Virginia Commonwealth University

VCU Massey Cancer Center

Molecular radiobiology and targeted imaging faculty

John C. Ford
Geoffrey Hugo
Ross B. Mikkelsen
Martin J. Murphy
Ford Sleeman
Kristoffer Valerie
Vasily A. Yakovlev

John Chetley Ford, Ph.D., M.B.A
Assistant professor
(804) 828-7418

Ford joined the Department of Radiation Oncology in 2009. He received his Ph.D. in physics at the University of Connecticut, studying nuclear magnetic resonance of metallic glasses. Following graduation, he was an NIH post-doctoral fellow at the University of Pennsylvania before joining the faculty as an assistant professor of radiology. He also performed research in MRI and served as technical director of the Animal MR facility. He subsequently spent a decade in industry designing and developing scientific and medical instrumentation and software, and held positions as senior scientist at Radiation Monitoring Devices in Watertown, MA, and chief science officer at MicroMRI in Philadelphia, PA. He has served as MR physicist at University of Massachusetts and at the VA Medical Center in Philadelphia. Ford's current research interest is utilization of MR image guidance to provide focal radiation therapy that maximizes tumor control while minimizing radiation to normal organs.

Representative publications:

DeLeo, M.J., Gounis, M.J., Hong, B., Ford, J.C., Wakhloo, A.K., Bogdanov, A.A. (2009). Carotid artery brain aneurism model: in vivo molecular enzyme-specific MR imaging of active inflammation in a pilot study. Radiology, 252(3):696-703.

Ford, J.C., Zheng, D., Williamson, J.F. (2011). Estimation of CT cone-beam geometry using a novel method insensitive to phantom fabrication inaccuracy: implications for isocenter localization accuracy. Med Phys., 38(6):2829-40.

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Geoffrey Hugo, Ph.D.
Assistant professor
(804) 628-3457

Hugo joined the Department of Radiation Oncology in 2008 as an assistant professor. He received his Ph.D. in biomedical physics from the University of California, Los Angeles. After obtaining his degree, he joined the staff of William Beaumont Hospital where he participated in the clinical implementation of cone beam CT and was actively involved in developing an adaptive radiotherapy program for lung cancer. At VCU, Hugo is also the director of the medical physics graduate program. His current research interests include respiration and motion management, image-guided adaptive radiotherapy for lung cancer and improving dynamic techniques to image moving anatomy.

Representative publications:

Balik, S., Weiss, E., Jan, N., Sleeman, W.C., Fatygo, M., Christensen, G.E., Zhang, C., Murphy, M.J., Lu, J., Keall, P., Williamson, J.F., Hugo, J.D. (2013). Evaluation of 4-dimensional computed tomography to 4-dimensional cone-beam computed tomography deformable image registration for lung cancer adaptive radiation therapy. International Journal of Radiation Oncology*Biology*Physics, 86, 372-379.

Robertson, S., Weiss, E., Hugo, G.D. (2013). Deformable mesh registration for the validation of automatic target localization algorithms. Medical Physics, 40, 701-721.

Weiss, E., Fatygo, M., Wu, Y., Dogan, N., Balik, S., Sleeman, W.C., Hugo, G.D. (2013). Dose escalation for locally advanced lung cancer using adaptive radiation therapy with simultaneous integrated volume adapted boost. International Journal of Radiation Oncology*Biology*Physics, 86, 414-419.

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Ross B. Mikkelsen, Ph.D.
Professor, division chair, vice-chair for research
(804) 628-0857

