BMCB-Faculty Research, Robert J. Gillies

Professor of Radiology, Biochemistry & Molecular Biophysics, and Physiology
Ph.D., University of California, Davis

Ions and cancer.

Research Interests

Our laboratory is focused on understanding the tumor microenvironment and the impact this has on cancer progression, and anti-cancer therapies. Our major tools are all related to advanced non-invasive imaging. Over the past two decades, there have been unprecedented, rapid and continued increases in the applications of biomedical imaging to problems in cancer. These advancements have impacted the study of basic cancer at the molecular and in vitro level with advanced microscopy, all the way up to impacting patient care with advances in in vivo imaging. We have participated in this growth primarily at the in vivo level by advancing the use of in vivo Magnetic Resonance Imaging (MRI), as well as other imaging modalities (optical and nuclear). Our work is divided into three, interrelated programs:

The Tumor Microenvironment (Collaborators: Drs. Robert Gatenby, Natarajan Raghunand and Ian Robey). This program seeks to understand the causes and consequences of the physiological microenvironment of tumors. As a consequence of poor perfusion, tumors are often hypoxic and acidic. In addition to developing methods to quantitatively image hypoxia and acidity, this program is also concerned with understanding how this hostile microenvironment develops and what consequences it has for tumor progression and therapy. Our current hypothesis states that hypoxia during early tumor development selects for cells, via somatic evolution, that are resistant to hypoxia through stabilization of transcription factors such as HIF-1a and c-myc. As a consequence, these tumors invariably consume more glucose and produce more acid which imposes an additional selection pressure for cells that are resistant to acid-mediated apoptosis. Ongoing projects include: (1) development of MRI techniques to non-invasively measure tumor pH and hypoxia; (2) molecular biological analyses to understand the mechanisms causing increased rates of glucose consumption in tumors; (3) immunohistochemistry and modeling of early cancers and pre-cancers from human patients to understand the relationship between gene expression and the physiological microenvironment; (4) mathematical modeling of the microenvironment as a selection pressure for the somatic evolution of cancers.

Non-invasive Measures of Therapy (Collaborators: Drs. Natarajan Raghunand, Amanda Baker, Ted Trouard, Jean-Philippe Galons and Alison Stopeck). MRI is an important biomedical imaging technique because it can be made to be exquisitely sensitive to changes in the structure and function of organ systems and patients can be interrogated over and over again, by virtue of the fact that the energies employed are so small. Our group has pioneered the use of diffusion MRI to characterize ultrastructural changes occurring in tumors as a result of anti-cancer chemotherapy. This is performed in pre-clinical (animal) and clinical (human patients) settings. We have observed that the apparent diffusion coefficient (ADC) of tumor water increases early during the course of successful therapy, presumably because of cell death or shrinking. We are also developing: (1) dynamic contrast enhanced (DCE) MRI; (2) blood oxygen level dependent (BOLD) MRI; and (3) magnetic resonance spectroscopy (MRS) as predictive and response biomarkers to novel therapies. These are being developed in animal models as well as in human patients under the auspices of the Imaging Response Assessment Team (IRAT) program; a national consortium of academic cancer centers to increase the use of imaging in clinical trials. The major hypotheses being tested in this work is that these imaging biomarkers can quantitatively improve the measurement and prediction of patient response, both in clinical care and during trials of new drugs.

Targeting Ligands (Collaborators: Drs. Victor Hruby, Hank Yamamura, Ron Lynch, Gene Mash, Josef Vagner (Bio5), Dave Morse (Bio5), Haiyong Han (TGen) and Mike Caplan (ASU). This multidisciplinary program is focused on the development of multimeric ligands to target the delivery of imaging agents and drugs to cancers. This work is focused on the hypotheses that: (1) novel cell surface targets can be identified using DNA arrays and validated in immunocytochemistry of tissue arrays; (2) novel ligands to these target receptors can be identified and developed using high throughput synthesis and screening approaches; and (3) that these ligands can be developed with improved specificity and affinity by stringing them together as homo- or hetero-multimers. This program includes collaborative arrangements with a target discovery group (TGen), a ligand discovery group (Bio5) and a modeling group (ASU). The ultimate goal of this program will be to develop novel targeting agents with high specificity and affinity which will deliver cytotoxic therapies to cancer cells in vivo, or “molecular surgery”.

Select Publications

Any link on the below references will take you off of the BMCB site and to an abstract of that particular paper.

