E C Holland

..Our data show that PDGFR signaling quantitatively regulates tumor grade and is required to sustain high-grade oligodendrogliomas...

..The ability of signaling activity to convert tumor cells from one lineage to another presents a mechanism for the development of tumors apparently comprised of cells from multiple lineages...

....

..These new technologies will hopefully support the use of GEMs in preclinical trials and help determine if trials in GEMs are more predicative than xenografts of human responses...

..These data imply that small molecules that promote differentiation may be a rational component of glioma therapy in combination with other drugs aimed at specific molecular signaling targets...

..They demonstrate that targeting signaling components downstream of tumor initiating mutations can be an effective therapeutic strategy for solid tumors...

..Although many studies have correlated deregulation of protein biosynthesis with cancer, it remains to be established whether this process is necessary and/or sufficient for neoplastic transformation and metastasis...

..The results of these mouse model experiments imply a potentially complex role for cell cycle arrest disruption in human gliomagenesis...

..In addition, these mouse-modeling experiments may identify essential targets for therapy and provide test animals for preclinical trials of mechanistically designed therapeutics...

..Recent modelling experiments in mice are helping to delineate the molecular aetiology of this disease and are providing systems to identify and test novel and rational therapeutic strategies...

..It is not known whether this effect is sufficient to induce cancer from cells with an initial non-neoplastic gene expression profile...

..We conclude that GFAP- expressing astrocytes, with appropriate signaling abnormalities, can serve as the cell of origin for oligodendrogliomas, astrocytomas, or mixed gliomas...

..Loss of Ink4a-Arf is not required for PDGF-induced glioma formation but promotes tumor progression toward a more malignant phenotype...

....

..These data support a model whereby Ras and Akt signaling primarily lead to cellular transformation by altering the transcriptome and producing a radical shift in the composition of mRNAs associated with actively translating polysomes...

..Our data strongly supports the view that one role of loss of Ink4a-Arf in gliomagenesis could be to sensitize astrocytes to transformation through dedifferentiation in response to the appropriate oncogenic stimuli...

....

..Therefore, La appears to be an important contributor to Akt-mediated translational regulation of these transcripts in murine glial cells...

..01). These results indicate that perifosine is an effective drug in gliomas in which Akt and Ras-Erk 1/2 pathways are frequently activated, and may be a new candidate for glioma treatment in the clinic...

..These mouse models, in turn, increase our understanding of brain tumor initiation, formation, progression, and metastasis, providing an experimental system to discover novel therapeutic targets and test various therapeutic agents...

..These genetically defined animal models for gliomas will allow for the testing of therapies that are targeted specifically at the gene products involved in the pathogenesis of gliomas...

..The current models provide tumors, which are genetically and histologically similar to their human counterparts, making them attractive to use in drug discovery for treatment of gliomas...

..YKL-40 serum levels were substantially elevated in many of the GBM patients. Statistical analysis of these data indicates that in patients with glioma, serum YKL-40 levels correlate with tumor grade and potentially tumor burden in GBM...

..These data provide insights into the biology and classification of human PNETs and suggest that multiple tumor types or variants can be generated from a fixed set of genetic abnormalities...

..To better define the histologic correlates of different patterns of 1p and 19q loss, we evaluated 1p/19q status in a large group of gliomas. This also allowed us to define a very small minimal deleted region (MDR) on 1p36...

....

..Lastly, we observe that SHH is similarly expressed in human gliomas and note that an intact tumor microenvironment or neurosphere conditions in vitro are required for Gli activity...

..We obtained prospective longitudinal serum samples from patients with gliomas to determine whether YKL-40 or MMP-9 could be used as serum markers...

....

..Our goal was to develop a robust and reproducible method of kinetic analysis for the quantitative evaluation of tumor proliferation...

..These cellular characteristics are similar to human medulloblastomas. Finally, inhibition of Akt signaling sensitizes cells in the perivascular region to radiation-induced apoptosis...

..Knowledge of the molecular biology of gliomas may improve therapy. This review highlights several recent studies on this topic...

..Examples showcasing the use of GEMMs in the testing of molecularly targeted therapeutics are given, and relevant topics, such as stem cell biology, in vivo imaging technology and radiotherapy, are also addressed...

..YKL-40 is a secreted glycoprotein (chitinase family). We compared YKL-40 with two ovarian cancer serum markers, CA125 and CA15-3, for the detection of early-stage ovarian cancer...

..However, activation of Notch alone is unable to induce this cellular expansion. These data suggest that Notch may have a contributing role in the stem-like character of glioma cells...

..In contrast, low-grade murine oligodendrogliomas do not reveal contrast enhancement, similar to human tumors. MRI can be used to identify mice with brain neoplasms as inclusion criteria in preclinical trials...

..To what degree this translational control is either necessary or sufficient for tumor formation or maintenance remains to be determined...

....

..11), and we show here that Akt activity is increased in most of these tumours, implying that combined activation of these two pathways accurately models the biology of this disease...

..The multiple mouse coil is simple in construction and may be implemented without any significant modification to the hardware or software on a clinical scanner...

..Sphere formation by EGFR-/ PTEN- GSCs was independent of EGF stimulation, but dependant on B27 growth supplement. Our data suggest that EGFR+/PTEN+ GSCs are susceptible to anti-EGFR therapy in vitro...

..Therefore, the purpose of this study was to develop a new method to better understand the proteomic profile of the entire population of cells within a sphere...

..These results suggest the possibility that these PDGFRA mutants behave as oncogenes in this subset of gliomas, and that the prevalence of such rearrangements may have been considerably underestimated...

