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Cancer Research at Guthrie
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2001-2002 Summary
 
Both laboratory and patient-oriented research cancer research have witnessed explosive growth over the past year at Guthrie.

Clinical Research
Clinical Research is an integral part of the Cancer Center at Guthrie. Research is utilized in active treatment, prevention and in follow-up of cancer patients. Research is offered to all patients based on protocol availability and eligibility criteria. Clinical Trials are available at Guthrie from the National Cancer Institute, pharmaceutical companies, and physician-initiated projects.
 
Guthrie affiliates with the Mayo Clinic in Rochester, Minnesota to obtain protocols from the Eastern Cooperative Oncology Group (ECOG) and North Central Cancer Treatment Group (NCCTG) and with Allegheny Cancer Center to obtain protocols from the National Adjuvant Breast and Bowel Program (NSABP). We are also a main institute with the American College of Surgery Oncology Group (AGOSOG).
 
Current sponsors of pharmaceutical studies at Guthrie include Aphton Corporation, Astra Zeneca, Bristol Myers Squibb, and Wyeth Research.
 
The program's aim is to have a menu of research protocols available to physicians to meet the treatment needs of their oncology patients. Protocols are classified by disease site and stage.
 
During the 2001 calendar year, over 90 protocols were available to our cancer patients. Enrollment into oncology clinical trials has increased for the last five consecutive years (Figure 1).
 
The Guthrie Clinical Research Department currently employs eight coordinators, half of whom are primarily dedicated to the oncology program. Kamie Hoey, RN CCRP manages the program, while Susan Hadlock, RN OCN, Shelley Jones, RNC, Susan Para, and Michelle Cianfoni serve as project coordinators.
 
Over 140 patients are currently being followed by the research team. A satellite office was approved by ECOG for the Corning Cancer Center. This will provide treatment options closer to home for many of our patients.
 
Basic Research
Basic research in cancer biology at Guthrie is centered in the Guthrie Research Institute. The Research Institute staff includes 8 principal investigators, 12 postdoctoral fellows/research fellows/visiting scientists and a support staff of 15. Institute scientists use biochemical, pharmacological, immunological and physiological techniques to address questions of fundamental importance in intercellular communication and signal transduction. Among the scientists pursuing cancer related studies are Drs. Nan-Shan Chang, Mary Cismowski, John Noti, Margaret Quinlan, and Carol Williams.
 
Dr. Nan-Shan Chang, Director of the Laboratory of Molecular Immunology, works on genes that suppress tumor growth. A tumor suppressor named WOX1 has been identified and shown to interact with another tumor suppressor p53. WOX1 and p53 cooperatively mediate cancer cell death. Suppression of WOX1 expression abolishes p53-mediated cell death, suggesting a role for these proteins in controlling cancer growth.
 
Dr. Mary Cismowski, Director of the Laboratory of Cellular Signaling, is studing the contribution of a new family of signal transduction regulators to the spread of cancer cells. The AGS1 proteins are unusual members of the Ras family of proteins which specifically activate heterotrimeric G protein-i/o signaling in the absence of receptor, suggesting a unique form of cross-talk between monomeric and heterotrimeric G protein signaling pathways. AGS1 blocks G protein-mediated signaling by directly competing for a limiting pool of intracellular heterotrimer. This may be significant in that activation of Gprotein-coupled receptors has been linked to cell proliferation, and the expression of a related protein, Rhes, is increased in endothelial tumor tissue. Thus, one function of the AGS proteins may be to inhibit cell proliferation/metastasis.
 
Dr. John Noti, Director of the Laboratory of Molecular Biology, has found that the leukocyte integrin receptor CD11d, a protein involved in a range of immune functions in blood leukocytes, is expressed on leukemic cells. He is beginning to unravel the molecular mechanisms that lead to the expression of this receptor on leukemic cells. Dr. Noti believes that the molecular switches that activate expression of this gene are also involved in the processes that convert normal leukocytes into leukemic cells. To date, Dr. Noti has identified nine nuclear proteins that stimulate expression of the CD11d gene.
 
Dr. Margaret Quinlan, Director of the Laboratory of Molecular Cell Biology, is investigating the mechanism by which tumor cells progress from a benign to a malignant state. Dr. Quinlan has identified 35 genes, including nine novel genes, whose expression is increased in invasive and/or metastatic tumors of the breast, lung, stomach and uterus. These genes seem to cause a loss of differentiation of the epithelial cells, thereby enabling them to ignore the normal regulatory signals from their neighboring cells and to act independently and aberrantly. The contribution of the loss of normal differentiation to tumor progression is further being investigated by analyzing the regulation of actin and actin-dependent structures, which are primary determinants of epithelial cell differentiation.
 
Dr. Carol Williams, Director of the Laboratory of Molecular Pharmacology, is studying the adhesion and proliferation of lung cancer. Dr. Williams has identified new ways to alter cell-cycle regulatory proteins in lung cancer cells, thereby inhibiting their proliferation. Some anti-cancer drugs appear to work by enhancing the adhesion of tumor cells to one another, which inhibits metastasis of the cells.

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Figure 1