UAMS.EDU

Robert J. Griffin, Ph.D.

Associate Professor

Director of Radiation Biology Division

 

Phone: (501) 526 7873

Fax: (501) 526 5934

E-mail: RJGriffin@uams.edu

 

Dr. Robert Griffin is an emerging leader in both established and developing in vivo and in vitro methods to study blood flow response, tissue oxygenation and cancer growth and metastasis in response to experimental therapeutics. In addition he has performed significant investigations on the biology of tumor and endothelial cells and the vascular response of cells and tissues to thermal and radiation therapy. The richness of his experience in tumor flow studies has been valuable in numerous studies in his lab and other collaborators laboratories related to tumor vascularity. Dr. Griffin’s expertise in blood flow and tumor physiology/tumor microenvironment is in the forefront of cancer biology with regard to drug delivery, cancer progression as well as resistance. These in vivo techniques are extremely difficult, but are in demand because of their direct functional predictability. Therefore, Dr. Griffin’s research and expertise is extremely helpful and in demand from numerous investigators at our institution and other institutions around the country and the world. He has led research projects and taught both graduate students and medical residents for over ten years in the field of radiation oncology/radiation biology and most recently has made strides to improve thermal and radiation therapy of solid tumors with both novel anti-angiogenic compounds and nanotherapeutics.

 

Research Interests and goals in the Radiation Biology Division

The biology of the tumor vascular network is the major research interest in the radiation biology laboratory as we study novel approaches to solid tumor therapy.  Importantly, we now know that the physical and abscopal influences  of one cell type on  another is an important but vastly underexplored aspect of tumor biology and may hold clues to translating the most effective treatments to the patient.  Two areas of investigation in our lab are using our understanding of cancer vascular biology to discover and develop improved methods for cancer treatment.  Our models are 2-D and 3-D tissue culture, cell and molecular biology in vitro studies, and in vivo study of rodent and large animal cancer.  In the animal, we study in detail changes in physiological and other markers using minimally invasive probes and immunohistochemistry to quantify and image the effects of therapy against experimental tumor systems and normal tissue.  The goals are to establish new knowledge that can be directly translated into the design of clinical trials for these, or similar, approaches.   A major future objective is to be in a position to significantly and positively contribute to translational research and clinical practice in an academic medicine setting.  As described below, the two main areas of research focus in our laboratory have significant and realistic potential to be translated into clinical practice.

First, we have a strong interest in anti-angiogenic or anti-vascular treatment strategies and the relationship of these agents to the success of other cancer treatments.   Complementary therapeutic strategies are required to destroy solid tumors and inhibit regrowth of metastatic or residual primary tumor. In theory, the combination of radiation therapy and anti-angiogenesis therapy meet these requirements. We are working on characterizing a novel anti-angiogenic peptide, anginex, against solid tumors. We have found that anginex has potent anti-angiogenic effects, preferentially binds to and radiosensitizes tumor endothelium, extends radiation-induced tumor growth delay and acts synergistically in combination with radiotherapy against murine and human xenografted tumors with no side effects.   One of the long-term research goals is to discover and develop strategies based on the tumor microenvironment to enhance the anti-tumor effect of radiation. This goal can be partially met by characterizing anginex-induced enhancement of radiation response in murine and human tumor models. We have recently developed a system to study the interaction of stromal cells and tumor cells in a 3-D culture environment and the role of this interaction on sensitivity of each cell  type to therapy.  The receptor  for the anginex peptide is galectin-1, a protein that is expressed in the membrane of cells as well as secreted into the tumor stroma and therefore is an extremely useful system to understand more about the stromal contribution to anti-tumor therapies.  In addition to our RO1 funded work that has been focused on anginex, we have also done a significant amount of work characterizing the FDA approved leukemia agent Arsenic Trioxide as an anti-vascular agent alone and in combination with radiotherapy and/or thermal therapy against solid tumor models and are currently focusing on delivery of arsenic to models of multiple myeloma.