..This Akt-induced ABCG2 activation results from its transport to the plasma membrane. Temozolomide, the standard treatment of gliomas, although not an ABCG2 substrate, increases the SP in glioma cells, especially in cells missing PTEN...

..These data strongly point to PARK2 as a tumor suppressor on 6q25.2-q27. Thus, PARK2, a gene that causes neuronal dysfunction when mutated in the germline, may instead contribute to oncogenesis when altered in non-neuronal somatic cells...

..This evidence strongly suggests that p190 regulates critical components of PDGF oncogenesis and can act as a tumor suppressor in PDGF-induced gliomas by down-regulating Rho activity...

..Our study suggests that the oncogenic effect of KRas in glioma formation may be transduced at least in part through Raf signaling and that therapeutic targeting of this pathway may be beneficial in glioma treatment...

..These results indicate that combined activation of the Shh/Ptc and IGF signaling pathways is an important mechanism in MB pathogenesis...

..We conclude that nestin-expressing neural progenitors, present in the cerebellum at birth, can act as the cells-of-origin for medulloblastoma, and that c-Myc cooperates with Shh to enhance tumorigenicity...

..In this view, glioma formation involves recruitment of cells from the adjacent brain and possibly other sites...

..This Review summarizes these developments in the context of the evolving notion of molecular pathology and discusses the implications that this work has on the design of new treatment regimens...

..1) It remains to be determined whether this mechanism of tumor resistance applies to the more complex stem-cell niche and tumor bulk of gliomas...

..In human gliomas, these two theories are not mutually exclusive. In this review we will summarize both theories, and highlight outstanding issues that remain to be resolved...

..Our results document a new epigenetic mechanism for PTEN regulation in glioma and further highlight dysregulation of Akt signaling as crucial to the development of these tumors...

..Understanding the regulatory mechanisms of NSCs may lend insight into deregulated mechanisms of GBM TSC invasion, proliferation, survival and resistance to current treatment modalities...

..This, in turn, served to create a learning algorithm that correctly predicted 96.4% of the samples as either normal or diseased...

..Our results establish a central role for YAP in counteracting radiation-based therapies and driving genomic instability, and indicate the YAP/IGF2/Akt axis as a therapeutic target in medulloblastoma...

....

..92). Perifosine + 10 Gy did not result in a significantly increased survival relative to 10 Gy alone (P = 0.23). This PDGF-induced BSG model can serve as a preclinical tool for the testing of novel agents...

..We will then present recent knowledge regarding basic glioma biology that speaks to their metastatic potential and suggest rational strategies for the post-transplant management of recipients of organs from donors with glioma...

..Characterization of the signaling pathways and intercellular communication between resident cell types in the microvascular niche of brain tumors is critical to the identification of potential BTSC-specific targets for therapy...

....

..The data raise many questions about the details of radiobiology of stem-like cells in their native environment within tumors in vivo. These answers may lead to better optimization of radiation treatments and schedules for these patients...

..Although overexpression of MYC is not sufficient to cause intraparenchymal tumors, it may facilitate PNET formation by sustaining the growth of undifferentiated progenitor cells...

..These technologies support more detailed preclinical trials and could enable other biological pathways to be monitored in living cells...

..It is likely that a complete description of the role of stem cells in brain tumors will be more complex than our current models...

..In this review, we discuss new insights into the parallels between glial differentiation and glioma formation as well as the potential application of differentiation-inducing therapy...

..This mechanism is conserved in human PDGFR amplified gliomas. The NO/cGMP/PKG pathway's promotion of stem cell-like character in the tumor PVN may identify therapeutic targets for this subset of gliomas...

..The development of small molecules that inhibit the PDGF receptor and various subsequent signaling components promises to introduce new approaches to the treatment of gliomas...

..By appreciating the inter-relationship between tumor formation and development, we maybe able to design new therapeutics targeting tumors for new modes of treatment...

..Thus, Ink4a and Arf have independent and differential tumor suppressor functions in vivo in the glial cell compartment...

..We present here a review of current models, with a focus on gliomas and medulloblastomas...

..Further investigation of HIP1 function in brain cancer biology and validation of its use as a prognostic or predictive brain tumor marker are now warranted...

..The nestin tv-a (Ntv-a) genetically engineered mouse spontaneously develops glioma when infected with ALV-A expressing platelet-derived growth factor, resulting in autocrine platelet-derived growth factor signaling...

..Thus, this study provides definitive evidence that IGFBP2 plays a key role in activation of the Akt pathway and collaborates with K-Ras or PDGFB in the development and progression of two major types of glioma...

..The downstream components of these pathways have provided therapeutic targets that are currently being tested in clinical trials...

..In these platelet-derived growth factor (PDGF)-driven oligodendrogliomas, G1 cell-cycle arrest is generated by blockade of either the PDGF receptor or mTOR using small-molecule inhibitors...

..Such technology for manipulating gene expression in PGCs will allow many of the molecular mechanisms regulating germ cell growth, behavior, and differentiation to be comprehensively analyzed...

..The results provide unique insights into the pharmacokinetics and pharmacodynamics of agents that modulate Akt activity, revealing the usefulness of this reporter for rapid dose and schedule optimization in the drug development process...

..Our findings also have important implications for future peptide biomarker discovery efforts...

..abstract_text> ..

..In this grant we will address these questions using the RCAS/tv-a mouse modeling system for Ras + Akt-induced gliomas. ..

....

..This grant proposes to use mouse models medulloblastomas and gliomas to understand the biology of stem cells in these tumors and their response to therapy. ..