Molecular Imaging of Cancer Biology
The primary goal of the Imaging Radiobiology Laboratory is to apply novel molecular imaging methods towards the study of radiation and cancer biology. To this end, we have focused on both the development and implementation of preclinical and clinical molecular imaging methods capable of visualizing and quantifying tumor behavior, and the use of these methods in laboratory and clinical studies to elucidate tumor biology and to improve the treatment of human disease.
The role of oxygen in tumor progression and response to therapy has been a topic of study for over 50 years. In the last 15 years, methods for non-invasively detecting and imaging regions of hypoxia within tumors have advanced to a stage where they may be employed both in the study of this phenomenon and in the development of hypoxia- directed therapeutic strategies. Our laboratory is involved in the evaluation of established hypoxia imaging methods in preclinical and clinical situations, development of novel hypoxia- and hypoxic signaling-specific imaging methods, and application of these techniques in studying cancer biology and devising improved treatments. In collaboration with the MIPS program, we have implemented radiochemical syntheses of the hypoxia PET agents fluoromisonidazole (FMISO), fluoroazomycin arabinoside (FAZA), and EF5. We have also engineered reporter gene approaches towards visualizing hypoxia and hypoxia-specific gene expression, and synthesized new imaging probes specific for hypoxia-induced proteins.
We have recently observed using in vivo bioluminescence imaging (BLI) that radiation modulates the migration of breast cancer cells. This process involves the expression of radiation-inducible cytokines that serve as chemoattractants for circulating tumor cells (CTCs). This phenomenon has important implications for using radiotherapy to cure patients whose tumors have shed cells into the circulation. We are currently elucidating the molecular and cellular mechanism of this process and evaluating its significance in clinical radiotherapy. This effort has expanded our ability to visualize the metastatic process.
Current research projects in this area include:
- Comparison of murine subcutaneous, orthotopic, and spontaneous models of cancer using hypoxia imaging
- Identification and molecular imaging of novel hypoxia-regulated protein targets
- Evaluation of hypoxia PET-directed radiotherapy strategies
- Development of imaging probes targeting the receptor tyrosine kinase Axl
- Study of tumor cell migration and metastasis, and the effects of radiation on this process
- Xiao N, Cao H, Chen CH, Kong CS, Ali R, Chan C, Sirjani D, Graves E, Koong A, Giaccia A, Mochly-Rosen D, Le QT. A Novel Aldehyde Dehydrogenase-3 Activator (Alda-89) Protects Submandibular Gland Function from Irradiation without Accelerating Tumor Growth. Clinical Cancer Research 2013; 19(16):4455-4464.
- Le QT, Fisher R, Oliner KS, Young RJ, Cao H, Kong C, Graves E, Hicks RJ, McArthur GA, Peters L, O'Sullivan B, Giaccia A, Rischin D. Prognostic and predictive significance of plasma HGF and IL-8 in a phase III trial of chemoradiation with or without tirapazamine in locoregionally advanced head and neck cancer. Clinical Cancer Research 2012; 18:1798-1807.
- Nair VS, Gevaert O, Davidzon G, Napel S, Graves EE, Hoang CD, Shrager JB, Quon A, Rubin DL, Plevritis SK. Prognostic PET 18F-FDG uptake imaging features are associated with major oncogenomic alterations in patients with resected non-small cell lung cancer. Cancer Research 2012; 72:3725-3734.
- Apte SD, Chin FT, Graves EE. Molecular Imaging of Hypoxia: Strategies for Probe Design and Application. Current Organic Synthesis 2011; 8:593-603.
- Chan DA, Sutphin PD, Nguyen P, Turcotte S, Lai EW, Chi JT, Wu J, Solow-Cordero DE, Bonnet M, Flanagan J, Bouley DM, Graves EE, Denny WA, Hay MP, Giaccia AJ. Targeting GLUT1 and the Warburg Effect in Renal Cell Carcinoma by Chemical Synthetic Lethality. Science Translational Medicine 2011; 3:94ra70.
- Graves EE, Maity A, Le QT. The tumor microenvironment in NSCLC. Seminars in Radiation Oncology 2010; 20:156-163.
- Graves EE, Vilalta M, Cecic IK, Erler JT, Tran PT, Felsher D, Sayles L, Sweet-Cordero A, Le QT, Giaccia AJ. Hypoxia in Models of Lung Cancer: Implications for Radiotherapy and Targeted Therapeutics. Clinical Cancer Research 2010; 16:4843-4852.
- Bennewith KL, Huang X, Ham CM, Graves EE, Erler JT, Kambham N, Feazell J, Yang GP, Koong A, Giaccia AJ. The Role of Tumor Cell-Derived Connective Tissue Growth Factor (CTGF/CCN2) in Pancreatic Tumor Growth. Cancer Research 2009; 69:775-784.
- Cairns R, Bennewith K, Graves E, Giaccia A, Chang D, Denko N. Pharmacologically increased tumor hypoxia can be measured by 18F FAZA PET and enhances tumor response to hypoxic cytotoxin PR-104. Clinical Cancer Research 2009; 15:7170-7174.
- Le QT, Koong A, Lieskovsky YY, Narasimhan B, Graves E, Pinto H, Brown JM, Spielman D. In vivo(1)H Magnetic Resonance Spectroscopy of Lactate in Patients with Stage IV Head-and-Neck Squamous Cell Carcinoma. International Journal of Radiation Oncology Biology Physics 2008; 71:1151-1157.
- Graves EE, Giaccia AJ. Imaging Tumoral Hypoxia: Oxygen Concentrations and Beyond. Oncology 2007, 21:368-378.
- Cecic I, Chan D, Sutphin P, Ray P, Gambhir SS, Giaccia A, Graves EE. Oxygen sensitivity of reporter genes: implications for preclinical imaging of tumor hypoxia. Molecular Imaging 2007, 6: 219-228.
- Cheng Z, Zhang L, Graves E, Xiong Z, Dandekar M, Chen X, Gambhir SS. Small-animal PET of melanocortin 1 receptor expression using a 18F-labeled alpha-melanocyte-stimulating hormone analog. Journal of Nuclear Medicine 2007, 48:987-994.