Pharmacology, Pharmacogenetics, And Pharmacogenomics

For additional information on cell signaling pathway research, see Current Projects.

Pharmacology is the science of characterizing the fate of drugs in the body following administration to patients and the study of how drugs work. Determining key features of a drug, such as concentrations in the blood, how long the drug remains in the body, and conversion of the parent drug to other molecules that might be involved in drug effects, is an important element in learning how to optimally use new drugs in the treatment of disease. Understanding drug behavior is particularly important for anticancer drugs because these agents must be used very carefully to maximize benefit and minimize side effects. Defining the pharmacology of new anticancer agents during their evaluation in early clinical trials is a major emphasis of the Developmental Therapeutics. This information is then used to develop optimal doses and schedules of administration to most effectively utilize new anticancer agents in our patients.

Pharmacogenetics is the study of the role of inheritance in the individual variation in drug response. We now recognize that an important component in the variable response of patients to anticancer agents, including side effects and antitumor effects, is due to genetic variation in specific genes that are responsible for drug metabolism. Program investigators routinely study the relationships between genetic variability and patient responses to new anticancer agents in early clinical trials at the Cancer Center. Based on studies by program investigators, treatment regimens for several important agents are individualized based on genetic data for each patient. At the same time, Program investigators are constantly studying additional genes at a fundamental level to identify new gene variants in populations, and to define the effects of those variants on drug responses. These fundamental pharmacogenomic studies are constantly adding to our repertoire of genetic variants to study in patients in order to optimize chemotherapy.

The Pharmacogenetics of Irinotecan
Matthew M. Ames, Ph.D. and Matthew P. Goetz, M.D.

Dr. Ames’ laboratory now routinely tests for the presence of more than 40 genetic variants of genes important in determining clinical responses to anticancer agents. These studies are incorporated into many Cancer Center clinical trials. One agent being extensively studied in this manner is Irinotecan, an important anticancer agent used in a variety of malignant diseases. Early pharmacologic studies determined that the parent drug was converted in the blood to the active cancer cell-killing derivative, and that subsequently a protein in the liver converted that active derivative to an inactive molecule readily excreted by the kidneys. Further, it became apparent that a subset of patients were much more prone to drug side effects at doses not affecting most patients. Dr. Goetz incorporated pharmacogenetic studies conducted in Dr. Ames’ laboratory into several irinotecan clinical trials conducted at the Cancer Center. These studies examined the sequence of part of the gene responsible for producing the inactivating protein, since one major genetic variant was known to be much less efficient at inactivating irinotecan. Results of these studies confirmed that patients carrying the genetic variant were at much greater risk for side effects. Drs. Ames and Goetz designed current studies that test patients for this genetic variant before receiving the drug and adjust the dose of irinotecan based on the genetic test results.

The Pharmacogenomics of Gemcitabine
Richard M. Weinshilboum, M.D. and Matthew M. Ames, Ph.D.

Dr. Weinshilboum is one of the world’s leading authorities and investigators in identifying new genetic variants of important genes. One of his major contributions has been to determine that a genetic variant is responsible for the serious side effects that occur in a small subset of children following administration of 6-mercaptopurine, an important drug in the treatment of childhood leukemia. He developed a simple genetic test now widely used to identify those children before therapy.

Gemcitabine is a relatively new anticancer agent that has improved the therapy of a number of malignancies that were previously very difficult to treat. A series of studies have defined the precise pathway by which this drug is taken up into cancer cells, converted into active cell-killing derivatives, and inactivated by cancer cells as well as other tissues in the body. The genes involved in producing the proteins responsible for each of these steps are now well known. Drs. Weinshilboum and Ames are currently defining the genetic variation in each of those genes, determining how the variant proteins produced by those variant genes differ from the normal or “wildtype” proteins, and then determining if genetic variability plays a role in differences in individual patient responses to gemcitabine. Dr. Weinshilboum has identified a number of genetic variants in the genes involved in gemcitabine antitumor activity. His laboratory also produces quantities of the variant proteins arising from those genes; and Dr. Ames’ laboratory has determined how those variant proteins differ in activity towards gemcitabine activation or inactivation in cancer cells. In aggregate, these studies may play an important role in gemcitabine chemotherapy by allowing optimal use of these agents in each patient.