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LICR Brain Cancer Initiative Meeting Report

New York, June 7 & 8

In the first week of June, a group of LICR investigators and close collaborators gathered for the Brain Cancer Initiative (BCI) meeting in the Institute’s administrative offices in New York. As outlined in the introduction by Dr. Andy Simpson (Scientific Director), the meeting’s main aims were to encourage collaboration, sharing of tumor banks, and advancement of laboratory research into clinical trials.

Glioblastoma multiforme (GBM) tumors, the most common cause of brain cancer death, are exceedingly difficult to control since they are complex, display heterogeneous characteristics, and easily develop resistance to targeting drug therapy. A majority of GBM tumors carry amplification of the epidermal growth factor receptor (EGFR) gene, which is often accompanied by mutations that cause expression of truncated, oncogenic forms of EGFR; most commonly the so-called de2-7 or deltaEGFR mutation (EGFR). Dr. Webster Cavenee (San Diego Branch Director) described how tumors can develop resistance to drugs that target EGFR by employing alternate signaling pathways, and presented studies in a xenograft mouse model aimed at uncovering such pathways. Dr. Frank Furnari (San Diego Branch) gave further insight into the problem of tumor heterogeneity by describing how signaling through EGFR, which is typically found in a minor cell population within GBM tumors, can drive tumorigenicity in the entire tumor cell population. In a successive talk, Dr. Furnari described different mechanisms that cause deregulation of PI3-kinase signaling downstream of EGFR, which is associated with poor response to EGFR inhibitors. Dr. Terry Johns (Melbourne Center) revealed new advantages of mAb806—a EGFR-targeting antibody recently developed by LICR investigators and currently in clinical trials—and discussed the necessity of simultaneously targeting different signaling pathways in GBM. This idea was further developed by Dr. Tony Burgess (Melbourne Branch Director), who proposed specific therapeutic strategies of combined targeting, and presented new insights into the function of EGFR family members obtained by crystallography and imaging studies. Another aspect of tumor complexity was addressed by Dr. Joan Seoane (Vall d’Hebron University Hospital Research Institute), who described how signaling by transforming growth factor beta (TGF), which confers tumor suppression in early stages of GBM, can turn oncogenic in aggressive tumors through various mechanisms including epigenetic regulation of the TGF -responsive PDGFB gene.

The meeting was very successful in uncovering a variety of resources that may be shared between investigators to aid discovery of new potential drug targets. Dr. Suely Marie (Affiliate, University of São Paulo) described a versatile central nervous system (CNS) tumor bank of patient samples collected over the last decade, and also a gene expression profiling study aimed at identifying genes that are differentially expressed in GBM. Dr. Greg Riggins (Ludwig Center at Johns Hopkins) presented an approach to identify and target the key signaling pathways that are disrupted by genetic alterations in GBM, based on large-scale genome analysis of tumor samples. One of LICR’s collaborators, Dr. Robert Strausberg (J. Craig Venter Institute), introduced advanced sequencing technologies applied by his laboratory for detecting genetic variations in tumors. Dr. Sandro De Souza (São Paulo Branch) described a comprehensive bioinformatics project, initiated by the São Paulo and New York Branches, aimed at identifying targets for treatment of various cancers. Finally, Dr. Achim Jungbluth (New York Branch) demonstrated the detection of cancer-testis (CT) antigens in different tumor samples using immunohistochemistry techniques and a collection of antibodies developed by the Branch.

Several presentations during the meeting conveyed remarkable discoveries that illuminate new directions in cancer research. Dr. Thomas Perlmann (Stockholm Branch Director) discussed how knowledge of CNS development can contribute to our understanding of GBM, and presented studies of neuronal differentiation that may provide innovative therapies for Parkinson’s disease. Expanding on the topic of neuronal differentiation, Dr. Jonas Muhr (Stockholm Branch) described how opposing activities of Sox transcription factors determine neuronal cell fate. Dr. Xin Lu (London Branch Director) described the apoptotic function of the novel tumor suppressor protein ASPP2, and Dr. Anamaria Camargo (São Paulo Branch) introduced ADAM23, a suppressor of metastasis in breast cancer. They are both are investigating putative implications of their findings for GBM.

The meeting concluded with some guidelines for clinical investigation. In a compelling talk, neurosurgeon Kate Drummond (Melbourne Comprehensive Cancer Centre) shared her insights into the clinical aspects of GBM research, and outlined opportunities for clinical investigation in the course of diagnosis and surgery. Dr. Jonathan Cebon (Melbourne Center) presented encouraging preliminary results from a clinical trial of the CT antigen NY-ESO-1 in patients with resected melanoma, which is ongoing as part of the Cancer Vaccine Collaborative. The model for the development of this vaccine—teamwork of numerous LICR investigators in several Branches with support from New York—served as an inspiration in the concluding discussion on how to implement translational and clinical development within the BCI.

The meeting was very successful and appreciated by the participants, with several collaborations being established during the sessions. The BCI’s long-term goal to develop strategies to control GBM is urgent. There are currently no therapies that substantially improve prognosis or prolong life of GBM patients; the disease remains dreadfully aggressive and opportunities for clinical investigation are very limited. In view of this reality, the rationale of the BCI Program to bring investigators together, establish platforms for sharing molecular and clinical data, and synchronize the work of researchers and clinicians is a timely and essential adjustment to conventional research.

The BCI meeting brought together 34 participants from six Branches (Melbourne, New York, San Diego, São Paulo, Stockholm, University College London), the Melbourne Center and six affiliated or collaborating institutions (J. Craig Venter Institute, USA; John Hopkins University School of Medicine, USA; Melbourne Comprehensive Cancer Centre, Australia; University of São Paulo, Brazil; Vall d'Hebron Research Institute, Spain; Weill Medical College of Cornell University, USA).

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