Mikkelsen joined the Department of Radiation Oncology in 1988. He received his Ph.D. from the University of California, Santa Barbara. After obtaining his degree, he held a Damon Runyon post-doctoral fellowship at Tufts University School of Medicine with Dr. Donald F.H. Wallach and then continued at Tufts as a faculty member. His research investigates mechanisms of how cells sense cytoplasmic ionization events and either activate or inhibit survival mechanisms. These studies demonstrate that when activated by radiation or other oxidative stress, like chronic inflammation, nitric oxide synthases (NOS) generate not only NO but other reactive nitrogen/oxygen species (RNS/ROS) that can selectively nitrate critical signaling proteins, such as p53, lkBα, PKCɛ and PP2A, resulting in changes in their activities and expression levels. Radiation-induced RNS/ROS also provides a mechanism for the observation that ionizing radiation activates autocrine regulated receptor tyrosine kinase activities by oxidizing the active site Cys of protein tyrosine phosphatases, thereby inhibiting phosphatase activity and enhancing protein tyrosine phosphorylation. In a similar way, the inflammatory microenvironment of tumors or in normal tissues under chronic inflammatory stress conditions (e.g. diabetic patients, inflammatory bowel disease) maintain the autoregulatory mechanisms of receptor tyrosine kinase pathways by shifting the balance of kinase/phosphatase activities. These studies investigate the role of NOS "uncoupling" due to reduced tetrahydrobiopterin levels in chronic inflammatory tissues as a switching mechanism from coupled pro-apoptotic to uncoupled anti-apoptotic signaling promoting carcinogensis and tumor progression in a chronic inflammatory environment and how recruitment of inflammatory cells to the sites of radiation-induced injury by enhancing NOS uncoupling promotes radioresistance. A small animal irradiator with CT (SARRP) is used for conformal treatment, an important experimental factor in studies on normal tissue injury and the inflammatory response of tumors and normal tissues to radiation.

Representative publications:

Bayden, A.S., Yakovlev, V.A., Graves, P.R., Mikkelsen, R.B., Kellogg, G.E. (2011). Factors influencing protein tyrosine nitration-structure based predictive models. Free Radical Biol. Med, 50(6), 749-762.

Cardnell, R.G., Mikkelsen, R.B. (2011). Nitric Oxide Synthase Inhibition Enhances the Antitumor Effect of Radiation in the Treatment of Squamous Carcinoma Xenografts. Plos ONE, 6(5), 1-9.

Cardnell, R.G., Rabender, C.S., Ross, G.R., Guo, C., Howlett, E.L., Alam, A., et al. (2013). Sepiapterin ameliorates chemically-induced murine colitis and azoxymethane-induced colon cancer. Journal of Pharmacology and Experimental Therapeutics. doi:10.1124/jpet.113.203828

Guo, C., Yi, H., Yu, X., Zuo, D., Qian, J., Yang, G., et al. (2012). In situ vaccination with CD204 gene-silenced dendritic cell, enhances radiation therapy of prostate cancer. Molecular Cancer Therapeutics, 11(11), 2331-2341.

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Martin J. Murphy, Ph.D.
(804) 628-7777

Murphy joined the Department of Radiation Oncology in 2003. He received his Ph.D. in physics from the University of Chicago. Subsequently, he held research posts in nuclear physics, astrophysics, X-Ray and gamma-ray astronomy at University of California, Berkley's Lawrence Radiation Laboratory, the University of Washington and the Lockheed Space Sciences Laboratory in Palo Alto, California. In 1992, Murphy became involved in research and development for the CyberKnife, a robotic image-guided radiosurgical system invented at Stanford University to treat cancer and central nervous system lesions. He was also a senior research scientist at Stanford. His research interests are in image fusion, computer-guided medical image segmentation, real-time image processing and registration and machine vision applied to radiotherapy. The goal of his research is to develop fast, automatic image-guided procedures for the planning and delivery of radiation treatments via both external beams and brachytherapy.

Representative publications:

Balik, S., Weiss, E., Jan, N., Roman, N., Sleeman, W.C., Fatyga, M., Christensen, G.E., Zhang, C., Murphy, M.J., Lu, J., Keall, P., Williamson, J.F., Hugo, G.D. (2013). Evaluation of 4-dimensional computed tomography to 4-dimensional cone-beam computed tomogrpahy deformable image registration for lung cancer adaptive radiation therapy. International Journal of Radiation Oncology*Biology*Physics, 86, 372-379.

Murphy, M.J., Salguero, F.J., Siebers, J.V., Staub, D., Vaman, C. (20120. A method to estimate the effect of deformable image registration uncertainties on daily dose mapping. Medical Physics, 39(2): 573-80.

