Overview

Cancer is actually hundreds of diseases, and each is complex. Each cell in our body contains all of the more than 32,000 genes found in human beings. Cancer develops when many genes or different combinations of genes change their expression. Thus, it will take not one but many drugs in combination to block the actions of these “bad” genes to create effective treatment for cancer. The best treatment for each patient can only be developed after identifying the genes that have gone bad in that individual patient. This laboratory performs a test called genomic profiling, which identifies the genes gone bad in a patient’s cancer. With this new technology, we can now determine the activity of all our genes in a patient’s cancer within a day.

Cancer is a complex disease in which key gene expression patterns regulating cell proliferation, differentiation, and cell death are altered in a normal cell to that of a dysregulated tumor cell capable of immortality.

To be able to understand the multiple signaling pathways that are altered, a global approach must be taken to examine gene expression in cancer cells and tissue. The cartoon at right illustrates the signaling pathways regulating cell proliferation, differentiation, apoptosis, cell adhesion, and secretion. Most of the molecules shown in the cartoon are classified as either oncogenes or tumor suppressor genes. Multiple signaling pathways regulate these phenotypic and ever changing processes directly and/or indirectly via crosstalk with other signaling cascades.

The recent advent of gene array technology brings the ability to classify disease states at the molecular level by examining changes in all mRNAs expressed in cells or tissues. Comparing changes in gene expression patterns between normal and diseased cells and/or tissues has elucidated unique subsets of genes identifiable to a specific disease. Already, new subclassifications of specific cancers have been discovered belying the fact that genomic profiling can uniquely distinguish a specific disease state and tissue of origin. The ability to examine global changes occurring in a cell or tissue(s), thereby allows the elucidation of alterations in dysregulated biological, biochemical, and molecular events leading to disease states.

We have taken this approach for renal cell carcinoma, a deadly cancer with no current predictive, effective chemotherapy. Once we have verified genes that are altered in tumor tissue as compared to normal kidney tissue, we use normal human kidney and tumor cell lines that we have developed to either express or suppress gene expression of the identified gene to determine its role in tumorigenesis. Using this approach allows us to identify molecular markers of tumor stage and progression, patient survival prognosis, and novel molecular targets for drug therapy. We also use the gene array approach to identify novel molecular targets used by anticancer drugs lending understanding of key molecular pathways needed block cancer cell survival. The figure at left is a dendogram or heat map of genes identified to be commonly regulated by two novel anticancer drugs in human pancreatic tumor cells. Red bars indicates high gene expression while bright green bars indicate low gene expression and black representing variations between high and low gene expression levels.

Futuristically, one could envision personalized patient therapies based upon identification of specific aberrant signaling pathways that can be targeted for drug therapy.