Ongoing Research

Current research activities by Neuro-Oncology Program members seek to achieve the following aims:

• Identify mechanisms of primary brain tumor initiation and progression, with the intention of identifying pathogenetic mechanisms of brain tumor biology in each of the four tumor types that comprise the Program's focus.
• Identify risk factors that lead to development of primary brain tumors, specifically "internal" risk factors, that is, genetic loci associated with glioma genesis . Through Mayo's Specialized Program of Research Excellence (SPORE) in Brain Cancer, Program members have collaborated with researchers in the Brain SPORE programs at Duke Comprehensive Cancer Center, the UCSF Helen Diller Family Comprehensive Cancer Center, and UAB Comprehensive Cancer Center to study environmental factors, especially carcinogens, and infectious agents.
• Identify and assess new biomarkers to diagnose brain tumors and to determine the prognosis, and predict the response to therapy of patients with brain tumors
• Develop new therapeutic approaches and new interventions that improve the overall survival, reduce symptoms and improve the quality of life for brain tumor patients

A relatively young Program, the Neuro-Oncology Program has strengthened its research base over the last five years, expanding its activities within each tumor type, and expanding intra- and inter-programmatic activity. Through a number of research programs, including the SPORE and the Neuro-Oncology National Institutes of Health Training Grant, the Program is able to conduct long-term research projects, develop and test novel clinical interventions and recruit and train outstanding young investigators to continue the tradition of research at Mayo Clinic Cancer Center.

The following are some of the ongoing research initiatives in the Neuro-Oncology Program:

Oligodendroglioma -- 1p/19q Deletions

Oligodendrogliomas are a unique form of brain tumor. These tumors affect young adults, with initial symptoms typically being seizures. Oligodendrogliomas are occasionally able to be surgically removed because of limited invasiveness, and they frequently respond to initial treatments.

Robert Jenkins, M.D., Ph.D., co-leader of the Neuro-Oncology Program, Mayo Clinic Cancer Center Associate Director, and principal investigator of the "Glioma Markers" P01 grant, a research program funded by the National Cancer Institute (NCI), contributed to the seminal discovery that deletions of regions in specific chromosomes (1p and 19q) are associated with oligodendrogliomas. Specifically, these deletions seem to predict prolonged survival and better sensitivity to chemotherapy in certain patients with those deletions. Dr. Jenkins, in collaboration with colleagues at Massachusetts General Hospital Cancer Center, has completed a detailed map of important chromosomal regions (19q13.3) in gliomas. These data form much of the basis of the research supported by Dr. Jenkins' NCI grant.

Based on work done at Mayo, there is sufficient reason to believe that most, if not all of the tumor's clinical characteristics are biologically driven, that is, due to the genetics of the tumor. Dr. Jenkins' research team also identified other relatively small chromosomal deletions (19q13.3) in two glioma cell lines (U87 and A172). These deletions completely encompass the commonly deleted region that the researchers mapped in patient gliomas, and therefore represent a potential resource to study these observations in the laboratory. In addition, the research team is attempting to develop oligodendroglioma human tumor cell lines. Such cell lines will facilitate the continued genetic studies. The identification of the 19q tumor suppressor gene and the evaluation of its function should lead to new diagnostic and new therapeutic approaches for treatment of glioma patients.

Primary Central Nervous System Lymphoma (PCNSL)

Primary central nervous system lymphoma (PCNSL) is a unique lymphoma and is invariably lethal without treatment. Current treatments are extending survival but are not increasing the number of cured patients, and the quality of life of such survival is poor. Variable tumor characteristics may reflect differing stimuli from within the tumor itself and/or differing responses by surrounding normal tissues, particularly specific cellular functions that control the normal B cell growth.