Staub, D., Murphy, M.J. (2013). A digitally reconstructed radiograph algorithm calculated from first principles. Medical Physics, 40(1): 011902. doi: 10.1118/1.4769413.

Staub, D., Docef, A., Brock, R.S., Vaman, C., Murphy, M.J. (20110. 4D Cone-beam CT reconstruction using a motion model based on principal component analysis. Medical Physics, 38(12): 6697-709.

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Ford Sleeman, M.S.
Scientific programmer
(804) 628-7778

Sleeman joined the Department of Radiation Oncology in 2007, after receiving his M.S. in computer engineering from Virginia Commonwealth University that same year. He also worked for SENTEL Corporation, an engineering services company headquartered in Alexandria, VA. As a software engineer at SENTEL, Sleeman wrote software to integrate sensors into physical security systems for government facilities. His research interests include control systems, parallel computing, embedded systems and signal processing.

Representative publications:

Badawi, A.M., Weiss, E., Sleeman, W.C., Hugo, G.D. (2012). Classifying geometric variability by dominant eigenmodes of deformation in regressing tumors during active breath-hold lung cancer radiotherapy. Phys Med Biol. 21;57(2): 395-413.

Balik, S., Weiss, E., Jan, N., Roman, N., Sleeman, W.C., Fatyga, M., Christensen, G.E., Zhang, C., Murphy, M.J., Lu, J., Keall, P., Williamson, J.F., Hugo, G.D. (2013). Evaluation of 4-dimensional computed tomography to 4-dimensional cone-beam computed tomography deformable image registration for lung cancer adaptive radiation therapy. International Journal of Radiation Oncology*Biology*Physics, 86, 372-379.

Weiss, E., Fatyga, M., Wu, Y., Dogan, N., Balik, S., Sleeman, W.C., et al. (2013). Dose escalation for locally advanced lung cancer using adaptive radiation therapy with simultaneous integrated volume-adapted boost. International Jounral of Radiation Oncology*Biology*Physics, 86(3), 414-419.

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Kristoffer Valerie, Ph.D.
(804) 628-1004

Valerie joined the Department of Radiation Oncology in 1989. He received his doctoral degree in biochemistry from the Royal Institute of Technology in Stockholm, Sweden. His thesis studies focused on the cloning and characterization of a small DNA repair gene from bacteriophage T4. His post-doctoral training with Martin Rosenberg at Smith Kline and French Laboratories was studying transcriptional regulation of the human immunodeficiency virus and stress-activated gene expression.

Valerie's laboratory focuses on DNA double-strand break (DSB) repair, radiation-induced signaling and developing novel approaches for sensitizing tumor cells to radiation. A major thrust is on investigating the role of ataxia telangiectasia mutated (ATM) in regulating DSB repair. ATM is a member of the phosphatidylinositol-3'-kinase-like kinase (PIKK) family of serine-threonine protein kinases. The PIKKs are important for regulating cellular homeostasis and the coordination of cell growth, senescence and DNA damage responses. ATM is critical for controlling the G1/S, intra-S and G2/M checkpoints and is also believed to play an important role in the repair of certain hard-to-repair radiation-induced DNA damage lesions. His lab recently demonstrated that ATM is important for efficient homologous recombination repair (HRR) in human cells. HRR is an essential error-free by minor type of DSB repair, whereas non-homologous end-joining (NHEJ) is the predominant type of DSB repair in human cells. NHEJ is considered more error-prone than HRR. Findings from the laboratory have shown that all three of the major signaling pathways - ERK, JNK and p38 - modulate HRR. The ERK pathway associated with pro-survival and cellular growth forms a regulatory feedback loop with ATM. MEK/ERK signaling appears to regulate the ATM kinase activity and vice versa, suggesting a close coordination between growth, DNA repair and survival of irradiated cells.

