Primary GBM, accounting for over 90% of human GBMs, develops rapidly or de novo with no prior clinical disease. Large-scale genomic analyses have contributed greatly to the definition of the overall glioma landscape and datasets (TCGA) have enabled the division of GBMs into subclasses based on their genomic, transcriptomic, and signal transduction patterns. Sadly, despite these insights into the genetics of the disease and advances in neurosurgery, radiation and chemotherapy, its dismal prognosis has not changed significantly. Unlike secondary GBM, the order and the timing of the genetic alterations that are acquired remain to be elucidated in primary GBM, and more importantly, how these acquired genetic alterations contribute to aggressive and malignant phenotypes in this devastating disease aren't well understood. Project 2 will utilize the p53'^^^'(R) model which mimics the pathogenesis of adult onset primary GBM with a high degree of nuclear atypia even in the earliest stages of gliomagenesis. The working hypothesis is that the eariiest lesion most likely comprises a small number of oncogenic mutations or amplifications that enables the targeted cell(s) to proliferate beyond normal means. Enhanced proliferation in conjunction with mutations that increase genomic instability may lead to further genomic lesions, including loss of tumor suppressor genes (e.g. Pten), further amplifying proliferation.
In Specific Aim 1, we will test the hypothesis that p53 deficiency facilitates the accumulation of critical genetic alterations in the SVZ stem/progenitor cells leading to clonal expansion and primary GBM formation. Acquisition of genetic alterations such as loss of chromosome 19 (harboring Pten) leads to rapid growth and GBM progression.
Specific Aim 2 will monitor the response of these evolving tumors to standard of care chemo/radiation therapy, with the goal of defining genetic alterations that result in resistance to therapy, a common feature of GBM.
Specific Aim 3 will test the hypothesis that the early stages of gliomagenesis represent the best therapeutic opportunities due to a more limited heterogeneity of clones. The presence of heterogeneous clones within a lesion leads to tumor adaptivity and recurrence an important contributor to therapeutic resistance in glioma. Due to the ability of MRI-PRM (developed in Project 3) to detect areas within the brain that will later develop a contrast enhancing lesion, we will use MRI to identify early genetic alterations in gliomagenesis through precise stereotaxic biopsy of early stage tumors for genomic analysis. We predict that targeted inhibition of key glioma-initiating signaling pathways will significantly enhance outcomes (survival) by preventing recurrence.
The proposed studies are based on the understanding that glioblastoma is the result of multiple pathway defects originating in multiple cells that evolves into the same disease. Through the use of a mouse model that develops glioblastoma that is heterogenous, we will decipher genetic changes that occur early in the disease and those that result in aggressive, fast growing disease. We will also investigate genetic changes that result in resistance to current therapies and investigate if targeted inhibition of genetic pathways early in the disease process results in improved outcomes.
|Galbán, Stefanie; Apfelbaum, April A; Espinoza, Carlos et al. (2017) A Bifunctional MAPK/PI3K Antagonist for Inhibition of Tumor Growth and Metastasis. Mol Cancer Ther 16:2340-2350|
|Hu, Xin; Martinez-Ledesma, Emmanuel; Zheng, Siyuan et al. (2017) Multigene signature for predicting prognosis of patients with 1p19q co-deletion diffuse glioma. Neuro Oncol 19:786-795|
|Nyati, Shyam; Young, Grant; Ross, Brian Dale et al. (2017) Quantitative and Dynamic Imaging of ATM Kinase Activity. Methods Mol Biol 1596:131-145|
|Chen, Daiqin; Yang, Dongzhi; Dougherty, Casey A et al. (2017) In Vivo Targeting and Positron Emission Tomography Imaging of Tumor with Intrinsically Radioactive Metal-Organic Frameworks Nanomaterials. ACS Nano 11:4315-4327|
|Galbán, C J; Hoff, B A; Chenevert, T L et al. (2017) Diffusion MRI in early cancer therapeutic response assessment. NMR Biomed 30:|
|Martinez, Carlos H; Diaz, Alejandro A; Meldrum, Catherine et al. (2017) Age and Small Airway Imaging Abnormalities in Subjects with and without Airflow Obstruction in SPIROMICS. Am J Respir Crit Care Med 195:464-472|
|Galbán, Stefanie; Al-Holou, Wajd N; Wang, Hanxiao et al. (2017) MRI-Guided Stereotactic Biopsy of Murine GBM for Spatiotemporal Molecular Genomic Assessment. Tomography 3:9-15|
|Yang, Dongzhi; Comeau, Anthony; Bowen, Wayne D et al. (2017) Design and Investigation of a [18F]-Labeled Benzamide Derivative as a High Affinity Dual Sigma Receptor Subtype Radioligand for Prostate Tumor Imaging. Mol Pharm 14:770-780|
|Belloli, Elizabeth A; Degtiar, Irina; Wang, Xin et al. (2017) Parametric Response Mapping as an Imaging Biomarker in Lung Transplant Recipients. Am J Respir Crit Care Med 195:942-952|
|Pompe, Esther; Galbán, Craig J; Ross, Brian D et al. (2017) Parametric response mapping on chest computed tomography associates with clinical and functional parameters in chronic obstructive pulmonary disease. Respir Med 123:48-55|
Showing the most recent 10 out of 163 publications