Bruce Robert Zetter
Our research is focused on the nature of highly aggressive, metastatic, late-stage cancers. We believe that such tumors differ markedly from less aggressive tumors and respond to different drugs than either primary tumors or dormant metastases. Essentially we believe that this represents a different kind of disease and that new treatment regimens need to be tested on models that recapitulate late-stage disease with established metastases. To study this, we have created a variety of models of late-stage cancer and use these to: 1) monitor changes in gene and protein expression that correlate with metastases; 2) measure changes in cellular phenotype associated with the propensity to metastasize; and 3) screen and develop drugs that specifically target late-stage cancers.
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 cancer drug resistance. Recent work suggests that pre-existing subpopulations of tumor cells that are unresponsive to particular drugs grow preferentially after the sensitive cells have been killed. This results in extremely aggressive recurrent disease. We have found that the protein Prohibitin1 (Phb1) is frequently upregulated in these resistant populations. Recently, we showed, in collaboration with Dr. Jinjun Shi at Brigham and Women's Hospital, that systemic silencing of Phb1 with nanoparticles containing Phb1 siRNA can retard tumor growth and resensitize tumor cells to drugs to which they have become resistant. Additionally, we propose that circulating Phb1 can be used to predict the presence of potentially resistant populations. Finally, as some of the protein resides on the cell surface, we may be able to target drugs to resistant cancer cells using a known Phb1-binding peptide.
Finally, we have identified a class of compounds that preferentially antagonize late-stage tumors. We are working with Lijun Sun at the Beth Israel Deaconess Medical Center to derive novel versions of these drugs with increased solubility and bioavailability for potential use in pre-clinical studies and eventual human clinical trials.
Vascular Biology Program, Karp 11.125
300 Longwood Ave
Boston, MA 02115