Rheal A. Towner, Ph.D.

The research in my laboratory centers on developing new ways to diagnose and predict the outcome of human diseases using non-invasive imaging and spectroscopic methods. These methods also allow us to evaluate new and existing drugs and determine optimal treatment protocols for the specific disease. In our studies, we use the techniques of magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to identify and study specific conditions of injured or diseased tissues in small animal models of disease. MRI is the newest and most advanced way to visualize structures inside the body since the invention of CT (or “CAT”) scans. Unlike CT scans, however, MRI does not involve radiation, but combines the use of a large magnet and radio waves. The hydrogen atoms in the body react to the magnetic field generated by MRI, while a computer analyzes the results and turns them into a picture. The image resolution of the picture is quite detailed and can detect very small changes in structures within tissues of the body. Our experimental approach of using MRI and MRS technology with small animal models of disease has many advantages, including the ability to investigate disease processes both in vivo, which means while the animal is alive, and in real time. Currently, we are most interested in understanding the molecular events that lead to the formation and development of cancer cells as well as the processes that cause tissue injury after the ingestion of natural toxins that can be found in contaminated food or water.

Both a fundamental and key issue in the early detection of cancer is to identify and understand characteristic molecular or metabolic events that occur in malignant cells but do not occur in normal cells. One way that we study this issue in my laboratory is to investigate specific components of metabolic reactions (metabolites), or molecular indicators, in malignant cells that are different from those in normal cells. These molecular indicators of cancerous tissues can then be used to predict and understand the development of nodules and tumors, from the initiation of a malignant cell throughout the progression of the cancer. Most recently, we are using this strategy in rodent (mice and rat) models of liver and brain cancer to investigate tumor morphology, new blood vessel formation, and fatty acid metabolism. We have discovered certain MRI techniques (MRI at 7 Tesla) that can detect tumor nodules in the liver as small as the thickness of a sheet of paper, allowing in vivo assessment of nodule/tumor development during the very first stages of formation of a cancer. The MRI techniques that we use are so sophisticated that they can even detect certain changes in metabolites inside the cells of the nodules or tumors and then correlate these changes with stages of tumor progression (also called tumor grading). One metabolic change that we have detected in cancer cells is an alteration in lipid unsaturated fatty acids. Additionally, we have found that certain enzymes involved in the metabolism or breakdown of fatty acids by cells are altered during tumor formation and thus, these findings may explain the metabolic changes that we observed by MRI. In similar studies, we use the same MRI strategies and techniques to measure metabolic changes in cells that occur after exposure to food- or water-borne toxicological agents, such as toxins produced by fungus and bacteria (mycotoxins, cyanobacteria toxins, etc.). The ability to correlate metabolic information obtained by MRI with tumor development and toxin-induced tissue injury should provide new insights into critical cell processes that are involved in malignancy and toxicity, as well as lead to a better understanding of mechanisms that occur in normal cells.

Another focus in our laboratory is on the discovery of “MRI molecular targeting agents”, or agents that selectively target or pinpoint tumor antigens on cancer cells and then allow the cancer cells to be visualized by MRI in live animals. By using in vivo MRI techniques to study tumors in the liver and brain of rodent models of cancer, we can simultaneously detect changes in tumor markers on the malignant cells, measure biochemical properties of the cancer cells, and determine the pathology of the tumor. We then correlate these molecular findings with progression of the disease. In fact, my laboratory was among the first to detect nodules/tumors in experimental animal models that express a specific receptor found in many human cancers (called c-MET), using the in vivo MRI molecular-targeting approach. These same MRI methods are also used to assess anti-cancer treatments in the animal cancer models and we have found a promising drug candidate that recedes tumor growth in an experimental model of brain cancer.

The ultimate goal of our research is to develop in vivo MRI methods that can be used in the clinic as tools for tumor grading and to predict the extent of tissue injury from toxin exposure in human patients. Having the ability to use a non-invasive technique such as in vivo MRI in both the diagnosis and therapy of cancer, among other diseases, provides great benefit to both the patient and physician.

A critical issue regarding in vivo early detection of many cancers is to define and identify characteristic molecular or metabolic events which represent malignant tumors. I utilize in vivo magnetic resonance (MR) technology, in particular MRI and image-guided MR spectroscopy (MRS), to detect nodules and/or tumors in liver and brain cancer models and simultaneously determine the pathology and biochemical properties of the lesions which reflect disease progression.

My research is focused on the investigation of in vivo tissue metabolic indicators that can be used to predict and understand nodule and tumor development from initiation through to progression. We have found that MRI at 7 Tesla can detect hepatic nodules/tumors >100 mm in diameter, allowing in vivo assessment of nodule/tumor development during carcinogenesis. In addition, MRS can detect nodule and tumor-specific metabolic events, such as alterations in lipid unsaturated fatty acids and correlate these metabolic changes with tumor grading. We have also found that fatty acid desaturase enzymes, stearoyl-CoA desaturase 1 (Scd1) and fatty acid desaturase (FADS or 6-desaturase) are found to be altered during tumor formation which may reflect alterations in lipid metabolism that we detect with in vivoMRS. Currently we are investigating in vivo tumor morphology and angiogenesis, using MRI and MR angiography, respectively, and fatty acid metabolism using image-guided MRS, in a transgenic mouse (TGF-/c-myc) hepatocarcinogenesis model and rat glioma models.