The application of heat (hyperthermia) as a cancer primary or adjuvant treatment continues to prove itself as a clinically viable and successful modality.  The number of positive clinical trial outcomes has steadily accumulated over the last two decades.  There is also a growing list of improved technology platforms for delivery of higher temperature ablative procedures with minimal to low invasiveness.  With increasing uses of various heating devices and strategies comes an increasing gap in knowledge pertaining to the biology and physiology associated with wide-ranging thermal dose patterns depending on the type of heating applied.  A further gap in knowledge exists in our limited abilities to intelligently use radiation therapy or other adjuvants such as anti-vascular compounds to maximize the anti-tumor effects thermal therapies (combined, multi-modality regimens). We have identified this missing knowledge as a largely unmet opportunity to advance the field of thermal therapy and significantly enhance cancer treatment options and this is the second major focus of the radiation biology program in our department. The central hypotheses of this area of investigation is that the reoxygenation pattern of sublethally heated tumor can be exploited to improve subsequent radiation therapy and that heat-induced tumor destruction can be significantly improved and controlled with novel anti-vascular agents (arsenic trioxide and cytokine-coated gold nanoparticles) at low and high thermal doses.  Detailed biological and physiological investigation of these approaches will empower clinical multi-modality therapy.  Our current goals are to support the educated clinical implementation of thermal therapy alone and in combination with radiotherapy by identifying the vascular response and reoxygenation patterns in tumor and normal tissues to varying time/temperature histories in combination with novel anti-vascular drugs.

Publications: Last 5 years

  1.    Asur RS, Sharma SS, Chang CW, Penagaricano J, Kommuru IM, Moros EG, Corry PM, Griffin RJ:  Spatially fractionated radiation induces cytotoxicity and changes in gene expression in bystander and radiation adjacent murine carcinoma cells.  In press, Radiation Res, 2012.

 2.    Griffin, RJ, Koonce NA, Dings RPM, Siegel E, Moros EG, Bräuer-Krisch E, Corry PM:  Microbeam radiation therapy alters microvascular architecture and tumor oxygenation and is enhanced by a galectin-1 targeted anti-angiogenic peptide.  In press, Radiation Res, 2012.

  3.  Park H-J, Griffin RJ, Hui S, Song CW:  Radiation-induced vascular damage in tumors: implications of vascular damage in ablative hypo-fractionated radiotherapy (SBRT and SRS). Radiation Res, 177: 311-327, 2012.

 4.   Przybyla B, Shafirstein G, Koonce NA, Webber JS, Griffin RJ:  Conductive thermal ablation of 4T1 murine breast carcinoma reduces severe hypoxia in surviving tumor.  Int J Hyperthermia, 28(2): 156-162, 2012.

 5.    Griffin RJ, Williams BW, Koonce NA, Bischof JC, Song CW, Srinath R, Upreti M:  Vascular disrupting agent arsenic trioxide enhances thermoradiotherapy of solid tumors.  Journal of Oncology, vol. 2012, Article ID 934918, 2012.

 6.    Upreti M, Jamshidi-Parsian A, Koonce NA, Webber JS, Sharma SK, Asea AA, Mader MJ, Griffin RJ:  Tumor-endothelial cell 3D spheroids: New aspects to enhance radiation and drug therapeutics.  Translational Oncology, 4(6):365-76, 2011.

 7.  Apana SM, Griffin RJ,  Koonce NA, Webber JS, Dings RPM, Mayo KH, Berridge MS:  Synthesis of [18F]anginex with high specific activity [18F]fluorobenzaldehyde for targeting angiogenic activity in solid tumors.  J.  Label.  Compd.  Radiopharm. 54 (11), 708-713 (2011). 

 8.    Chen D, Xia R, Chen X, Shafirstein G, Griffin RJ, Corry P, Moros EG:  SonoKnife: Feasibility of a Line-Focused Ultrasound Device for Thermal Ablation Therapy.  Med Phys. Jul;38(7):4372-85, 2011.

 9.  Shafirstein G, Baumler W, Hennings L, Siegel E, Friedman R, Moreno MA, Webber JS, Jackson C, Griffin RJ:  Indocyanine Green Enhanced Near Infrared Laser Treatment of SCK Tumors in a Mouse Model. Int J Cancer, 130(5):1208-15, 2011.

