Daniel Gustafson

Biography of Investigator:
B.S., Biology, Santa Clara University, Santa Clara, CA
Ph.D., Cell and Molecular Pharmacology and Physiology, University of Nevada, Reno, NV
Postdoc, Radiation Biology/Pharmacology, Colorado State University, Fort Collins, CO and University of Colorado Health Sciences Center, Denver, CO

Research Focus:
My laboratory focuses on developing therapeutic treatment modalities for cancer with an emphasis on the pharmacology of agents used for the treatment of cancer. This includes characterizing optimum drug combinations and treatment schedules for newer molecularly targeted drugs with cytotoxic chemotherapy and/or ionizing radiation. The development and utilization of model systems that better reflect the clinical progression and pathology of cancer are also a focus. Model systems that we utilize include animal cell tissue culture, rodent models and collaborations with medical, radiation and surgical oncologists that utilize human and veterinary cancer patient populations.  Methods that we use include molecular biology, biochemistry, analytical chemistry as well as computer modeling approaches. A strong emphasis is placed on quantitative assessment and mathematical or statistical approaches to data analysis with prediction and simulation of drug levels and effects in patient populations as a final goal.

Current Work/Projects:
MEK Inhibition and Drug Combinations for the Treatment of Melanoma
This project focuses on the mechanism of action and pharmacology of the MEK inhibitor AZD6244 in human melanoma cell lines and tumor xenografts in mouse models alone and in combination with cytotoxic chemotherapy.  Emphasis is on pharmacologic interaction and pharmacokinetic/pharmacodynamic endpoints of drug therapy.

Dual Compartmental Targeting of Cancer
This project focuses on drug combinations that target both stromal and cancer cells that make up tumors.  The questions that are being addressed revolve around the scheduling of cytotoxic chemotherapy in combination with signal transduction inhibitors that block signaling in stromal (endothelial) and cancer cells.  Emphasis is on pharmacokinetically-directed dosing to achieve defined pharmacodynamic endpoints and correlate dose-response to therapeutic effect.   

Pharmacology Core:
My laboratory is part of the Core services for the University of Colorado Comprehensive Cancer Center and we provide drug analysis and data modeling support for researchers and clinicians across the UCCC consortium including the University of Colorado-Denver, University of Colorado-Boulder and Colorado State University.  The core facility is GLP-compliant and operates collaboratively with investigators as a fee for service center.

Population Modeling of Cancer Chemotherapeutic Agent:
This project focuses on incorporating physiologically-based pharmacokinetic (PBPK) modeling, Monte Carlo simulation and population pharmacokinetic modeling methodologies to study drug-drug interactions, genetic polymorphisms and other variables in drug exposure and effects in veterinary and human patient populations.  Emphasis is on incorporating laboratory and computer based experiments iteratively to describe, simulate and then predict effects in a given population.

Drug Therapy for Canine Melanoma:
This project focuses on determining optimal targeted and cytotoxic chemotherapeutic agents for the treatment of canine melanoma.  Comparisons between human and canine melanomas are also being done to determine if experimental drug treatments in clinical canine melanoma patients can be beneficial to human trials.  These studies include molecular, biochemical and pharmacologic comparisons with emphasis on translation to clinical trials.

LC/MS/MS Instrumentation:
The Gustafson Laboratory includes instrumentation to carry out analytical, molecular and biochemical studies.  This includes small laboratory equipment such as electrophoresis gel boxes and power supplies, shakers, vortex mixers and other benchtop equipment.  Larger instrumentation includes two mass spectrometers and associated liquid chromatography equipment (listed below as LC/MS/MS Instrumentation) as well as an IVIS 100 Imaging System and Camera capable of monitoring fluorescence and luminescence in living animals.Two ABI3200 QTrap linear ion trap triple quadropole mass spectrometers

