At Mayo Clinic Cancer Center, patient care and research are interdependent. Researchers and physicians translate discoveries from the research lab into innovative therapies for patients. Then, clinical studies evaluate such therapies and send data back to basic researchers for analysis. Mayo Clinic neuro-oncology research has a broad geographic reach, with multidisciplinary teams of basic, clinical and population science investigators at Mayo's sites in Rochester, Minn., Jacksonville, Fla., and Scottsdale, Ariz. Mayo physicians and researchers form powerful collaborations across programs, organ areas, and specialties such as neurology, surgery, and radiology to multiply the potential for breakthroughs in research and treatment. A brief overview of selected advances is listed below.
Astrocytomas and Epidermal Growth Factor Receptor (EGFR)
Astrocytomas are the most common glial tumor. These tumors affect patients of all ages, especially young children and older adults. They may be more likely to occur in patients with several genetic diseases that lead to high incidences of certain cancers. These tumors are only occasionally surgically removable because of their large size prior to diagnosis and because of their invasiveness. They appear to evolve from low-grade to high-grade forms by gradually acquiring molecular changes in the tumors, similar to the course of many colon cancers. Often, their pattern of failure is such that they acquire a number of these changes and "dedifferentiate" to become much more malignant, high-grade astrocytoma or glioblastoma multiforme, the most common and most lethal form of primary brain tumor of adults.
Mayo researchers determined that an important molecule called EGFR (epidermal growth factor receptor) appears in higher concentrations in astrocytomas, another of the three principal kinds of glioma and the most common. Researchers are looking for ways to inhibit the cellular receptors and the pathways of EGFR to impede malignant behavior of tumors. Approaches include small molecule anticancer agents, gene therapy and radiation sensitization.
Medulloblastomas and Patched Mutations (PTCH)
Medulloblastomas are the most common brain tumor of children. Unlike adult brain tumors, these tumors most often occur in the hind part of the brain and arise from cells of neuronal lineage. Because of their often compact growth they are potentially curable by surgery. However, despite the tendency of these tumors to present as compact masses, they often spread via the cerebrospinal fluid. This increases the challenge of their treatment, increases the risk of toxicity to the developing nervous system of these pediatric patients, and considerably reduces the chance of cure or prolonged disease-free survival. The basic biological and genetic features responsible for this behavior are at best poorly understood, and were the basis for Mayo researchers becoming the first to demonstrate mutations in an important gene "patched" (PTCH) mutations in medulloblastomas. Based on current understanding of the functions of PTCH and the targets of this protein in tumor cell functions (growth, etc.) the investigators hypothesized that other genes involved in those PCTH-driven cellular functions might also be mutated in medulloblastomas. Research based on this hypothesis led to discovery of mutations in a gene called b-catenin in a subset of these tumors.
Mayo's SPORE-based panel of serially-transplantable glioblastoma multiforme xenografts established from patient tumors is now being used to evaluate novel therapeutic strategies including combinations of novel signal transduction inhibitors with radiation and temozolomide (Clinical Cancer Research 2006;12:2264-71).
In addition, in a collaborative effort between the Brain SPORE; Mayo's Neuro-Oncology, and Gene and Virus Therapy Programs; and the Department of Molecular Medicine; Eva Galanis, M.D., recently activated a trial of intratumoral and resection cavity administration of a measles virus derivative producing CEA in patients with recurrent glioblastoma multiforme. This trial represents the first human application of measles vibrotherapy in the treatment of GBM. The whole translational process to include generation and efficacy testing of the engineered virus strain, vector production and toxicology testing were performed through the Cancer Center. This completely 'in house' bench-to-bedside effort is just one of many innovative ideas being moved from the laboratory to clinical application through the Neuro-Oncology Program's translational research efforts.
O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status and expression in human glioblastoma multiforme
Caterina Giannini, M.D., and neuropathology colleagues, in conjunction with the TACMA and the Biospecimens Accessioning and Processing Shared Resources have completed a study of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status and expression in human glioblastoma multiforme. MGMT DNA repair gene methylation silencing has been associated with longer survival in patients with glioblastoma multiforme, especially receiving chemotherapy with alkylating agents.
This study provided a cautionary note regarding the usefulness of MGMT analysis. Methylation-specific polymerase chain reaction (PCR) was successful in only 78 percent of specimens. MGMT promoter methylation was present in 15 cases (38.5 percent) and absent in 24 (61.5 percent). Immunostain scoring was difficult due to MGMT expression in non-neoplastic cells (endothelial cells, glia, microglia, macrophages, and lymphocytes). MGMT expression was present in tumor cells in seven cases (18 percent). In 70 percent of specimens, there was discordance between promotor methylation and IHC-defined MGMT expression. There was no significant correlation between MGMT methylation and expression nor significant survival difference observed in the methylated vs unmethylated groups (mean survival 487 and 453 days respectively), or negative versus positive immunohistochemistry. (Applied Immunohistochemistry and Molecular Morphology. 2008; 16(1):59-65).
