Douglas Thamm

Biography of Investigator:
Dr. Thamm is an Associate Professor of Oncology at the Colorado State University Animal Cancer Center, within the College of Veterinary Medicine and Biomedical Sciences. He is also a member of the Developmental Therapeutics Program of the University of Colorado Comprehensive Cancer Center and the Cell and Molecular Biology Graduate Program at Colorado State University, and co-directs the Experimental Therapeutics Cluster within the CSU Cancer Academic Supercluster. Dr. Thamm received his Bachelors and V.M.D. degrees from the University of Pennsylvania. He completed a Residency in Medical Oncology at the University of Wisconsin, and was employed as a postdoctoral researcher there for 5 additional years. He is the author of over 60 peer-reviewed publications, 15 book chapters and 100 research abstracts in the field of veterinary oncology and cancer research.

Classes Taught/Currently Teaching:

• CMB510 Introduction to Cancer Biology
• VS701 Postgraduate Medicine
• VM780 Cancer Biology Clinical Practicum
• VM753 Clinical Sciences III
• VM773 Clinical Sciences IV

Research Focus:
Our translational research group is primarily involved in investigating novel therapies in pets with spontaneous neoplasia. The dog is an excellent translational model for the investigation of novel antineoplastic therapies. Unlike murine models, the canine model utilizes relatively outbred, immunocompetent animals with spontaneously occurring tumors, with a spectrum of tumor histotypes and biological behavior similar to that found in humans. The relatively large size of canine tumors when compared with murine tumors may more closely approximate human solid tumors with respect to important biological factors such as hypoxia and clonal variation, and allows for serial sampling of tumor tissue over time. Finally, the relatively rapid time course of disease progression, when compared with human cancer, allows for more rapid assessment of therapeutic endpoints than is possible in many human clinical trials.

Laboratory studies in support of these efforts, including standard cell biology assays for growth, apoptosis, migration/invasion, cytokine production and identification biomarkers of drug activity. Techniques such as western analysis, immunocytochemistry, immunohistochemistry and RT-PCR, are commonly employed in our laboratory in human and animal cancer cell lines and primary tissues.

Name of Laboratory:
Experimental Therapeutics

Laboratory Personnel:
Laboratory Manager
Barbara Rose: barb.rose@colostate.edu

Student Hourly Workers:
Amber Wolf-Ringwall: amber.wolf@colostate.edu

List of Major Laboratory Equipment

1. 1,200 square feet of laboratory space within the CSU Animal Cancer Center
2. Three tissue culture hoods, four tissue culture incubators
3. -80 degree freezer, liquid nitrogen storage with computerized storage databases
4. Two -20 degree freezers and two 4 degree refrigerators
5. Three variable speed, refrigerated benchtop centrifuges, two microfuges
6. Two adjustable-temperature water baths
7. Equipment for nucleic acid and protein electrophoresis
8. Stratagene MX3000P real-time PCR workstation
9. Bio-Tek Synergy HT Multi-Mode Microplate Reader
10. BTX ECM 800 electroporator

Current Work/Projects:
Expression and Function of Survivin in Canine Osteosarcoma
The goal of this study is to determine the phenotypic effects of survivin knockdown on canine osteosarcoma cells, and the prognostic significance of survivin expression in primary canine osteosarcoma.
Role: Principal Investigator

In Vitro Chemosensitizing Effect of PARP Inhibition with ABT472 in Canine Non-Hodgkins Lymphoma
The goal of this study is to investigate the in vitro efficacy of ABT472 against canine lymphoma cell lines and primary cultures.
Role: Principal Investigator

Tumor Immunotherapy by Monocyte and Macrophage Depletion
This is a clinical trial of the macrophage-depleting pharmacologic agent liposome clodronate in dogs with spontaneous soft-tissue sarcoma.
Role: Co-Investigator

Altered Mutagen Sensitivity as a Predisposition to Cancer in Golden Retrievers
Golden retrievers have a higher incidence of cancer-related mortality (70% of all deaths) than almost any other dog breed. This study seeks to determine if a breed-specific sensitivity to mutagens may play a role in this predisposition.
Role: Principal Investigator