 10.  Bischof JC, Griffin RJ et al.  Nanoparticle Pre-Conditioning for Enhanced Thermal Therapies in Cancer; Nanomedicine, 6(3):545-63, 2011.

 11.   Chen X, Moros E, Corry P, Webber JS, Griffin RJ:   An Alternating Focused Ultrasound System for Thermal Therapy Studies Using Small Animals.  Med Phys Apr;38(4):1877-87, 2011.

 12.  Suva LJ, Washam C, Nicholas R, and Griffin RJ:  Bone Metastasis: Mechanisms and Therapeutic Opportunities. Nature Reviews Endocrinology, 7(4):208-18, 2011.

13.  Dings RPMD, Loren M, Mikkelson S, Corry PM, Griffin RJ:  Tumor thermotolerance, a physiological phenomenon involving vessel normalization. Int J Hyperthermia, 27(1):42-52, 2011.

 14.   Upreti M, Koonce NA, Hennings L, Chambers T, Griffin RJ:  IRF-1 mediates melanoma sensitivity to chemotherapy and induces senescence in endothelial cells.   Cell Death and Disease, (8):e67 2010.

 15.  de Jong EP,  Xie H, Onsongo G, , Stone MD, Chen X-B, Griffin RJ, Ondrey FG, Rhodus NL, Carlis JV, Griffin TJ et al.  Quantitative proteomics reveals myosin and actin as promising saliva biomarkers for distinguishing pre-malignant and malignant oral lesions, Plos One, June 2010, 5(6): 1-8.

 16.  Griffin, RJ, Dings RPM, Parsian AJ, Song CW:  Mild temperature hyperthermia and radiation therapy:  role of tumor vascular thermotolerance and relevant physiological factors.   Int J Hyperthermia 26(3):256-63, 2010.

 17.  Jia D, Koonce NA, Halakatti R, Jackson C, Li X, Yaccoby S, Swain F, Suva L, Hennings L, Berridge MS, Apana SM, Mayo KH, Corry PM, Griffin RJ:   Repression of Multiple Myeloma Growth and Relapse with Combined Radiotherapy and Anti-angiogenic Agent.  Radiation Research 173(6):809-17, 2010.

 18.   Jia D, Koonce NA, Griffin RJ, Jackson C, Corry PM:  Protection and Rescue of Mice from Abdominal Irradiation (AI)-induced Acute Death by antioxidant N-acetyl-cysteine (NAC).  Radiation Research, 173(5):579-89, 2010.

 19.   Miller MW, Riedel G, Hoistad D, Sutherland C, Juhn SK, Adams GL, Griffin R, Ondrey FG.  Ototoxicity after combined platinum and fractionated radiation in a novel guinea pig model.   Am J Otolaryngol. Jan-Feb;30(1): 1-7, 2009.

 20.   Shafirstein G, Kaufman Y, Hennings L, Siegel E, Griffin RJ, Novák P, Ferguson S, Moros EG:  Conductive Interstitial Thermal Therapy (CITT) inhibits recurrence and metastasis in rabbit VX2 carcinoma model.  Int J Hyperthermia 25(6):  446-454, 2009.

 21.   Suva L, Griffin RJ, Makhoul I:  Review:  Breast cancer and bone metastasis. Endocrinology reviews 16: 703-713, 2009.

22.  Novák P, Parsian AJ, Benson DG, Webber JS, Moros EG, Shafirstein G, Griffin RJ:   Multi-angle switched HIFU:  A new ultrasound device for controlled non-invasive induction of small spherical ablation zones- simulation and ex vivo results.  8th International Symposium on Therapeutic Ultrasound, ES Ebbini, ed., American Institute of Physics, 387-391, 2009.

23.   Griffin RJ and Corry PM:  Hyperthermia Classic Paper:  Tumour oxygenation is increased by hyperthermia at mild temperatures. Int J Hyperthermia 25(2):96-98, 2009.

