Brain Cancer Initiative Meeting, September 17-18, 2009
Brain cancers, in particular glioblastomas, remain very difficult to treat although there has been steady progress over the decade with average survival for newly diagnosed patients being having been extended from around nine months to now close to twenty months. Moreover, progress in the understanding of these aggressive tumors has been extremely rapid in recent years. There is a growing consensus that this knowledge is ripe for translation into novel approaches to therapy and control making this an invigorating era in brain cancer research.
Brain cancer is the focus of one of LICR’s Cancer Initiatives. The Cancer Initiatives, which receive important outside support from the Conrad N. Hilton Foundation, seek to facilitate the translation of fundamental research within LICR towards selected tumor types by facilitating access to clinical samples and other patient specimens, promoting interaction with leaders in the field, fostering development of potential clinical reagents and conducting appropriate clinical trials. A LICR Brain Cancer Initiative meeting was held on September 17-18, 2009 at the J. Craig Venter Institute (JCVI) in Rockville Maryland. The meeting was supported by funds from the Hilton-Ludwig Cancer Metastasis Initiative with additional support from the National Foundation for Cancer Research who sponsored several of the participants and which was represented at the meeting by their President, Franklin Salisbury and members of their senior management. The meeting agenda was organized by Web Cavenee, Director of the LICR’s San Diego Branch, and was co-hosted by Andy Simpson, Scientific Director, LICR and close genomics collaborator Bob Strausberg, Deputy Director of the JCVI. The 19 invited speakers included some of the most distinguished investigators in brain cancer research in the US together with investigators from several of the Ludwig Institute Branches as well as the Ludwig Trust Center at Johns Hopkins Medical School. The meeting highlighted the rapid pace of research and stimulated optimism that improved therapies to brain cancer will result from this progress.
One of the key components of all LICR Cancer Initiatives is the generation and maintenance of high quality tumor banks. Long term LICR Affiliate, Suely Marie, of the University of Sao Paulo, plays this crucial role for the Brain Cancer Initiative. She informed the assembled group that her banks now include several hundred very accurately collated specimens that have been used in numerous collaborative studies within the Initiative. She emphasized her willingness to continue to explore further collaborations that would benefit from this high quality clinical access. Concerning her own studies she discussed MELK, LOX and PLP2, targets that had been identified from gene expression analyses of her astrocytoma samples.
Other speakers also discussed potential therapeutic targets they are currently pursuing through a variety of approaches. These included IDH1, an enzyme involved in energy metabolism that had been identified as a potential target through large scale sequencing projects (presented by Victor Velculescu and Greg Riggins from the Ludwig Trust Center at Johns Hopkins, Linda Liau from UCLA and Lynda Chin from Dana Farber, see below). In addition, Andrew Scott, from the LICR Centre for Clinical Sciences in Melbourne, presented data on antibody targeting of EGFR and EphA3 and Paul Fisher, Virginia Commonwealth University, discussed AEG-1, a newly identified oncogene that is strongly expressed in glioblastomas. An alternative target, discussed by Aristidis Moustakas from the LICR Uppsala Branch, is TGF-beta and its signaling pathway terminating in the transcription factor Snail that drives epithelial-mesenchymal transition (EMT).
Identification of targets comes from novel insights into the molecular basis of brain tumor development. In this regard, Susanne Schlisio, LICR-Stockholm, discussed the disruption of oxygen and metabolic sensing in nervous system tumors focusing on EglN3 and KIF1B-beta, and raised the question of whether cancer cells predominantly utilize glycolysis for energy generation to escape oncogene induced apoptosis. Xin Lu from the LICR Oxford Branch linked the ASPP family proteins, and in particular ASPP2, to brain cancer research with a focus on its potential role as a tumor suppressor in medulloblastoma.
At the cellular level, Jeremy Rich, Cleveland Clinic, presented data on the role and characteristics of brain tumor stem cells and how to study these more effectively. David Gutmann, Washington University School of Medicine, discussed glioma-stroma co-dependency with particular focus on NF1 and the use of genetically engineered mouse models to explore this relationship. In addition, Scott VandenBerg, UCSD, presented data on the motility and invasive dispersion of glioma cells and the role of CXCR4 and CXCR7 as mediators of migration and motility and double cortin as a migration/invasiveness marker.
Glioblastoma has been the focus of intense attention through genomic studies. Lynda Chin, Dana-Farber, presented the work of The Cancer Genome Atlas (TCGA) that has undertaken a pivotal pilot project with glioblastoma The challenges that lie ahead in terms of community-wide data sharing were discussed as well as the ultimate goal of using genomics to predict tumor phenotype and likely response to treatment. Victor Velculescu presented an integrated genomic analysis of glioblastoma undertaken by the Ludwig Center for Molecular Genetics and Therapeutics at the John Hopkins Medical Center. The highlight of this work was the discovery of frequent mutation of IDH1, the presence or absence of which defines two distinct categories of glioblastoma.Greg Riggins, also from the Ludwig Trust Center at John Hopkins Medical Center, presented a number of strategies for translating research into therapy, including drug combinations based on a growing understanding of signaling pathways operative in glioblastoma, metabolic inhibition and most strikingly the use of bacterial therapy that targets the hypoxic areas of the tumor, directly promotes tumor destruction and also stimulates the immune response in a synergistic overall therapeutic attack. Michael Berens from The Translational Genomics Research Institute (TGRI) described the development of a directed project aimed at testing a range of available drugs with a panel of glioblastoma xenografts in order to try and identify potentially powerful combinations.
Drug delivery is a long standing problem in the treatment of glioblastomas. Ed Oldfield, University of Virginia, gave an update and appraisal of convection-enhanced drug delivery for glioma. A crucial aspect of glioblastoma research is the basis of this tumor’s capacity to resist most forms of therapy. In this context, David Rowitch, UCSF, discussed an oppositional Olig2-p53 axis that regulates tumor growth and radiation resistance. Olig2 is highly expressed in glioblastomas and is a direct repressor of p21.
Two presentations reported investigation of EGFR signaling and its implications in the treatment of glioblastoma patients. Paul Mischel, UCLA, discussed interactivity between the EGFR signaling pathway and fatty acid biosynthesis and that inhibition of the latter might promote angiogenesis. Frank Furnari from the LICR Branch in San Diego reported on PTEN inactivation mechanisms and resistance to EGFR inhibitor therapy.Linda Liau, UCLA, described her work on adoptive transfer of immune cells stimulated by the patient’s own tumor cells. The success of this immunotherapy was reported to be possibly influenced by the presence of TGF-beta expression and T-cell infiltration of the tumors. New targets and methods of improving the therapeutic efficacy of the approach were discussed. An alternative approach to immunotherapy was presented by Amy Heimberger, University of Texas-MDACC, who described an active vaccination protocol using an EGFR peptide that resulted in both delay of progression and prolonged survival in glioblastoma patients. In order to augment this response the group proposes to investigate the use of a potent inhibitor of STAT-3, WP1066, to overcome the immunosuppression exerted by the tumor that interferes with an otherwise potentially protective immune response stimulated by vaccination. This and other combinations of small molecule inhibitors together with immunotherapies emerged as exciting possible routes to improved control of brain tumors in the course of the meeting. The Institute is extremely grateful to all those who participated. We are keenly following several new collaborative projects that have emerged directly from the meeting. We expect to hold a similar meeting in 2011. A meeting of the Colon Cancer Initiative is being planned for 2010.