Rethinking Brain Tumors: The Fourth Mouse Models of Human Cancers Consortium Nervous System Tumors Workshop

Abstract

Despite increased understanding of molecular changes in brain tumorigenesis and successful establishment of mouse brain tumor models, the prognosis for brain cancer has improved only slightly over the past several decades. In November 2007, members of the brain tumor mouse models community convened to discuss how to effectively leverage mouse models to better understand brain tumorigenesis and discover targets for therapy. Discussions focused on identification of molecular targets and cell lineage, microenvironment, and genomic contributions to tumor development and maintenance. Herein, we present recommendations for optimizing mouse models to achieve better outcomes for brain tumor patients. Since the first National Cancer Institute (NCI) Mouse Models of Human Cancer Consortium (MMHCC) meeting in 2000 (1), many mouse models of brain cancer have been developed, and the field has progressed from generating models to using models to gain insights into the cellular and molecular pathogenesis of brain tumors. In November 2007, an international meeting sponsored by the MMHCC and the Office of Rare Diseases convened to discuss the current status of mouse brain tumor modeling and make recommendations for exploiting these models to address fundamental questions in brain tumor biology (for participants, see Supplemental Appendix). A major theme of the meeting was the growing appreciation of the complexity of brain tumors (Supplementary Fig. S1). Development of the central nervous system (CNS) requires ordered and tightly regulated signals that instruct cells to grow, die, mature, and move at the right time and place. Tumors of the nervous system form as a result of mutations that co-opt these signals to promote inappropriate proliferation, survival, differentiation, and migration – the hallmarks of cancer (2). Because brain tumorigenesis may reflect improper responses to instructions important for normal brain development, a more integrated view of brain cancer is needed. A central focus of the meeting was how to apply lessons and techniques from developmental biology to the study of brain tumorigenesis. At the molecular level, the signaling pathways important for brain tumorigenesis are multiple, not necessarily linear, with feedback mechanisms that must be taken into account when designing molecularly targeted interventions. At the cellular level, brain tumors are heterogeneous, composed of tumor stem cells and differentiated tumor cells with different characteristics and susceptibilities to therapy. At the level of the organ, brain tumors co-evolve with their environment, with stromal cells and factors in the surrounding microenvironment being important for tumor maintenance and progression, offering additional targets for intervention. Finally at the organism level, genetic variations between individuals can dictate how tumors initiate, progress, and respond to treatment. Mouse models allow researchers to rigorously test hypotheses developed from examining human tumors using genetic manipulation and controlling specific variables (e.g., environmental influences) to better understand the roles of different pathways, cell types, stromal factors, and genetic variation. Searching for Achilles’ Heel in the Brain -- Targeting Molecular Pathways in Tumors The topic of molecular targets for brain tumors was led by Drs. Marco Giovannini (INSERM, Paris, France) and Martine Roussel (St. Jude Children’s Research Hospital, Memphis, TN), and focused on the characterization of specific molecular targets and signaling pathways, as well as development of effective drug delivery methods in preclinical mouse models. Several experts discussed loss or constitutive activation of key tumor suppressors and oncogenes, respectively, with an emphasis on PI3K/PTEN and RB/TRP53/INK4A-ARF tumor suppressor pathways. Dr. Suzanne Baker (St. Jude Children’s Research Hospital, Memphis, TN) discussed the importance of feedback inhibition in signaling pathways, and the need to test putative targets, such as intermediates in the PI3K/PTEN/S6/mTOR pathway, in different contexts to determine whether targeting the pathway is likely to be universally successful, or successful only in certain contexts. Because molecular signaling pathways can branch and activate compensatory signaling pathways, inhibition of specific targets (e.g., mTOR) can actually lead to release of inhibition of certain branches of the pathway, culminating in increased tumor growth. Similarly, Dr. Terry Van Dyke (National Cancer Institute-Frederick, MD/University of North Carolina, Chapel Hill, NC) presented intriguing data on the levels of EGFR expression in accelerating or inhibiting Ras-driven brain tumors. In addition to their use in identifying important molecular targets and understanding interactions between signaling pathways, mouse models can be powerful tools for developing drug delivery approaches and high-throughput evaluation of targets and therapies. Dr. Martine Roussel discussed micro-RNA as an additional layer of complexity, whereby many pathways may be altered by loss of expression or misexpression of a single micro-RNA (3). Dr. John Ohlfest (University of Minnesota, Minneapolis, MN) presented a novel approach to generate humanized spontaneous gliomas using transposons expressing human proteins in neonatal mouse brains (manuscript submitted). Because the resulting tumor-bearing mice are immune-competent expressing human proteins, this model can be used to test immunotherapies. Dr. Alain Charest (Tufts University, Boston, MA) discussed the use of nanoparticles for effective delivery of siRNAs to treat GBM in mice.