Martinez-Zaguilan, R., L.S. Tompkins, R.J. Gillies, and R.M. Lynch. 2006. Simultaneous analysis of intracellular pH and Ca2+ from cell populations. Methods in Molecular Biology 312: 269-287.

Garcia-Martin, M.L., G.V. Martinez, N. Raghunand, A.D. Sherry, S. Zhang, and R.J. Gillies. 2006. High resolution pH(e) imaging of rat glioma using pH-dependent relaxivity. Magnetic Resonance in Medicine 55: 309-315.

Jordan, B.F., M. Runquist, N. Raghunand, R.J. Gillies, W.R. Tate, G. Powis, and A.F. Baker. 2005. The thioredoxin-1 inhibitor 1-methylpropyl 2-imidazolyl disulfide (PX-12) decreases vascular permeability in tumor xenografts monitored by dynamic contrast enhanced magnetic resonance imaging. Clinical Cancer Research 11: 529-536.

Gillies, R.J., J.M. Hoffman, K.S. Lam, A.E. Menkens, D.R. Piwnica-Worms, D.C. Sullivan, and R. Weissleder. 2005. Meeting report: high-throughput technologies for in vivo imaging agents. Molecular Imaging 4: 98-103.

Handl, H.L., J. Vagner, H.I. Yamamura, V.J. Hruby, and R.J. Gillies. 2005. Development of a lanthanide-based assay for detection of receptor-ligand interactions at the delta-opioid receptor. Analytical Biochemistry 343: 299-307.

Gillies, R.J., and D.L. Morse. 2005. In vivo magnetic resonance spectroscopy in cancer. Annual Review of Biomedical Engineering 7: 287-326.

Galons, J.P., S. Lope-Piedrafita, J.L. Divijak, C. Corum, R.J. Gillies, and T.P. Trouard. 2005. Uncovering of intracellular water in cultured cells. Magnetic Resonance in Medicine 54: 79-86.

Robey, I.F., A.D. Lien, S.J. Welsh, B.K. Baggett, and R.J. Gillies. 2005. Hypoxia-inducible factor-1alpha and the glycolytic phenotype in tumors. Neoplasia 7: 324-330.

Jordan, B.F., M. Runquist, N. Raghunand, A. Baker, R. Williams, L. Kirkpatrick, G. Powis, and R.J. Gillies. 2005. Dynamic contrast-enhanced and diffusion MRI show rapid and dramatic changes in tumor microenvironment in response to inhibition of HIF-1alpha using PX-478. Neoplasia 7: 475-485.

Morse, D.L., D. CarrollL. Weberg, M.C. Borgstrom, J. Ranger-Moore, and R.J. Gillies. 2005. Determining suitable internal standards for mRNA quantification of increasing cancer progression in human breast cells by real-time reverse transcriptase polymerase chain reaction. Analytical Biochemistry 342: 69-77.

Handl, H.L., and R.J. Gillies. 2005. Lanthanide-based luminescent assays for ligand-receptor interactions. Life Sciences 77: 361-371.Morse, D.L., H. Gray, C.M. Payne, and R.J. Gillies. 2005. Docetaxel induces cell death through mitotic catastrophe in human breast cancer cells. Molecular Cancer Therapeutics 4: 1495-1504.

Jordan, B.F., K. Black, I.F. Robey, M. Runquist, G. Powis, and R.J. Gillies. 2005. Metabolite changes in HT-29 xenograft tumors following HIF-1alpha inhibition with PX-478 as studied by MR spectroscopy in vivo and ex vivo. NMR in Biomedicine 18: 430-439.

Monguchi, Y., J. Vagner, H.L. Handl, U. Jana, L.J. Begay, V.J. Hruby, R.J. Gillies, and E.A. Mash. 2005. Design, synthesis, and validation of rigid linkers for bioactive peptides. Tetrahedron Letters 46: 7589-7592.

Gillies, R.J., and D.L. Morse. 2005. In vivo magnetic resonance spectroscopy in cancer. Annual Review of Biomedical Engeering 7: 287-326.

Handl, H.L., J. Vagner, H.I. Yamamura, V.J. Hruby, and R.J. Gillies. 2004. Lanthanide-based time-resolved fluorescence of in cyto ligand-receptor interactions. Analytical Biochemistry 330: 242-250.

Gillies, R.J., N. Raghunand, M.L. Garcia-Martin, adn R.A. Gatenby. 2004. pH imaging. A review of pH measurement methods and applications in cancers. IEEE Engineering in Medicine and Biology Magazine 23: 57-64.

