2012 Retreat

2012 Retreat

On May 14 and 15, 2012, the Brain Tumor Center (BTC) marked its fifth anniversary by hosting its first collaborative retreat.

The first day of the retreat was held at the American Museum of Natural History and was attended by more than 100 people from 14 institutions. Ten clinical departments and four Sloan Kettering Institute programs were represented among Memorial Sloan Kettering’s attendees, as well as the BTC’s external advisory board, its executive board, clinical and basic science fellows, and invited guests. The BTC has been successful in its efforts to build a collaborative community spanning these varied groups, as evidenced by the recognition and ease of conversation among the attendees.

Day one began with a welcome from BTC Administrator Desert Horse-Grant who updated the group on the BTC’s five-year progress, which has been summarized in the BTC Progress Report. The welcoming remarks were immediately followed by three panels on central areas in brain cancer research and treatment.

The first panel was on stem cell research, the second was on pediatric research, and the last was on imaging. Each panel consisted of experts from various institutions who spoke on their clinical and research experiences and advances in each area. The morning concluded with a talk titled “IDH Mutation and Epigenomic Reprogramming in Glioma,” given by Timothy Chan, a Memorial Sloan Kettering radiation oncologist and member of the Human Oncology and Pathogenesis Program (HOPP).

A poster session held the first day showcased 19 posters submitted from previous BTC grant winners as well as fellows from several Memorial Sloan Kettering departments and programs. The Cancer Biology and Genetics Program, the Molecular Pharmacology and Chemistry Program, the Department of Neurology, the Department of Pediatrics, and HOPP were represented.

Poster presenters from outside institutions represented New York University’s Center for Biomedical Imaging, the Scripps Research Institute’s Department of Molecular and Experimental Medicine, and the National Institutes of Health’s Surgical and Molecular Neuro-Oncology Unit. The poster presenters shared and sought advice from senior faculty and three posters were chosen for awards.

The afternoon session started off with clinical talks by Mark Bilsky, of Memorial Sloan Kettering’s Spine Tumor Center in the Department of Neurosurgery, and Kathryn Beal, a Memorial Sloan Kettering radiation oncologist.

That session was followed by a panel on genetically stratified clinical trials, moderated by Lisa DeAngelis, a Co-Executive Director of the BTC and Chair of the Department of Neurology. Genetically stratified clinical trials aim to allow clinicians to group patients together based on specific genetic differences and pair patients with treatments to which they are most likely to respond. The panel included BTC grant winner Jason Huse, of Memorial Sloan Kettering’s Department of Pathology and Human Oncology and Pathogenesis Program; Patrick Wen, a neuro-oncologist from Dana-Farber Cancer Institute; Alfred Yung, a neuro-oncologist from M. D. Anderson Cancer Center; and Antonio Omuro, a Memorial Sloan Kettering neurologist and medical oncologist.

Philip Gutin, a Co-Executive Director of the BTC and Chair of the Department of Neurosurgery, gave the closing remarks on the first day.

The second day of the BTC retreat was held in the Rockefeller Research Laboratories Auditorium. The day began with a scientific talk by Memorial Sloan Kettering President Craig Thompson, who discussed the metabolism of brain tumors and the role of IDH mutations in gliomas.

Dr. Thompson’s talk was followed by a feedback session on a Program Project Proposal by three Memorial Sloan Kettering investigators: neurosurgeon and HOPP member Cameron Brennan, molecular biologist Andrew Koff, and cancer biologist Robert Benezra. The scientific talks were rounded out with a presentation from neurosurgeon, cancer biologist, and BTC Director Eric Holland on new models of glioma using the replication-competent ALV splice-acceptor (RCAS) viral vector system.

The retreat concluded with a keynote address delivered by BTC external advisory board member Richard Gilbertson, who is a developmental neurobiologist at St. Jude Children’s Research Hospital. Dr. Gilbertson discussed the origin of ependymomas and how mouse and zebrafish models of this tumor are being used to develop novel therapies.

The external advisory board expressed its support of the scientific advances highlighted at the retreat and was impressed by the BTC faculty’s leadership in the field, which was been established by forming specialized excellence groups within the disease.

See full retreat agenda

2012 Poster Winners

 Debyani Chakravarty
EGFR-PDGFRA Heterodimerization as a Potential Driver Event in Tumorigenesis of Glioblastoma Multiforme
Debyani Chakravarty