• Two ABI3200 QTrap linear ion trap triple quadropole mass spectrometers
• Agilent 1200 Series LC System
  • 2 LC Pumps (capable of 9000 PSI operation)
  • Temperature Controlled Column Oven
• Shimadzu LC Systems
  • 4 LC20A Solvent Delivery Modules
  • 2 CBM20A System Controllers
  • SIL-20A Refrigerated Autosampler
  • CTO 20A Column Oven
• 2 HTC-PAL Autosamplers (1 has refrigerated sample compartment)
• 2 Computer workstations with Analyst Software
  • MS/MS data analysis
  • Linear Ion Trap data analysis
  • Metabolite ID analysis

Publications:
Gustafson, D.L., Rastatter, J.C., Colombo, T. and Long, M.E. (2002). Doxorubicin pharmacokinetics: macromolecule binding, metabolism and excretion in the context of a physiological model. J Pharm Sci. 91:1488-1501.

Gustafson, D.L., Siegel, D., Rastatter, J.C., Merz, A.L., Parpal, J.C., Kepa, J.K., Ross, D., and Long, M.E. (2003). Kinetics of NAD(P)H:quinone oxidoreductase inhibition by mitomycin C in vitro and in vivo. J Pharmacol Exp Therap. 305:1079-1086.

Gustafson, D.L., Long, M.E., Zirrolli, J.A., Duncan, M.W., Holden, S.N., Pierson, A.S. and Eckhardt, S.G. (2003). Analysis of docetaxel pharmacokinetics in humans with the inclusion of later sampling time points afforded by the use of a sensitive tandem LCMS assay. Cancer Chemother Pharmacol. 52:159-166.

Witta, S.E., Gustafson, D.L., Pierson, A.S., Menter, A., Holden, S.N., Basche, M., Persky, M., O’Bryant, C.L., Baron, A., Long, M.E., Gibbs, A., Kelly, K., Bunn, P.A. Jr., Chan, D.C., Pallansch,P. and Eckhardt, S.G. (2004). A phase I and pharmacokinetic study of exisulind and docetaxel in patients with advanced solid tumors. Clin Cancer Res. 10:7229-7237.

Gustafson, D.L., Merz, A.L. and Long, M.E. (2005). Pharmacokinetics of combined doxorubicin and paclitaxel in mice. Cancer Lett. 220:161-169.

Gustafson, D.L., Long, M.E., Bradshaw, E.L., Merz, A.L. and Kerzic, P.J. (2005).  Alterations in paclitaxel pharmacokinetics and tissue distribution with multiple dosing. Cancer Chemother Pharmacol. 56:248-254.

Zirrolli, J.A., Bradshaw, E.L., Long, M.E. and Gustafson, D.L. (2005).  LC/MS/MS analysis of the novel tyrosine kinase inhibitor ZD6474 in mouse plasma and tissues. J Pharmaceut Biomed Anal. 39:705-711..

Guo, W., Reigan, P., Siegel, D., Zirrolli, J., Gustafson, D.L. and Ross, D. (2005). Formation of 17-AAG hydroquinone by NAD(P)H:quinone oxidoreductase 1 (NQO1): Role of 17-AAG hydroquinone in Hsp90 inhibition. Cancer Res. 65:10006-10015.

Selting, K.A., Ogilvie,G.K., Gustafson, D.L., Long, M.E., Lana, S.E., Walton, J.A., Hansen, R.A., Turner, A.S., Laible, I. and Fettman, M.J. (2006). Evaluation of the effects of dietary n-3 fatty acid supplementation on the pharmacokinetics of doxorubicin in dogs with lymphoma. Am J Vet Res. 67:145-151.

Gustafson, D.L., Bradshaw-Pierce, E.L., Merz, A.L., and Zirrolli, J.A. (2006). Tissue distribution and metabolism of ZD6474 in tumor bearing nude mice following oral dosing. J Pharmacol Exp Therap. 318:872-880.