Aging, Cellular Senescence and Chronic Renal Failure in Cats
This study seeks to determine whether accelerated senescence plays a role in the development of chronic renal insufficiency in cats.
Role: Co-Investigator

Phase-I Clinical Investigation of IPI-926 in Dogs with Spontaneous Osteosarcoma
This is a pilot clinical trial of the Hedgehog pathway inhibitor IPI-926 in dogs with osteosarcoma.
Role: Principal Investigator

c-Kit Mutation and Localization Status as Response Predictors in Canine Mast Cell Tumors Treated with Toceranib or Vinblastine: A Response-Adaptive Randomized Trial
This study will evaluate the value of c-kit gene mutation or altered KIT protein localization in predicting response to the kinase inhibitor toceranib or the antimitotic agent vinblastine in dogs with mast cell tumors.
Role: Principal Investigator

Pending Projects:
Multiple Myeloma and Cancer Therapies via Largazole Analogs
These studies involve the synthesis and in vitro and in vivo characterization of a series of synthetic HDAC inhibitors based around the marine natural product largazole.
Role: Co-Investigator

Glycolysis Inhibition to Control Cancer Metastasis
These studies seek to evaluate the antimetastatic effects of glycolysis inhibition with the glucose analog 2-deoxyglucose in vitro, in mouse models, and in dogs with spontaneous tumors.
Role: Principal Investigator

Publications:
Selected peer-reviewed publications (from 64 published or in press).

Vail DM, Chun R, Thamm DH, Garrett LD, Cooley AJ, Obradovich JE. Efficacy of pyridoxine to ameliorate the cutaneous toxicity associated with doxorubicin containing pegylated (Stealth) liposomes: A randomized, double blind clinical trial using a canine model. Clin Cancer Res. 4: 1567-1572, 1998.

Thamm DH, Mauldin EA, Vail DM. Prednisone and vinblastine chemotherapy for canine mast cell tumor: 41 cases (1992-1997). J Vet Intern Med. 13: 491-497, 1999.

Thamm DH, MacEwen EG, Phillips BS, Hershey AE, Burgess KM, Pettit GR, Vail DM. Preclinical study of dolastatin-10 in dogs with spontaneously arising tumors. Cancer Chemother Pharmacol. 49: 251-255, 2002.

Thamm DH, Kurzman ID, MacEwen EG, Feinmehl R, Towell TL, Longhofer SL, Johnson CM, Geoly FJ, Stinchcomb DT. Lipid-complexed intralesional cytokine / superantigen immunogene therapy for spontaneous canine tumors. Cancer Immunol Immunother. 52: 473-480, 2003.

MacEwen EG, Kutzke J, Carew J, Pastor J, Schmidt JA, Tsan R, Thamm DH, Radinsky R. C-Met tyrosine kinase receptor expression and function in human and canine osteosarcoma cells. Clin Exp Metastasis. 20(5): 421-430, 2003. **Corresponding author

MacEwen EG, Pastor J, Kutzke J, Tsan R, Kurzman ID, Thamm DH, Wilson M, Radinsky R. IGF-1 receptor contributes to the malignant phenotype in human and canine osteosarcoma. J Cell Biochem. 92(1): 77-91, 2004. ** Corresponding author

Thamm DH, Kurzman ID, King I, Li Z, Sznol M, Dubielzig RR, Vail DM, MacEwen EG. Systemic administration of an attenuated, tumor-targeting Salmonella typhimurium to dogs with spontaneous neoplasia: phase I evaluation. Clin Cancer Res. 11(13): 4827-4834, 2005.

Thamm DH, Dickerson EB, Akhtar N, Lewis R, Auerbach R, Helfand SC, MacEwen EG. Biological and molecular characterization of a canine hemangiosarcoma-derived cell line. Res Vet Sci. 81(1): 76-86, 2006.

Thamm DH, Turek MM, Vail DM. Outcome and prognostic factors following adjuvant prednisone/vinblastine chemotherapy for high-risk canine mast cell tumour: 61 cases. J Vet Med Sci. 68(6): 581-587, 2006.