Oligodendrogliomas and 1p/19q deletions
A team of Mayo Clinic Neuro-Oncology Program investigators led by Robert Jenkins, M.D., Ph.D.; discovered that combined deletion of chromosomes 1p and 19q is associated with improved prognosis and responsiveness to therapy in patients with anaplastic oligodendroglioma, one of three principal kinds of glioma.
The deletions usually involve whole chromosome arms, suggesting a t(1;19)(q10;p10). Using stem cell media the researchers cultured a small number of oligodendrogliomas; one was found to have an unbalanced 45,XX,t(1;19)(q10;p10). Interphase fusion of CEP1 and 19p12 probes were developed to detect the t(1;19). Paraffin-embedded tissue was obtained from 21 Mayo Clinic patients and 98 patients enrolled in two North Central Cancer Treatment Group (NCCTG) low-grade glioma trials.
Among Mayo Clinic oligodendrogliomas, the prevalence of fusion was 81 percent. Among NCCTG tumors CEP1/19p12 fusion prevalence was 55 percent, 47 percent and 0 percent among the oligodendrogliomas, mixed oligoastrocytomas and astrocytomas, respectively. Ninety-one percent of NCCTG gliomas with and 12 percent without 1p/19q deletion had CEP1/19p12 fusion (p<0.001, chi-square test). The results demonstrate that a t(1;19)(q10;p10) mediates the combined 1p/19q deletion in human gliomas
Dr. Jenkins and his colleagues further clarified the prognostic significance of combined 1p and 19q deletion and the t(1;19) in the low grade NCCTG gliomas. The t(1;19) was associated with prolonged survival compared with the absence of the deletions. The median overall survival (OS) for all patients was 8.1 years without and 11.9 years with translocation (p=0.003). The median OS for pts with low grade oligodendroglioma was 9.1 years without and 13.0 years with translocation (p=0.01). Similar significant median OS differences were observed for patients with combined 1p/19q deletions. The absence of alterations was associated with a significantly shorter OS for patients who received higher doses of radiotherapy. Like combined 1p/19q deletion, the 1;19 translocation is associated with superior OS and progression-free survival in low-grade glioma patients. (Cancer Research, 66(20): 9852-9861; 2006).
The identification of the 19q tumor suppressor gene and the evaluation of its function should lead to new diagnostic and therapeutic approaches for patients who have gliomas. In conjunction with Caterina Giannini, M.D., and other colleagues in Neuropathology, Dr. Jenkins developed a test utilizing fluorescent probes that can specifically detect the chromosomal deletion discussed above. This test may eventually improve the ability to target specific therapies to individual patients.
A secondary aim has been to utilize Mayo resources and bring forward novel therapies in "orphan" tumor states and then launch them through clinical trial "portals". One such effort is related to neurofibromatosis, type I. Since NF1 is strongly associated with CNS and PNS tumors discovery in this "orphan" may impact more common sporadic tumors that are histologically similar, such as pilocytic astrocytoma.
Dusica Babovic-Vuksanovic, M.D., led a Phase I study of pirfenidone, an anti-fibrotic cytokine developed "in house", on NF-associated plexiform neurofibromas. Her Department of Defense grant (DAMD17-2-1-064-01) was given a "no-cost extension" to continue a Phase II Children's Oncology Group study of pirfenidone. Dr. Babovic-Vuksanovic is also the primary investigator of a Mayo Phase 2 Consortium grant leading a pilot study of AZD2171, an anti-angiogenic compound, with novel translational components relevant to angiogenesis.
Primary Central Nervous System Lymphoma (PCNSL)
Ahmet Dogan, M.D., Ph.D., who specializes in B-cell malignancies, in conjunction with Brian O'Neill, M.D., and Dr. Giannini, used interphase FISH to demonstrate that the frequency of specific chromosomal abnormalities in PCNSL differed from systemic diffuse large B-cell lymphoma, suggesting a distinct pathogenesis (plenary presentation at the United States and Canadian Academy of Pathology 2007 meeting). Since PCNSL may have infectious and immune components this finding may provide a tumorigenic clue in addition to having biomarker potential.
Dr O'Neill, in conjunction with Ricardo Lloyd, M.D., Ph.D., extended preliminary observations regarding a role for SV40 in PCNSL tumorigenesis. Antigen was convincingly localized to CD20-positive large lymphocytes and informed a new R03 grant designed to localize antigen and determine its potential as a "homing" cue. Drs. O'Neill and Lloyd also identified prolonged survival in the cohort of PCNSL patients whose tumors demonstrated SV40 suggesting that identification of SV40 antigen may have biomarker potential.
Quality of Life
Paul Brown, M.D., and colleagues in Mayo's Psychiatry, Behavioral Neurology, and Genetic Epidemiology and Risk Assessment Programs, as part of Mayo's Neurobehavioral Conference Group, have completed and published the results of a prospective study evaluating quality of life (QOL) in newly diagnosed high-grade glioma patients. As a component of this study they included analyses of the extent of surgical resection and its impact on QOL. Another completed study looked multidisciplinary interventions to improve QOL for patients with advanced cancers. Other prospective studies of specific interventions are underway, including erythropoietin for fatigue in central nervous system metastases, and citalopram for depression in glioma patients.
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