The purpose of this career development award is to obtain support to design and conduct clinical trials that utilize novel, mechanism-based agents while also mentoring fellows and junior faculty in the discipline of early clinical trials research. The overall objective of the clinical and translational research is to develop novel regimens for the treatment of colorectal cancer that target specific biological alterations thereby resulting in strategies that are not only more effective, but also potentially less toxic than current chemotherapy regimens.
The Specific Aims of the research proposal are to: 1) Develop preclinical models of mechanism-based therapy for colorectal cancer that targets both tumor and endothelial cells using the dual VEGF-R and EGF-R tyrosine kinase inhibitor, ZD6474, chemotherapy, and celecoxib, 2) Develop novel combinations of targeted agents (without chemotherapy) that impact upon signal transduction and pro-survival factors as potential maintenance regimens in CRC after best response, and 3) Clinically test the regimens developed in Specific Aims 1 and 2 in patients with metastatic CRC, incorporating detailed pharmacological, biological and imaging studies to assess the relationships between drug exposure, biological effect and patient benefit.
These Specific Aims reflect the areas of interest and expertise of the Principal Investigator and demonstrate the focus of hypothesis-driven research that would be funded by this proposal. To facilitate the training of physicians in high quality patient-oriented research, the Principal Investigator will continue a training and mentoring program in Developmental Therapeutics which will utilize the above Specific Aims and a focused curriculum as a means to advance the careers of fellows and junior faculty in disease-directed clinical and translational cancer research.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24CA106349-02
Application #
7022288
Study Section
Subcommittee G - Education (NCI)
Program Officer
Gorelic, Lester S
Project Start
2005-03-01
Project End
2010-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
2
Fiscal Year
2006
Total Cost
$181,218
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Spreafico, Anna; Tentler, John J; Pitts, Todd M et al. (2013) Rational combination of a MEK inhibitor, selumetinib, and the Wnt/calcium pathway modulator, cyclosporin A, in preclinical models of colorectal cancer. Clin Cancer Res 19:4149-62
Morelli, M Pia; Tentler, John J; Kulikowski, Gillian N et al. (2012) Preclinical activity of the rational combination of selumetinib (AZD6244) in combination with vorinostat in KRAS-mutant colorectal cancer models. Clin Cancer Res 18:1051-62
Tentler, John J; Bradshaw-Pierce, Erica L; Serkova, Natalie J et al. (2010) Assessment of the in vivo antitumor effects of ENMD-2076, a novel multitargeted kinase inhibitor, against primary and cell line-derived human colorectal cancer xenograft models. Clin Cancer Res 16:2989-2998
Pitts, Todd M; Tan, Aik Choon; Kulikowski, Gillian N et al. (2010) Development of an integrated genomic classifier for a novel agent in colorectal cancer: approach to individualized therapy in early development. Clin Cancer Res 16:3193-204
Tentler, John J; Nallapareddy, Sujatha; Tan, Aik Choon et al. (2010) Identification of predictive markers of response to the MEK1/2 inhibitor selumetinib (AZD6244) in K-ras-mutated colorectal cancer. Mol Cancer Ther 9:3351-62
Pitts, Todd M; Morrow, Mark; Kaufman, Sara A et al. (2009) Vorinostat and bortezomib exert synergistic antiproliferative and proapoptotic effects in colon cancer cell models. Mol Cancer Ther 8:342-9
Morelli, M Pia; Brown, Amy M; Pitts, Todd M et al. (2009) Targeting vascular endothelial growth factor receptor-1 and -3 with cediranib (AZD2171): effects on migration and invasion of gastrointestinal cancer cell lines. Mol Cancer Ther 8:2546-58
Eckhardt, S Gail; De Porre, Peter; Smith, David et al. (2009) Patient-reported outcomes as a component of the primary endpoint in a double-blind, placebo-controlled trial in advanced pancreatic cancer. J Pain Symptom Manage 37:135-43
O'Bryant, C L; Lieu, C H; Leong, S et al. (2009) A dose-ranging study of the pharmacokinetics and pharmacodynamics of the selective apoptotic antineoplastic drug (SAAND), OSI-461, in patients with advanced cancer, in the fasted and fed state. Cancer Chemother Pharmacol 63:477-89
Lieu, Christopher; Chow, Laura; Pierson, A Scott et al. (2009) A phase I study of bortezomib, etoposide and carboplatin in patients with advanced solid tumors refractory to standard therapy. Invest New Drugs 27:53-62

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