GI Cancer Research at the University of Colorado Cancer Center
Featured Researcher
S. Gail Eckhardt , MD , is Professor and Head of the Division of Medical Oncology at the University of Colorado Denver School of Medicine, where she also holds the Stapp/Harlow Endowed Chair for Cancer Research. In 1999, Dr. Eckhardt joined the faculty of the University of Colorado to set up a Phase I program, and in 2004 she became director of the UCCC Developmental Therapeutics Program. Dr. Eckhardt has served on many committees and study sections, including the ASCO Molecular Oncology Task Force, the ASCO Board of Directors, the FDA Oncology Drugs Advisory Committee and the NCI Developmental Therapeutics Study Section. She is also a member of two NCI Steering Committees: Gastrointestinal and Investigational Drugs. In addition, Dr. Eckhardt has been an associate editor of Clinical Cancer Research, the Journal of Clinical Oncology, and Investigational New Drugs. Dr. Eckhardt is the Principal Investigator on three NIH grants involving early clinical trials, mentoring and colorectal cancer research and has conducted numerous phase I and II clinical trials. She has published more than 90 manuscripts and serves on numerous advisory boards. Her area of interest is in the preclinical and clinical development of combinations of molecularly targeted compounds, with a laboratory focus on colorectal cancer.
Gastrointestinal cancer research is a burgeoning enterprise at the University of Colorado Cancer Center. During 2007, the GI medical oncology team grew with three recruitments, including new director Wells Messersmith, MD , who came from Johns Hopkins.
GI cancer research includes:
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Anal cancer
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Bile duct cancer
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Carcinoid tumors
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Colorectal cancer
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Esophagus cancer
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Liver cancer
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Pancreatic cancer
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Small intestine cancer
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Stomach cancer
GI cancer research at UCCC tends toward developmental therapeutics and prevention and control focuses, as many of the researchers work within the Cancer Center's Developmental Therapeutics and AMC Cancer Prevention and Control Programs. However, the group prides itself on being multidisciplinary, with people from all cancer disciplines taking part—surgical oncologists, medical oncologists, radiation oncologists, pathologists and basic scientists alike.
Research Focuses
Growth Factor Receptor Inhibition
Dr. Steve Leong
Humans have 58 encode receptor tyrosine kinase proteins. These receptors regulate normal cellular processes, and they play a critical part in cancer development and progression. We are investigating how to block some of these receptors—called growth factors—using drugs and other therapies, because lab work shows that when you block the receptor, you cause cell death. In particular, we are working on Insulin Growth Factor 1 Receptors (IGF-1R), Epidermal Growth Factor Receptors(EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR2).
- IGF-1 signaling pathway is a key regulator of normal cell proliferation, differentiation and apoptosis (programmed cell death). There is growing evidence regarding its importance in transformation, tumor cell growth and survival, metastasis, and angiogenesis, making IGF-1R is an attractive therapeutic cancer target. Dr. Steve Leong recently presented promising results from an IGF-1R inhibitor at a national meeting, and he is principal investigator of an upcoming clinical research trial with an IGF-1R inhibitor.
- Dr. Leong recently opened the investigator-initiated Phase I Study of Gemcitabine, Capecitabine and ZD6474 (ZACTIMA) in Patients with Advanced Solid Tumors, with an Expanded Cohort of Patients with Biliary and Pancreatic Malignancies. ZD6474 is a receptor tyrosine kinase that inhibits both the Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR2) which are frequently overexpressed in both biliary and pancreatic malignanices. The combination of ZD6474 and chemotherapy agents has shown additional benefit in preclinical studies. This trial is actively enrolling, and there will be correlative studies to examine potential biomarkers which maybe useful as predictors of early response.
- Dr. Wells Messersmith is working on using a combination of drugs to block the EGFR pathway to restore the cancer-killing effects of drugs used in colorectal cancer that were ineffective alone. He wrote an NIH-approved protocol, along with an R21 grant funded by the NIH, that combines sorafenib—a drug approved to treat kidney and liver cancer—with two standard colorectal cancer agents—cetuximab and irinotecan. Cetuximab blocks the EGFR pathway at the receptor level (cell surface), whereas sorafenib blocks a downstream EGFR signaling protein inside the cancer cell. Sorafenib also blocks blood vessel growth, which is a validated strategy in advanced colorectal cancer. This project includes tumor biopsies pre- and post-treatment to carefully dissect the effects of the drugs on the cancer cells themselves.
Signal Transduction Inhibitors in Pancreatic Cancer
Dr. Colin Weekes
We're also studying drugs that may prevent cancer cells from being able to multiply quickly and invade other tissues. In particular, Dr. Colin Weekes is looking at using the metabolomic profiles generated by tumor cells treated by signal transduction inhibitors as biomarkers to identify which patients with pancreatic cancer will respond best to this treatment. His lab is also looking at using this technique to combine signal transduction inibitors to treat pancreatic cancer.