A multidisciplinary team of individuals led by Brian O'Neill, M.D., has been working together for more than a decade on this tumor. Dr. O'Neill's group has systematically contributed to the knowledge base of PCNSL by sequentially studying large numbers of patients with regard to their disease, treatment and outcomes with the intent of identifying risk factors, and better approaches to management and treatment of this disease. From these studies has come emerging basic and translational PCNSL research focused on the identification of an infectious agent(s) that might stimulate the tumor-producing cascade and abnormal immune cell (B cell cellular functions). There is already pilot data that a specific virus is involved in at least some of the cases. This work has continued within the Iowa/Mayo Lymphoma SPORE grant. Other outgrowths of this ongoing research include the development, launch, conduct, completion, analysis, and publication of a number of investigator-initiated clinical trials sponsored by the North Central Cancer Treatment Group.

Mediators of Invasion

The research of Panos Anastasiadis, Ph.D., and Joseph Loftus, Ph.D. , demonstrates the Program's Mayo Clinic system-wide functionality. Although each laboratory is investigating mediators of invasion, their work focuses on different mechanisms and is complementary (Loftus: Biochemical and Biophysical Research Communications. 2006; 349(3): 939-947; Anastasiadis: Journal of Cell Biology. 2006; 174: 1087-96). The research teams exchange data and have emerging collaborations between themselves and other Mayo colleagues. A unique focus of the Anastasiadis laboratory is the differential expression of invasion mediators including key components of the cadherin-catenin complex in pediatric age group astrocytomas compared to their adult counterparts.

Joon Uhm, M.D., and colleagues, have accrued compelling evidence that galectin-1 is an important mediator of glioma invasion. This research extensively utilized the Brain SPORE Xenograft Core. RNA was extracted by way of laser capture microdissection from the periphery (invasive edge) and core of tumor and the RNA was analyzed for differential gene expression by Affymetrix microarray analysis. Galectin-1 was identified as one of the genes overexpressed uniquely at the invasive margin of human glioblastoma tumor. Overexpression of galectin-1 resulted in increased invasiveness in vitro. Moreover, these galectin-1 overexpressing cells, when implanted intracranially, led to shortened survival. The data generated from this research is the basis for a recently submitted R01 grant.

Haplotypes containing the GLTSCR1-exon-1 T allele are significantly associated with increased oligodendroglioma risk (Cancer. 2005; 103: 2363-2372). The haplotype containing the GLTSCR1-exon-1 C allele are significantly inversely associated with glioma risk. Ping Yang, M.D., Ph.D., and Dr. Jenkins are currently validating these results using independent sets of Mayo Clinic gliomas and oligodendrogliomas in Radiation Therapy Oncology Group trial 9402. This work is also a major component of the GLIOGENE consortium.

New Therapeutic Approaches

Phase I/II clinical trials for new therapeutic approaches usually originate within Mayo Clinic Cancer Center, while Phase II/III trials are often developed through the North Central Cancer Treatment Group. However, many other pathways can bring candidate interventions into the Neuro-Oncology Program for clinical application. These include (but are not limited to) National Institutes of Health Phase I and Phase II contracts or R21 "Quick Trials", NCI's Cancer Therapy Evaluation Program, the SPORE Program, commercial sources, and consortium agreements. The following are some of the ongoing clinical trials activities in the Neuro-Oncology Program:

• Phase III Randomized Evaluation of Convection Enhanced Delivery of IL13-PE38QQR at First Recurrence of Glioblastoma Multiforme
• A Pilot and Phase II Study of OSI-774 and Temozolomide in Combination with Radiation Therapy in Glioblastoma Multiforme
• A Phase II Study of a Temozolomide-Based Chemoradiotherapy Regimen for High Risk Low-Grade Gliomas
• Phase III trial of radiosurgery alone versus radiosurgery plus whole brain radiation for patients with one to three metastases
• Enzastaurin versus lomustine in recurrent Glioblastoma Multiforme
• A Phase I Study of CCI-779 and Temozolomide in Combination with Radiation Therapy in Glioblastoma Multiforme
• Phase I/II Trial of Imatinib Mesylate; (Gleevec; STI571) in Treatment of Recurrent Oligodendroglioma and Mixed Oligoastrocytoma