Research Abstract
Our research is focused on the changes in gene and protein expression that take place as tumors progress from highly differentiated, non-aggressive lesions to poorly differentiated, metastatic tumors. The phenotype required for metastasis includes decreased cell aggregation, increased angiogenesis, increased cell migration and increased tissue degradation. The goal of our laboratory is to identify these molecules, to determine the mechanism by which their expression is altered in tumor progression and to employ them for both diagnostic and therapeutic purposes.
Using proteomics tools, we have identified a variety of proteins altered in tumor progression in breast, pancreas, prostate, bladder and other tumor sites. Our model systems include tumor cell lines that differ in their metastatic potential, as well as transgenic animal models in which tumors arise spontaneously in the prostate or pancreas at distinct times after birth. Using this approach, we have developed tests for biomarkers that are useful in cancer diagnosis, prognosis, recurrence monitoring and in determining responsiveness to particular therapeutic agents.
We have recently focused on the development of resistance to taxanes. Taxanes such as paclitaxel and docetaxel are now front-line treatment for patients with a variety of metastatic cancers, yet their efficacy is diminished by the rapid development of drug resistance. We have found that the protein Prohibitin1 is upregulated on the surface of taxane-resistant cells. We believe that Prohibitin1 can be used as a biomarker to reveal which patients have tumors that will be resistant to taxane treatment. In addition, cell surface Prohibitin1 could serve as a target to direct other drugs to taxane-resistant tumor cells.
Because metastasis is the end point for most human cancers and because metastatic lesions are so often resistant to conventional therapies, we have initiated a drug screen to identify new therapies that act preferentially on metastatic tumors. We have identified several candidate therapies that we now wish to move rapidly to clinical trial.