Basche, M., Gustafson, D.L., Holden, S.N., O'Bryant, C.L., Gore, L., Witta, S., Schultz, M.K., Morrow, M., Grolnic, S., Conrad, D., Levin, A., Creese, B.R., Kangas, M., Roberts, K., Nguyen, T., Davis, K., Addison, R.S., Moore, J. and Eckhardt, S.G. (2006). A phase I and pharmacokinetic study of PI-88 in patients with advanced solid tumors. Clin Cancer Res. 12:5471-5480.

Guo, W., Reigan, P., Siegel, D., Zirrolli, J., Gustafson, D.L. and Ross, D. (2006). The bioreduction of a series of benzoquinone ansamycins by NAD(P)H:quinone oxidoreductase 1 (NQO1) to more potent heat shock protein 90 (HSP90) inhibitors, the hydroquinone ansamycins. Mol Pharmacol. 70:1194-1203.

Flaig, T.W., Gustafson, D.L., Su, L-J., Zirrolli, J., Harrison, G., Pierson, A.S., Agarwal, R. and Glode, L.M. (2007). A phase I and pharmacokinetic study of silybinin phytosome in prostate cancer patients. Invest New Drugs. 25:139-146.

Lana, S., U’ren, L., Plaza, S., Elmslie, R., Gustafson, D.L. and Dow, S. (2007). Comparison of continuous low-dose oral chemotherapy with conventional doxorubicin chemotherapy for adjuvant therapy of hemangiosarcoma in dogs. J Vet Intern Med. 21:764-769.

Bradshaw-Pierce, E.L., Eckhardt, S.G. and Gustafson, D.L. (2007). A physiologically-based pharmacokinetic model of docetaxel disposition: from mouse to man. Clin Cancer Res. 13:2768-2776.

Troiani, T., Serkova, N.J., Gustafson, D.L., Henthorn, T.K., Lockerbie, O., Merz, A., Long, M., Morrow, M., Ciardiello, F., and Eckhardt, S.G. (2007). Investigation of two dosing schedules of vandetanib (ZD6474), an inhibitor of vasculat endothelial growth factor receptor and epidermal growth factor receptor signaling, in combination with irinotecan in a human colon cancer xenograft model. Clin Cancer Res. 13:6450-6458.

Gustafson, D.L., Frederick, B., Merz, A.L. and Raben, D. (2008). Dose scheduling of the dual VEGFR and EGFR tyrosine kinase inhibitor vandetanib (ZD6474, Zactima®) in combination with radiotherapy in EGFR-positive and EGFR-null human head and neck tumor xenografts. Cancer Chemother Pharmacol. 61:179-188. EPub, 3/29/2007.

Bradshaw-Pierce, E.L., Steinhauer, C.A., Raben, D. and Gustafson, D.L. (2008). Pharmacokinetic-directed dosing of vandetanib and docetaxel in a mouse model of human squamous cell carcinoma. Mol Cancer Therap. (In Press)

Denton, C.L. and Gustafson, D.L. (2008). Rates of proliferation but not mutation status predict sensitivity of human melanoma cells to MEK inhibition by AZD6244 (ARRY-142886). Cancer Res. (Submitted.)

Laboratory Personnel:
Cathrine L. Denton – Graduate Student
cathrine.denton@colostate.edu
B.S., Microbiology, North Carolina State University, Raleigh NC

Ryan J. Hansen, Ph.D. – Postdoctoral Fellow
ryan.hansen@colostate.edu
B.A., Biology, St. John’s University, Collegeville, MN
Ph.D., Cancer Biology, University of Chicago, Chicago, IL

Susan Hudachek, Ph.D.- Postdoctoral Fellow
susan.hudachek@colostate.edu
B.S., Pre-Med, Notre Dame University, South Bend, IN
Ph.D., Cell and Molecular Biology (Cancer Biology), Colorado State University, Ft. Collins, CO

Jared S. Fowles – Graduate Student
jared.fowles@colostate.edu
B.S., Biology, Utah State University, Logan, UT

Bradley J. Samber – Professional Research Associate
bradley.samber@colostate.edu
B.A., Biochemistry, Colorado College, Colorado Springs, CO

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