Reiser H, Wang J, Watkins, WJ, Ray AS, Shibata R, Birkus G, Cihlar T, Wu S, Li B, Liu X, Henne IN, Wolfgang G, Desai M, Rhodes GR, Fridland A, Lee WA, Plunkett W, Vail DM, Thamm DH, Jeraj R, Tumas DB. GS-9219 – a novel prodrug of the acyclic nucleoside phosphonate PMEG with potent anti-neoplastic activity in human hematopoietic tumor cell lines and in dogs with spontaneous non-Hodgkin’s lymphoma. Clin Cancer Res. 14(9): 2824-2832, 2008.

Thamm DH, O’Brien MG, Vail DM. Effect of serum vascular endothelial growth factor on postsurgical outcome in dogs with osteosarcoma. Vet Compar Oncol. 6(2): 1206-132, 2008.

Ptitsyn A, Weil M, Thamm DH. Systems biology approach to identification of biomarkers for metastatic progression in cancer. BMC Bioinformatics. 9 (Suppl 9): S8, 2008.

Rebhun R, Charles B, Ehrhart EJ, Lana SE, Thamm DH. Prognostic and comparative analysis of survivin expression in untreated and relapsed canine lymphoma. J Vet Intern Med. 22(4): 989-995, 2008.

*Vail DM, *Thamm DH, Reiser H, Ray AS, Wolfgang GHI, Babusis D, Kurzman ID, Jeraj R, Plaza S, Anderson C, Wessel MA, Robat C, Lawrence J, Tumas DB. A novel prodrug (GS-9219) demonstrates activity against non-Hodgkin’s lymphoma: a pet dog model. Clin Cancer Res. 15(10): 3503-3510, 2009. * Equal effort reported

Sottnik JL, U’Ren LW, Thamm DH, Withrow SJ, Dow SW. Chronic bacterial osteomyelitis suppression of tumor growth requires innate immune responses. Cancer Immunol Immunother 59(3): 367-378, 2010.

Sottnik JL, Hansen RJ, Gustafson DL, Dow SW, Thamm DH. Induction of VEGF by tepoxalin does not lead to increased tumor growth in a canine osteosarcoma xenograft. Vet Comp Oncol, (In press 2010).

Thamm DH, Huelsmeyer MK, Mitzey AM, Qurollo BA, Rose BJ, Kurzman ID.  RT-PCR based tyrosine kinase display profiling of canine melanoma: IGF-1 receptor as a potential therapeutic target. Melanoma Res. 20(1): 35-42, 2010.

Thamm DH, Kurzman ID, Clark MA, Ehrhart EJ, Kraft SL, Gustafson DL, Vail DM. Preclinical investigation of PEGylated tumor necrosis factor alpha in dogs with spontaneous tumors: phase-I evaluation. Clin Cancer Res 16: 1498-1508, 2010.

Sottnik JA, Duval DL, Ehrhart III EJ, Thamm DH. An orthotopic, postsurgical model of luciferase transfected murine osteosarcoma with spontaneous metastasis. Clin Exp Metastasis 27(3): 151-160, 2010.

Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B, Li J, Pan Z, Thamm DH, Miller RA, Buggy JJ. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B cell activation and is efficacious in models of autoimmune disease and B cell malignancy. Proc Natl Acad Sci USA 107(29): 13075-13080, 2010.

Wittenburg LA, Gustafson DL, Thamm DH. Phase I pharmacokinetic and pharmacodynamic evaluation of combined valproic acid / doxorubicin treatment in dogs with spontaneous cancer. Clin Cancer Res 16(19): 4832-4842, 2010.

Wittenburg LA, Bisson L, Rose BJ, Korch C, Thamm DH. The histone deacetylase inhibitor sodium valproate sensitizes canine and human osteosarcoma to doxorubicin. Cancer Chemother Pharmacol, Epub ahead of print 2010.

Kennedy KC, Qurollo BA, Rose BJ, Thamm DH. Epidermal growth factor promotes the malignant phenotype in canine mammary carcinoma. Vet Comp Oncol, (In press 2010).

Post Doctoral Fellows/Graduate Students:
Name: Jenette Shoeneman
Email Address: jenette.shoeneman@colostate.edu
Area of Study: Effects of survivin expression and inhibition in canine osteosarcoma.

Name: Emma Warry
Email Address: emma.warry@colostate.edu
Area of Study: Regulation of Hif-1 alpha and VEGF by mutant KIT protein in canine mast cell tumor.

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