Glioblastoma (GBM) is the most common malignant brain tumor in adults and is both histopathologically and genetically heterogeneous. The majority of primary GBM harbor amplification and/or mutation of a receptor tyrosine kinase (RTK), most commonly EGFR (40-50%) or PDGFRA (~15%); however, clinical trials directed at EGFR or PDGFRA as single targets have been notably unsuccessful in unselected patient populations and RTK status alone has not been found to be predictive of survival. The latter observation may be due to the fact that selection for a single RTK amplicon may not reflect the diversity of RTK expression and activation in these tumors. Recently, our lab demonstrated that at least 5% of primary GBM harbor focal amplification of two RTKs, most commonly EGFR and PDGFRA. In coamplified tumors M753 and M561, identified from the Brain Tumor Center at Memorial Sloan Kettering for which frozen tumor and tumor sphere lines were available, FISH and FACS analysis demonstrated a predominant pattern of distinct subpopulations with the majority of cells harboring single RTK amplification and expression (EGFR or PDGFRA) and a minority of cells harboring both amplicons/receptors in the same cell. In this study, selection from the initial TS753 cultures of the specific RTK-amplified subpopulations by expansion in either EGF and imatinib or PDGF and gefitinib supplement revealed differential signaling properties in the two subpopulations. Interestingly, in the EGF/imatinib selected subpopulation, PDGFRA was stimulated by EGF and deactivated at tyrosine 720 by EGFR-specific inhibitors gefitinib and lapatinib. Indeed, three additional primary GBM of differing genotypes demonstrated the same non-canonical signaling as observed in the coamplified line TS753, suggesting that the phenomenon of GBM tumor cell subpopulations with distinct RTK activation is more common than predicted by RTK coamplification alone. No synergistic growth was observed when coculturing the receptor-enriched subpopulation-derived lines mixed in different proportions, and targeting both RTK subpopulations was necessary to inhibit downstream PI(3) kinase and MAP kinase signaling as well as to elicit growth inhibitory effects. Coimmunopreciptation experiments in both the coamplified line TS753 and the RTK wildtype line TS600 revealed PDGFRA activation and binding to EGFR upon EGF stimulation. Therefore, heterodimerization of the EGFR and PDGFRA allowing for transactivation of these RTKs and activation of non-canonical downstream signaling may be a prevalent mechanism and possibly the rate-limiting step conferring growth advantage to tumor-initiating cells in GBM.

 Eli Diamond
Two Cases of Erdheim-Chester Disease Mimicking Infratentorial Malignancy
Eli Diamond

Erdheim-Chester disease (ECD) is an extremely rare non-Langerhans histiocytosis with a wide range of clinical and radiographic manifestations. Multiple organ systems can be involved, including the lungs, cardiovascular system, retroperitoneum, bones, orbits, and infrequently the CNS. We report two patients who presented for evaluation of infratentorial mass lesions that were clinically and radiographically progressive over months. They were referred to our center for management of these lesions as putative malignancies after unrevealing diagnostic evaluations. In both cases, attention to concomitant systemic signs and symptoms unexplainable by their CNS lesions raised suspicion for a systemic histiocytosis. Biopsy of asymptomatic sclerotic bone lesions identified by nuclear bone scintigraphy demonstrated a xanthomatous CD68+/CD1a- histiocytic infiltration with surrounding fibrosis, consistent with ECD. This is a rare disorder that can mimic malignant lesions and should be included in the differential diagnosis for enhancing lesions in the posterior fossa in the appropriate clinical context.

 Ken Pitter
Dexamethasone Modulates Tumor Proliferation in an In Vivo Model of Glioma and Is Associated with Decreased Survival in Human Patients
Ken Pitter

Glioblastoma multiforme (GBM) is the most common and malignant primary brain neoplasm. Standard therapy for GBM is surgical resection followed by radiation therapy (RT) and temozolomide. Additionally, the corticosteroid dexamethasone (Dex) is frequently used for symptomatic improvement prior to surgical resection and, in many cases, maintenance during postoperative radiation therapy. A variety of studies have investigated the role of Dex in symptom management using various glioma models, but the results have been inconsistent. The purpose of this study was to investigate the effect of Dex on the PDGF-driven RCAS/t-va model of glioma, and to elucidate possible mechanisms of action. Upon becoming symptomatic, mice were treated with Dex at 10 mg/kg for three days and tissue was collected for immunohistochemical and microarray analysis.

We found that the majority of the differentially expressed genes were down-regulated by Dex and were involved in cell cycle progression and proliferation, which was confirmed by PCNA and Ki67 immunohistochemistry.

Interestingly, when primary mouse glioma cultures were treated in vitro with escalating concentrations of DEX, there was no decrease in proliferation, suggesting that the anti-proliferative phenotype observed in vivo might be mediated via the tumor microenvironment. When these genes were investigated in the TCGA data set, we found that high expression of the genes down-regulated by Dex predicts a significantly longer survival compared to tumors with lower levels. In summary, our data suggests that Dex inhibits tumor cell proliferation, potentially through and tumor microenvironment interaction. TCGA analysis suggests that down-regulation of our Dex-induced gene set may have an adverse effect on survival. It is possible that if Dex decreases tumor cell proliferation it may also decrease the efficacy of antineoplastic therapy that is most toxic to proliferating cells. This study underscores the importance of defining the mechanism of how DEX affects tumor and stromal cells in glioma.