Bascunan-Castillo, E.C., R.P. Erickson, C.M. Howison, R.J. Hunter, R.H. Heidenreich, C. Hicks, T.P. Trouard, and R.J. Gillies. 2004. Tamoxifen and vitamin E treatments delay symptoms in the mouse model of Niemann-Pick C. Journal of Applied Genetics 45: 461-467.

Gatenby, R.A., and R.J. Gillies. 2004. Why do cancers have high aerobic glycolysis? Nature Reviews. Cancer 4: 891-899.

Handl, H.L., J. Vagner, H. Han, E. Mash, V.J. Hruby, and R.J. Gillies. 2004. Hitting multiple targets with multimeric ligands. Expert Opinion on Therapeutic Targets 8: 565-586.

Baggett, B., R. Roy, S. Momen, S. Morgan, L. Tisi, D. Morse, and R.J. Gillies. 2004. Thermostability of firefly luciferases affects efficiency of detection by in vivo bioluminescence. Molecular Imaging 3: 324-332.

Theilmann, R.J., R. Borders, T.P. Trouard, G. Xia, E. Outwater, J. Ranger-Moore, R.J. Gillies, and A. Stopeck. 2004. Changes in water mobility measured by diffusion MRI predict response of metastatic breast cancer to chemotherapy. Neoplasia 6: 831-837.

Raghunand, N., B.P. Mahoney, and R.J. Gillies. 2003. Tumor acidity, ion trapping and chemotherapeutics. II. pH-dependent partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic chemotherapeutic agents. Biochemical Pharmacology 66: 1219-1229.

Mahoney, B.P., N. Raghunand, B. Baggett, and R.J. Gillies. 2003. Tumor acidity, ion trapping and chemotherapeutics. I. Acid pH affects the distribution of chemotherapeutic agents in vitro. Biochemical Pharmacology 66: 1207-1218.

Gillies, R.J., and V.J. Hruby. 2003. Expression-driven reverse engineering of targeted imaging and therapeutic agents. Expert Opinion on Therapeutic Targets 7: 137-139.

Schornack, P.A., and R.J. Gillies. 2003. Contributions of cell metabolism and H+ diffusion to the acidic pH of tumors. Neoplasia 5: 135-145.

Gillies, R.J. 2003. Noninvasive imaging of anticancer therapy. Molecular Cancer Therapeutics 2: 333-334.

Raghunand, N., C. Howison, A.D. Sherry, S. Zhang, and R.J. Gillies. 2003. Renal and systemic pH imaging by contrast-enhanced MRI. Magnetic Resonance in Medicine 49: 249-257.

Raghunand, N., R.A. Gatenby, and R.J. Gillies. 2003. Microenvironmental and cellular consequences of altered blood flow in tumours. The British Journal of Radiology 76 Suppl 1: S11-22.

Gillies, R.J. 2002. In vivo molecular imaging. Journal of Cellular Biochemistry Supplement 39: 231-238.

Gillies, R.J., N. Raghunand, G.S. Karczmar, and Z.M. Bhujwalla. 2002. MRI of the tumor microenvironment. Journal of Magnetic Resonance Imaging 16: 430-450.

Raghunand, N., S. Zhang, A.D. Sherry, and R.J. Gillies. 2002. In vivo magnetic resonance imaging of tissue pH using a novel pH-sensitive contrast agent, GdDOTA-4AmP. Academic Radiology 9 Suppl 2: S481-483.

Jennings, D., B.N. Hatton, J. Guo, J.P. Galons, T.P. Trouard, N. Raghunand, J. Marshall, R.J. Gillies. 2002. Early response of prostate carcinoma xenografts to docetaxel chemotherapy monitored with diffusion MRI. Neoplasia 4: 255-262.

Bhujwalla, Z.M., D. Artemov, P. Ballesteros, S. Cerdan, R.J. Gillies, and M. Solaiyappan. 2002. Combined vascular and extracellular pH imaging of solid tumors. NMR in Biomedicine 15: 114-119.

Contact Information

Mailing:
Robert J. Gillies, Professor
Department of Radiology
University of Arizona
Medical Research Building 110
P.O. Box 245215
Tucson, AZ 85724-0241

Telephone:
520-626-5050 (Office)
520-626-5052 (Lab)

Fax:
520-626-5051

Email:
gillies@email.arizona.edu

Please e-mail any comments to:
bmcb@email.arizona.edu