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

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