A related area of research that we have commenced in my laboratory is to design MRI-detectable molecular targeting agents to visualize nodule and tumor antigens in vivo. We are the first to detect nodules/tumors in experimental models that express c-MET, a tyrosine kinase receptor found in many human cancers, using the in vivo MRI molecular-targeting approach. The aim is to be able to use MRS and molecular-targeted MRI as clinical diagnostic tools for in vivo tumor grading. We are also using MR methods to assess anti-cancer drugs in experimental animal cancer models.

Other areas of interest in my laboratory include studies regarding oxidative stress mechanisms associated with carcinogens, such as aflatoxin. We were the first to detect and characterize hydroxyl and arachidonyl radicals from the in vivo metabolism of aflatoxin in mammals.

Education
B.Sc., University of Guelph, Ontario, Canada, 1982
M.Sc., University of Guelph, Ontario, Canada, 1985
Ph.D., University of Guelph, Ontario, Canada, 1989

Memberships
International Society of Magnetic Resonance in Medicine
International Society of Magnetic Resonance
The Australian and New Zealand Society for Magnetic Resonance
The International Society for EPR (ESR) Spectroscopy
The Society for Free Radical Research
Society for Free Radical Biology and Medicine
American Association for Cancer Research
Oklahoma Center for Neurosciences

Joined OMRF Scientific Staff in 2002.

Recent Publications

Ziegler J, Bastian A, Lerner M, Bailey-Downs L, Saunders D, Smith N, Sutton J, Battiste JD, Ihnat MA, Gangjee A, Towner RA. AG488 as a therapy against gliomas.  Oncotarget. 2017 May 30. . [Epub ahead of print] PMID: 28621261

*Ziegler J, Pody R, Coutinho de Souza P, Evans B, Saunders D, Smith N, Mallory S, Njoku C, Dong Y, Chen H, Dong J, Lerner M, Mian O, Tummala S, Battiste J, Fung KM, Wren JD, Towner RA. ELTD1, an effective anti-angiogenic target for gliomas: preclinical assessment in mouse GL261 and human G55 xenograft glioma models. Neuro Oncol. 2016 Jul 14. pii: now147. [Epub ahead of print] [Abstract]

Madka V, Mohammed A, Li Q, Zhang Y, Biddick L, Patlolla JM, Lightfoot S, Towner RA, Wu XR, Steele VE, Kopelovich L, Rao CV. Targeting mTOR and p53 Signaling Inhibits Muscle Invasive Bladder Cancer In Vivo. Cancer Prev Res (Phila). 2016 Jan;9(1):53-62. Epub 2015 Nov 17.  [Abstract]

Selected Publications

Coutinho de Souza P, Mallory S, Smith N, Saunders D, Li XN, McNall-Knapp RY, Fung KM, Towner RA. Inhibition of Pediatric Glioblastoma Tumor Growth by the Anti-Cancer Agent OKN-007 in Orthotopic Mouse Xenografts. PLoS One. 2015 Aug 6;10(8):e0134276. eCollection 2015. [Abstract] PMCID: PMC4527837

*Dong Y, Wu H, Rahman HN, Liu Y, Pasula S, Tessneer KL, Cai X, Liu X, Chang B, McManus J, Hahn S, Dong J, Brophy ML, Yu L, Song K, Silasi-Mansat R, Saunders D, Njoku C, Song H, Mehta-D’Souza P, Towner R, Lupu F, McEver RP, Xia L, Boerboom D, Srinivasan RS, Chen H. Motif mimetic of epsin perturbs tumor growth and metastasis. J Clin Invest. 2016 Mar 21. pii: 87344. [Abstract] [Epub ahead of print]  PMID: 26999611

Rajagopalan V, Zhang Y, Ojamaa K, Chen YF, Pingitore A, Pol CJ, Saunders D, Balasubramanian K, Towner RA, Gerdes AM. Safe Oral Triiodo-L-Thyronine Therapy Protects from Post-Infarct Cardiac Dysfunction and Arrhythmias without Cardiovascular Adverse Effects. PLoS One. 2016 Mar 16;11(3):e0151413.  eCollection 2016. [Abstract]  PMID: 26981865

Tarantini S, Hertelendy P, Tucsek Z, Valcarcel-Ares MN, Smith N, Menyhart A, Farkas E, Hodges EL, Towner R, Deak F, Sonntag WE, Csiszar A, Ungvari Z, Toth P. Pharmacologically-induced neurovascular uncoupling is associated with cognitive impairment in mice. J Cereb Blood Flow Metab. 2015 Nov;35(11):1871-81. Epub 2015 Jul 15. [Abstract] PMCID: PMC4635246

* He T, Smith N, Saunders D, Pittman BP, Lerner M, Lightfoot S, Silasi-Mansat R, Lupu F, Towner RA. Molecular MRI differentiation of VEGF receptor-2 levels in C6 and RG2 glioma models. Am J Nucl Med Mol Imaging 3:300-311, 2013. [Abstract]

* Towner RA, Garteiser P, Bozza F, Smith N, Saunders D, d'Avila JC, Magno F, Oliveira MF, Ehrenshaft M, Lupu F, Silasi-Mansat R, Ramirez DC, Gomez-Mejiba SE, Mason RP, Faria-Neto HC. In Vivo Detection of Free Radicals in Mouse Septic Encephalopathy using Molecular MRI and Immuno-Spin-Trapping. Free Radic Biol Med 65C:828-837, 2013. [Abstract]

Advanced Magnetic Resonance Center, MS 60
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, OK 73104

Phone: (405) 271-7383
Fax: (405) 271-3980
E-mail: Rheal-Towner@omrf.org

Nataliya Smith, Ph.D.
Associate Staff Scientist

Debra Saunders
Senior Research Assistant