found that cells lacking SOCS3 are more sensitive to radiation because they fail to activate the expression of p21, a molecule that is critical for radioprotective responses such as cell cycle arrest and DNA repair. In contrast, cells expressing SOCS3 can more effectively recover from irradiation by undergoing p21-mediated cell cycle arrest. The research team concluded that SOCS3 overexpression in GBM can increase radiation resistance by promoting p21 expression, cell cycle arrest, and DNA repair following therapeutic doses of radiation. This work suggests that molecular targeting of SOCS3 may be a novel strategy for overcoming radiation resistance of tumor cells and increasing the effectiveness of radiation therapy.
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Figure 1. The difference in treatment volume coverage by traditional RT vs. PORT. Note that by attempting to spare normal tissues such as blood vessel, nerve or airway (which may be safely treated by traditional RT with relatively lower dose), the border of PORT may inadvertently spare microscopic tumor cells not detected by radiological scans. |
UCLA Researcher Co-Authors New PET/CT Head and Neck Study
Percy Lee, M.D., Assistant Professor and Director of the Stereotactic Body Radiation Therapy (SBRT) program at UCLA was a co-author with investigators from Stanford University on a study in-press in the International Journal of Radiation Oncology, Biology and Physics (IJROBP), the top radiation oncology journal. In this study, 85 head and neck patients received 18-flurodeoxyglucose positron emission tomography (18- FDG PET/CT)-guided chemoradiotherapy. High metabolic tumor volume (MTV), as defined by PET, was found to be a poor prognostic factor for disease relapse and survival. Dr. Lee was one of the principal investigators and the first author of a similar study in lung cancer recently published in IJROBP, the very first study of its kind. Read full article.
These results support the use of metabolic information from PET for radiation planning, and suggest that MTV was a more reliable measure of tumor burden and therefore, treatment outcome. At UCLA, we are one of few expert centers that routinely incorporate metabolic information in radiation treatment planning. In addition, we lead in investigating the role of PET/CT in radiation therapy with the ultimate goal of benefiting our patients and improving their outcomes.
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