TRAIL Pathway
TRAIL is a protein that tells cells to begin dying when it plugs into specific death-encoded receptors. Cells can be tricky, however, and produce decoy receptors that, when a TRAIL ligand plugs into them, does not cause cell death. Dr. Steve Leong is looking into the role TRAIL may in causing anti-cancer drugs and radiation to fail. Ultimately, TRAIL's death receptors represent potential targets for promoting death of cancer cells.
Stromal Cells
Adenocarcinoma tumors of the pancreas have a large stromal component as well as tumor cells. Dr. Weekes is developing therapies that target the tumor cell-stromal cell interaction along with the pancreatic tumor cell. His goal is to develop therapeutic strategies that can be directly translated into clinical studies to advance the therapy of pancreatic cancer.
Chemokines
- Dr. Weekes is also investigating the role of chemokines in pancreatic cancer. Chemokines are proteins that activate the white blood cells—the body's immune system—to go to the site of an infection. He is looking at how chemokines may modulate the antitumor effects of signal transduction inhibitors and how they may home in cells that form new blood vessels within growing tumors.
- Dr. Weekes is also investigating the role chemokines may play in pancreatic tumor metastases and microenvironment regulation.
Colorado Colorectal Screening Program
The Colorado Colorectal Screening Program provides funding to more than 65 centers throughout Colorado to carry out colorectal screenings for lawfully present Coloradans. These community clinics offer free endoscopic screenings to people who are:
- Age 50 or older (at average risk) or under 50 at increased risk for colorectal cancer (personal or family history of cancer or polyps)
- Have no health insurance
- Have household income below 250% of the federal poverty level
- Are legal Colorado residents
- Are eligible for a colorectal screening according to American Cancer Society clinical guidelines
The program began in January 2006 with a grant from the Colorado Department of Public Health and Environment from state tobacco sales tax revenues. In its first year, the program screened more than 2,000 patients and removed polyps from about 50 percent of the patients. About 20 percent of the polyps were pre-cancerous, and 14 colorectal cancers were diagnosed.
Other Research Projects
- Dr. Weekes has embarked upon the development of a primary explant pancreas xenograft model with the help of Drs. Rick Gonzalez, Martin McCarter and Nathaniel Pearlman in the Department of Surgery and Drs. Stephen Leong, Wells Messersmith and Gail Eckhardt in Medical Oncology to perform these investigations.
Publications
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Dr. Wells Messersmith
- Messersmith W, Oppenheimer D, Peralba J, Sebastiani V, Amador M, Jimeno A, Embuscado E, Hidalgo M, Iacobuzio-Donahue C, Assessment of epidermal growth factor receptor (EGFR) signaling in paired colorectal cancer and normal colon tissue samples using computer-aided immunohistochemical analysis. Cancer Biology and Therapy 2005;4(12)
- Messersmith WA, Hidalgo M, Carducci M, Eckhardt SG. Novel Targets in Solid Tumors: MEKInhibitors. Clinical Advances in Hematology & Oncology 2006;11(4):831-836.
- Troiani T, Serkova NJ, Gustafson DL, Henthorn TK, Lockerbie O, Merz A, Long M, Morrow M, Ciardiello F, Eckhardt SG.Investigation of two dosing schedules of vandetanib (ZD6474), an inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling, in combination with irinotecan in a human colon cancer xenograft model.Clin Cancer Res. 2007 Nov 1;13(21):6450-8.
- O'Dwyer PJ, Eckhardt SG, Haller DG, Tepper J, Ahnen D, Hamilton S, Benson AB 3rd, Rothenberg M, Petrelli N, Lenz HJ, Diasio R, DuBois R, Sargent D, Sloan J, Johnson CD, Comis RL, O'Connell MJ; Gastrointestinal Scientific Leadership Council of the Coalition of Cancer Cooperative Groups.Priorities in colorectal cancer research: recommendations from the Gastrointestinal Scientific Leadership Council of the Coalition of Cancer Cooperative Groups.J Clin Oncol. 2007 Jun 1;25(16):2313-21.
- Chow LQ, Eckhardt SG.Sunitinib: from rational design to clinical efficacy.J Clin Oncol. 2007 Mar 1;25(7):884-96.
- Camidge DR, Eckhardt SG, Gore L, Oʼbryant CL, Leong S, Basche M, Holden SN, Musib L, Baldwin J, Darstein C, Thornton D, Finn RS, Britten CD.A phase I safety, tolerability, and pharmacokinetic study of enzastaurin combined with capecitabine in patients with advanced solid tumors.Anticancer Drugs. 2008 Jan;19(1):77-84.