PROJECT 3: Malignant gliomas are uniformly fatal tumors and there is an urgent need for improving our biological understanding of these lesions in order to rationally develop treatments. Molecular imaging can be adopted for interrogating the complex oncogenic pathways which impact their aggressive phenotype. Furthermore, targeted disruption of one or several signaling processes at once may provide an avenue for improving the overall survival of patients. However, the interconnecting pathways can provide tumors with redundancies in the signaling cascades allowing for it to adapt and thereby evade treatment. Moreover, recent studies have shown that gliomas also contain a therapeutically resistant subpopulation of cancer stem cells which can provide for repopulation of the mass following conventional therapeutic interventions. Therefore, in this Project, we seek a paradigm shift in approaching the development of improved therapeutic strategies for neurooncology patients by development and incorporation of novel molecular imaging tools to address three key aspects believed to frustrate current treatment of gliomas: (1) Unknown effects of inhibiting signaling molecules on other signaling pathways and how the glioma cell can evade treatment using redundancies (escape routes) within the interconnected signaling pathways (2) How these signaling pathways differ in the glioma stem cell population and;(3) How we can use this information to eliminate the glioma stem cell population along with the bulk mass of cells within the tumor site. Optical molecular imaging reporters for key molecular events including Met kinase activity, Akt kinase activity, EGFR activity and Caspase-3 will be expressed in human glioma cells and used as readouts for evaluating the response of treatment interventions on the oncogenic signaling activities in the glioma stem and non-stem cell populations both in vitro and in vivo. We will engineer a human glioma cell line such that CD133 expression will correlate with bioluminescence activity. This will enable us to quantify the growth and survival of the tumor stem cell population. The ability to monitor tumor burden using MRI as well as the cancer stem cell population using this engineered reporter line will result in the identification and validation of novel treatments/combinations wherein cancer stem cell dependent repopulation is delayed and thereby improving the clinical outcome of brain tumor patients. Public Health: The studies proposed here will provide the foundation of incorporating molecular imaging reporters and applications into the drug development and evaluation process for improving our understanding treatment resistance which should lead to a more rationale approach for selection of treatments. Overall, the success of this Project will lead to improved survival of patients with gliomas.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-SRRB-9)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Ann Arbor
United States
Zip Code
Joshi, Bishnu P; Pant, Asha; Duan, Xiyu et al. (2016) Multimodal Video Colonoscope for Targeted Wide-Field Detection of Nonpolypoid Colorectal Neoplasia. Gastroenterology 150:1084-6
Al-Dujaili, Saja A; Koh, Amy J; Dang, Ming et al. (2016) Calcium Sensing Receptor Function Supports Osteoblast Survival and Acts as a Co-Factor in PTH Anabolic Actions in Bone. J Cell Biochem 117:1556-67
Nyati, Shyam; Chator, Areeb; Schinske, Katerina et al. (2016) A Requirement for ZAK Kinase Activity in Canonical TGF-β Signaling. Transl Oncol 9:473-481
Stacer, A C; Fenner, J; Cavnar, S P et al. (2016) Endothelial CXCR7 regulates breast cancer metastasis. Oncogene 35:1716-24
Zhou, Juan; Joshi, Bishnu P; Duan, Xiyu et al. (2015) EGFR Overexpressed in Colonic Neoplasia Can be Detected on Wide-Field Endoscopic Imaging. Clin Transl Gastroenterol 6:e101
Boes, Jennifer L; Hoff, Benjamin A; Bule, Maria et al. (2015) Parametric response mapping monitors temporal changes on lung CT scans in the subpopulations and intermediate outcome measures in COPD Study (SPIROMICS). Acad Radiol 22:186-94
Bowman, Brittany M; Sebolt, Katrina A; Hoff, Benjamin A et al. (2015) Phosphorylation of FADD by the kinase CK1α promotes KRASG12D-induced lung cancer. Sci Signal 8:ra9
Nyati, Shyam; Schinske-Sebolt, Katrina; Pitchiaya, Sethuramasundaram et al. (2015) The kinase activity of the Ser/Thr kinase BUB1 promotes TGF-β signaling. Sci Signal 8:ra1
Chang, S Laura; Cavnar, Stephen P; Takayama, Shuichi et al. (2015) Cell, isoform, and environment factors shape gradients and modulate chemotaxis. PLoS One 10:e0123450
Luker, K E; Pata, P; Shemiakina, I I et al. (2015) Comparative study reveals better far-red fluorescent protein for whole body imaging. Sci Rep 5:10332

Showing the most recent 10 out of 156 publications