The tumor suppressor BRCA1 is associated with both HRR and NHEJ. BRCA1 appears to play a role in modulating the fidelity of DSB repair. The role of phosphorylation of BRCA1 in DSB repair using DSB repair assays based on the I-Scel restrition enzyme system is currently being investigated. Valerie and his research team have also developed technology that replaces wlid-type BRCA1 with mutant forms by using inducible RNAi approaches. Preliminary results suggest that one of the major ATM BRCA1 phosphorylation sites, serine-1387, appears to regulate cytoplasmic-nuclear localization of BRCA1 that affects radioresistance and HRR. The effect of BRCA1 phosphorylation and other post-translational modifications on high-fidelity NHEJ are also being investigated. These studies are extended into identifying novel BRCA1-interacting proteins by mass spectrometry and radiation-induced post-translational modifications of BRCA1. BRCA1 mutants have been constructed that fail to bind phospho-proteins to the carboxy-terminal BRCT domains. These mutants are expected to be impaired in binding DNA repair accessory proteins important for DSB repair.

Many of Valerie's DSB repair studies focus on mechanisms occuring in brain cancer. Recent studies from other laboratories suggest that glioma stem cells have potent DNA damage checkpoints and DSB repair, accounting for the unusual radioresistance of GBM. The long-term goal of his laboratory is to identify novel molecular targets in the DSB repair-signaling circuitry that could be used in combination with radiation to improve cancer therapy. Recently, his team has shown that small molecule inhibition of ATM kinase preferentially sensitizes p53-mutant gliomas to radiation.

Representative publications:

Beckta, J.M., Henderson, S.C., Valerie, K. (2012). Two and three dimensional live cell imaging of DNA response proteins. Journal of Visualized Experiments, 28(67).

Biddlestone-Thorpe, L., Sajjad, M., Rosenberg, E., Beckta, J.M., Valerie, K., Tokarz, M., et al. (2013). ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation. Clinical Cancer Research, 19(12): 3189-3200.

Denver, S.M., White, E.R., Hartman, M.C., Valerie, K. (2012). BRCA1-directed enhanced and aberrant homologous recombination: mechanism and potential treatment strategies. Cell Cycle, 11(4): 687-94.

Golding, S.E., Rosenberg, E., Adams, B.R., Wignarajah, S., Beckta, J.M., O'Connor, M.J., Valerie, K. (2012). Dynamic inhibition of ATM kinase provides a strategy for glioblastoma multiforme radiosensitization and growth control. Cell Cycle, 11(6): 1167-73.

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Vasily A. Yakovlev, MD, Ph.D.
Assistant professor
(804) 828-7751

Yakovlev joined the Department of Radiation Oncology in 2003 for post-doctoral training. He graduated from the Russian State Medical University and completed post-graduate training in the Department of Combined Methods of Treatment and Laboratory of Experimental Diagnostic and Biotherapy of Tumors in the All-Russian Cancer Research Center. His thesis work was on molecular tumor markers as the factors of prognosis in the treatment of colorectal cancer. After joining VCU for training with Ross Mikkelsen, his research focused on the modulation of activity of transcription factors NF-κB and p53 by chronic inflammatory levels of reactive nitrogen species (RNS). These studies have directed his research into defining the role of the increased level of RNS in the regulation of genetic and chromosomal instability during chronic inflammation. His recent work has focused on chronic inflammation and the regulation of DNA repair genes, such as BRCA1.

Representative publications:

Bayden, A.S., Yakovlev, V.,A., Graves, P.R., Mikkelsen, R.B., Kellog, G.E. (20110. Factors influencing protein tyrosine nitration-- structure-based predictive models. Free Radical Biology and Medicine, 50(6): 749-762.

Yakovlev, V.A. (2013). Nitric oxide-dependent downregulation of BRCA1 expression promotes genetic insability. Cancer Research, 73(2): 706-715.

Yakovlev, V.A., Mikkelsen, R.B. (2010). Protein tyrosine nitration in cellular signal transduction pathways. Journal of Receptors and Signal Transduction, 30(6): 420-429.

Yakovlev, V.A., Rabender, C.S., Sankala, H., Gauter-Fleckenstien, B., Fleckenstein, K., Batinic-Haberle, I., Jackson, I., Vujaskovic, Z., Anscher, M.S., Mikkelsen, R.B., and Graves, P.R. (2010). Proteomic analysis of radiation-induced changes in rat lung: modulation by the superoxide dismutase mimetic MnTE-2-PyP5+. International Journal of Radiation Oncology*Biology*Physics, 78(2): 547-554.

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