The purpose of this K-24 grant proposal is to provide the support necessary for the principal investigator to conduct and to mentor trainees in the conduct of patient-oriented clinical research that bridges early phase clinical trials of novel cancer therapies with laboratory correlative studies. Trainees will be supervised in their clinical research by the principal investigator and in their laboratory research by a basic scientist skilled in that area. Research projects pursued under this grant will involve the development and use of laboratory models to guide clinical trial design and the establishment of laboratory assays to measure the impact of the therapeutic intervention on tissue and plasma samples collected during the course of the clinical trial. Two examples are provided. One involves measurement of the change in matrix metalloproteinase level and activity in tumor tissue obtained from a cohort of patients treated with a novel matrix metalloproteinase inhibitor. The other involves the development of in vitro and in vivo models leading to the clinical evaluation of the combination of cytotoxic chemotherapy and cyclooxygenase-2 inhibitors on established cancers. This hypothesis is based on 3 main observations: 1) COX-2 overexpression has an inhibitory effect on apoptosis; 2) most cytoxic agents exert their antitumor effect through apoptosis; and 3) many drug-resistant tumors, including more than 70 percent of adenocarcinomas of the colon and lung,overexpress COX-2. The principal investigator has been continuously involved in patient-oriented clinical research in a variety of capacities for 13 years. His work has focused primarily on new drug development in oncology and he has been extensively involved in the design and conduct of the clinical trials that led to the FDA approval of gemcitabine (for pancreatic cancer) and irinotecan (CPT-11) (for colorectal cancer). He currently directs the Phase I Drug Development Program at the Vanderbilt Cancer Center. This grant will permit the candidate to extend his experience to work more closely with basic researchers and clinical trainees in the development of integrated laboratory/clinical trials that can provide the greatest amount of information regarding the activity of novel cancer therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
1K24CA082301-01
Application #
2884075
Study Section
Subcommittee G - Education (NCI)
Program Officer
Gorelic, Lester S
Project Start
1999-09-01
Project End
2004-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Manning, H Charles; Merchant, Nipun B; Foutch, A Coe et al. (2008) Molecular imaging of therapeutic response to epidermal growth factor receptor blockade in colorectal cancer. Clin Cancer Res 14:7413-22
Stover, Daniel G; Lockhart, A Craig; Berlin, Jordan D et al. (2008) Phase I trial of pemetrexed plus oxaliplatin administered every other week in patients with metastatic cancer. Invest New Drugs 26:339-45
Rao, Gautam; Crispens, Marta; Rothenberg, Mace L (2007) Intraperitoneal chemotherapy for ovarian cancer: overview and perspective. J Clin Oncol 25:2867-72
Lockhart, Albert Craig; Cropp, Gillian F; Berlin, Jordan D et al. (2006) Phase I/pilot study of SU5416 (semaxinib) in combination with irinotecan/bolus 5-FU/LV (IFL) in patients with metastatic colorectal cancer. Am J Clin Oncol 29:109-15
Rothenberg, Mace L; LaFleur, Bonnie; Levy, Donna E et al. (2005) Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma. J Clin Oncol 23:9265-74
Lockhart, A Craig; Howard, Martin; Hande, Kenneth R et al. (2004) A phase I dose-escalation and pharmacokinetic study of brostallicin (PNU-166196A), a novel DNA minor groove binder, in adult patients with advanced solid tumors. Clin Cancer Res 10:468-75
Rothenberg, Mace L; Oza, Amit M; Bigelow, Robert H et al. (2003) Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 21:2059-69
Rothenberg, Mace L; Liu, P Y; Braly, Patricia S et al. (2003) Combined intraperitoneal and intravenous chemotherapy for women with optimally debulked ovarian cancer: results from an intergroup phase II trial. J Clin Oncol 21:1313-9
Rothenberg, Mace L; Berlin, Jordan D (2003) Therapeutic strategies for metastatic colorectal cancer: simultaneous, sequential, or specific? J Clin Oncol 21:3716-7