Brain tumors (astrocytomas or gliomas) represent the leading cause of cancer-related death in children and the fourth leading cause in adults. While there have been considerable advances in our ability to partially arrest their growth by targeting the genetic and molecular changes within cancer cells, a substantial number of patients with gliomas succumb to their disease, develop secondary brain dysfunction as a result of treatment, or fail to regain normal neurologic function despite treatment. We hypothesize that improved patient outcome from brain tumor treatment requires that therapies consider the bi-directional interactions between neoplastic cells and non-neoplastic cells in the tumor surround. Over the past five years, we have developed and validated several genetically-engineered mouse models (GEMMs) of low-grade glioma that recapitulate the salient features of the human condition. In this application, we will exploit these accurate GEMM systems to understand (1) the role of the tumor microenvironment, including important immune system cells, in gliomagenesis and tumor growth, (2) the effects of glioma growth on normal neuronal function, and (3) the secondary effects of chemotherapy and radiation therapy on non-neoplastic brain cells. Using a cross-disciplinary approach, we aim to unravel the cellular and molecular determinants that underlie the bi-directional interactions between neoplastic cells and non-neoplastic cells in low-grade glioma, and use these insights to identify novel strategies aimed at improving the outcome of patients with these cancers. To this end, we have assembled a new team of investigators with prior involvement in large-scale cooperative research initiatives and expertise in mouse model generation (Dr. David Gutmann), stromal interactions in brain tumors (Drs. David Gutmann, Joshua Rubin), advanced small-animal imaging (Dr. Joel Garbow), genomic influences on tumorigenesis (Dr. Karlyne Reilly), and multi-modality imaging (Dr. Mark Ellisman). Finally, we have individually leveraged the rich research environments at Washington University, University of California-San Diego, and The National Cancer Institute to tackle this complex problem in cancer biology.
This proposal aims to employ robust and validated genetically-engineered mouse models of the most common genetic cause of childhood brain tumor (Neurofibromatosis type 1;NF1) to define the bi-directional interactions between neoplastic cells and non-neoplastic cells in the tumor surround that contribute to gliomagenesis and continued growth relevant to the design of more effective therapies for these tumors.
|Solga, Anne C; Toonen, Joseph A; Pan, Yuan et al. (2017) The cell of origin dictates the temporal course of neurofibromatosis-1 (Nf1) low-grade glioma formation. Oncotarget 8:47206-47215|
|Anderson, David M G; Van de Plas, Raf; Rose, Kristie L et al. (2016) 3-D imaging mass spectrometry of protein distributions in mouse Neurofibromatosis 1 (NF1)-associated optic glioma. J Proteomics 149:77-84|
|Kaul, Aparna; Toonen, Joseph A; Cimino, Patrick J et al. (2015) Akt- or MEK-mediated mTOR inhibition suppresses Nf1 optic glioma growth. Neuro Oncol 17:843-53|
|Galanis, Evanthia; Atherton, Pamela J; Maurer, Matthew J et al. (2015) Oncolytic measles virus expressing the sodium iodide symporter to treat drug-resistant ovarian cancer. Cancer Res 75:22-30|
|Kaul, Aparna; Toonen, Joseph A; Gianino, Scott M et al. (2015) The impact of coexisting genetic mutations on murine optic glioma biology. Neuro Oncol 17:670-7|
|Solga, Anne C; Pong, Winnie W; Kim, Keun-Young et al. (2015) RNA Sequencing of Tumor-Associated Microglia Reveals Ccl5 as a Stromal Chemokine Critical for Neurofibromatosis-1 Glioma Growth. Neoplasia 17:776-88|
|Solga, A C; Gianino, S M; Gutmann, D H (2014) NG2-cells are not the cell of origin for murine neurofibromatosis-1 (Nf1) optic glioma. Oncogene 33:289-99|
|Diggs-Andrews, Kelly A; Brown, Jacquelyn A; Gianino, Scott M et al. (2014) Sex Is a major determinant of neuronal dysfunction in neurofibromatosis type 1. Ann Neurol 75:309-16|
|Anastasaki, Corina; Gutmann, David H (2014) Neuronal NF1/RAS regulation of cyclic AMP requires atypical PKC activation. Hum Mol Genet 23:6712-21|
|Wozniak, David F; Diggs-Andrews, Kelly A; Conyers, Sara et al. (2013) Motivational disturbances and effects of L-dopa administration in neurofibromatosis-1 model mice. PLoS One 8:e66024|
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