24.   McTavish H, Griffin RJ, Terai K, Dudek AZ:  Novel insulin-like growth factor-methotrexate covalent conjugate inhibits tumor growth in vivo at lower dosage than methotrexate alone.  Translational Research 153(6):275-82, 2009.

 25.  Peñagarícano J, Griffin R, Corry P, Moros E, Yan Y, Ratanatharathorn V. Spatially fractionated (GRID) Therapy for large and bulky tumors. Journal of the Arkansas Medical Society 2009; 105(11): 263-265.

26. Hennings L, Corry P, Griffin RJ, Shafirstein et al.:  Dead or Alive?  Autofluorescence Distinguishes Heat-fixed from Viable Cells.  Int J Hyperthermia, 25(5): 355-363, 2009.

27.  Dings RPM, Van Laar ES, Webber J, Griffin RJ, Waters SJ, MacDonald JR, Mayo KH:  Ovarian tumor growth regression using a combination of vascular targeting agents anginex or topomimetic 0118 and the chemotherapeutic irofulven.  Cancer Letters, Jul 8;265(2):270-80, 2008.

28.   Lee BW, Olin MR, Johnson GL, Griffin RJ:  In vitro and in vivo apoptosis detection using membrane permeant, fluorescent labeled inhibitors of caspases.  Methods Mol Biol,  414:109-35, 2008.

29.   Xie H, Onsongo G, Popko J, Carlis JV, Griffin RJ, Rhodus NL, Griffin TJ:  Proteomic analysis of cells in whole saliva from oral cancer patients via value-added three-dimensional peptide fractionation and tandem mass spectrometry.  Molecular and Cellular Proteomics, Mar;7(3):486-98, 2008.

30.   Griffin RJ, Williams BW, Bischof JC, Olin M, Johnson GL, Lee BW:  Use of a Fluorescently Labeled Poly-Caspase Inhibitor for in vivo Detection of Apoptosis Related to Vascular-Targeting Agent Arsenic Trioxide for Cancer Therapy.  Technology in Cancer Research and Treatment, Dec. 2007 6(6):  2007.

31.   Farooqui M, Li Y-F, Rogers T, Poonawala T Griffin RJ, Song CW, Gupta K:  Cox-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumor growth, metastasis and mortality, without compromising analgesia.  British J Cancer 97(11):1523-31, 2007.

32.   Visaria RK, Bischof JC, Williams BW, Ebbini ES, Griffin RJ:  Nanotherapeutics for thermal therapy enhancement. International Journal of Hyperthermia 23(6):  501-511, 2007.

33.   Dudek  AZ,  Bodempudi V, Griffin RJ, Brandon Welsh et al.:  Systemic inhibition of tumor angiogenesis by endothelial cell-based gene therapy.  British J Cancer, 97(4):513-22, 2007.

 34.   Choi EK, Terai K, Ji IM, Kook, YH, Park KH, Oh ET, Griffin RJ, Park HJ et al.:  Radiation-induced up-regulation of NAD(P)H:Quinone Oxidoreductase (NQO1) potentiates the effect of bioreductive β-lapachone against cancer cells. Neoplasia, 9(8):  634-642, 2007.

 35.   Dings RPMD, Heun H, Griffioen AW, Mayo KM, Griffin RJ:  Scheduling of radiation with angiogenesis inhibitors Avastin and Anginex improves therapeutic outcome via vessel normalization.  13(11):3395-402, Clin Cancer Res, 2007.

 36.   Amano M, Suzuki M, Andoh S,  Monzen H, Terai K, Williams BW, Song CW, Mayo KM, Hasegawa T, Dings RPM,  Griffin RJ:  Anti-angiogenesis therapy using  a novel angiogenesis inhibitor, anginex, following radiation causes tumor growth delay.  Int J Clin Oncology, 12: 42-47, 2007.

 37.   Arerangaiah R, Chalasani N, Udager AM, Manivel JC, Griffin RJ, Song CW, Gupta K:  Opioids Induce Renal Abnormalities in Tumor Bearing Mice.  Nephron Exp Nephrol., 105(3): 80-9, 2007.