Douglas Thamm

Biography of Investigator:
Dr. Thamm is an Assistant 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 Section 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 45 peer-reviewed publications, 15 book chapters and 90 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

Research Associate
Kristen Grunerud: kristen.grunerud@colostate.edu

Student Hourly Workers:
Barbara Qurollo: barbara.qurollo@colostate.edu
Inhibition of receptor tyrosine kinase signaling in canine melanoma and mammary cancer: Evaluation of curcumin in feline vaccine-associated sarcoma cells.

Jessica Cantrell: jessica.cantrell@colostate.edu
Efficacy and toxicity of the HDAC inhibitor largazole and its analogs in murine cancer models: Expression of thyroid stimulating hormone receptor in canine thyroid carcinoma.

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:
Phase-I Study of GS-343074 and GS-424044 in Dogs with Lymphoma and Solid Tumors
These studies are evaluating the toxicity, efficacy and pharmacokinetics of 2 novel nucleotide analog prodrugs in dogs with spontaneous cancer.
Role: Principal Investigator

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

Hedgehog Signaling and Its Inhibition in Canine Tumors
The goal of this study is to determine the expression of hedgehog pathway members in canine osteosarcoma and lymphoma, and determine the in vitro and in vivo antitumor effects of a novel Hh pathway inhibitor.
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

Preclinical Evaluation of a Novel BTK Inhibitor, PCI-32765, in Dogs with Spontaneous Non-Hodgkin’s Lymphoma
This is a clinical trial evaluating PCI-32765 in dogs with spontaneous B-cell lymphoma.
Role: Principal 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

Bisphosphonate-Targeted Chemotherapy to Treat Osteosarcoma Pain
This is a pilot/phase-I clinical trial evaluating a novel bisphosphonate/chemotherapy conjugate in dogs with spontaneous osteosarcoma.
Role: Principal Investigator

2-Deoxy D-Glucose as Therapy for Hypoxic Tumor Cells in Canine Osteosarcoma
This in vitro study is investigating the antiproliferative and cytotoxic effects of the glucose analog 2-DG in canine osteosarcoma cell lines, and attempting to correlate drug efficacy with glucose transporter expression.
Role: Co-I

Lymphoma-Targeting Doxorubicin Loaded Minicells: Proof of Concept in Spontaneous Canine Lymphoma
This clinical trial is evaluating the safety and antitumor efficacy CD3 or CD21-targeted bacterial minicells loaded with doxorubicin as a therapy for spontaneous canine lymphoma.
Role: Principal Investigator

Pending/Future Directions:
Comparative Pathway Analysis of Canine and Human Melanoma
This study seeks to compare dysregulated pathways associated with pathogenesis in canine and human melanoma, using informatic methods and in vitro drug sensitivity.
Role: Co-PI

Synthesis of Amino Acid Containing Natural Products
These studies involve the synthesis and in silico, in vitro and in vivo characterization of a series of synthetic HDAC inhibitors based around the marine natural products FK228 and largazole.
Role: Co-I

Publications:
Selected peer-reviewed publications (from 50 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.

Marr AK, Thamm DH, Kurzman ID, Vail DM, MacEwen EG. In vitro effects of 2-methoxyestradiol on canine tumor cells. Vet Compar Oncol. 1(3): 159-167, 2003.

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

Poirier VJ, Huelsmeyer MK, Kurzman ID, Thamm DH, Vail DM. The bisphosphonates alendronate and zoledronate are inhibitors of canine and human osteosarcoma cell growth in vitro. Vet Compar Oncol. 1(4): 207-215, 2004.

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

Katayama R, Huelsmeyer MK, Kurzman ID, Thamm DH, MacEwen EG, Vail DM. Imatinib mesylate inhibits platelet-derived growth factor activity and increases chemosensitivity in feline vaccine-associated sarcoma. Cancer Chemother Pharmacol. 54(1): 25-33, 2004.

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.

U'ren LW, Biller BJ, Elmslie RE, Thamm DH, Dow SW. Evaluation of a novel tumor lysate vaccine in dogs with hemangiosarcoma. J Vet Intern Med. 21: 113-120, 2007.

Kamstock D, Elmslie R, Thamm DH, Dow SW. Pilot study of xenovaccination against VEGF for inhibition of tumor growth and angiogenesis in canine soft tissue sarcoma. Cancer Immunol Immunother. 56(8): 1299-1309, 2007.

Turek MM, Thamm DH, Mitzey A, Kurzman ID, Huelsmeyer MK, Dubielzig RR, Vail DM. hGM-CSF DNA cationic-lipid complexed autologous tumor cell vaccination in the treatment of canine B-cell multicentric lymphoma. Vet Compar Oncol. 5(4): 219-231, 2007.

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.

Kow K, Thamm DH, Terry J, Bailey S, Withrow SJ, Lana SE. Impact of telomerase status on canine osteosarcoma patients. J Vet Intern Med. 22(6): 1366-1372, 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.

Thamm DH, Charles JB III, Elce YA, Ehrhart EJ. Cyclooxygenase-2 expression in equine tumors. Vet Pathol. 45: 825-828, 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

Rowe MD, Thamm DH, Kraft SL, Boyes SG. Polymer modified gadolinium metal-organic framework nanoparticles used as multifunctional nanomedicines for the targeted imaging and treatment of cancer. Biomacromolecules. 10(4): 983-993, 2009.

Rowe MD, Chang C-C, Thamm DH, Kraft SL, Harmon Jr. JF, Vogt AP, Sumerlin BS, Boyes SG. Tuning the magnetic resonance imaging properties of positive contrast agent nanoparticles by surface modification with RAFT polymers. Langmuir. 25(16): 9487-9499, 2009.

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, Epub ahead of print 2009.

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. Am J Vet Res. (In press 2009).

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. (In press 2009).

Post Doctoral Fellow/Graduate Students:
Name: Luke Wittenburg
Email Address: luke.wittenburg@colostate.edu
Area of Study: Histone deacetylase inhibition to enhance osteosarcoma chemosensitivity.

Name: Joe Sottnik
Email Address: joseph.sottnik@colostate.edu
Area of Study: Role of macrophages and infection in cancer progression.

Name: Jenette Shoeneman
Email Address: jenette.shoeneman@colostate.edu
Area of Study: Effects of survivin expression and inhibition in canine osteosarcoma.

Name: Janet Petty
Email Address: janet.petty@colostate.edu
Area of Study: Antitumor and antimetastatic effects of 2-deoxyglucose in osteosarcoma.

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