Joint Fellowship Training Program
Mentor:
Deborah A. Hursh, PhD
Organizational Affiliation and Position:
Principle Investigator, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research (CBER), FDA
Email:
deborah.hursh@fda.hhs.gov
Phone:
(301) 827-06705
Running Title of Program:
Lung cancer gene therapy and drug discovery/analysis in model organisms
Research Project Summary:
Lung cancer results in the highest cancer mortality rate in the United States with a large majority of these being non-small-cell lung cancers (NSCLC). NCSLC patients with advanced local or advanced cases, receiving the current standard of care, have a long-term survival rate of less than 25%. To improve these results new and targeted approaches need to be developed. We have identified a gene in the fruit fly, which we have named Caliban, whose human ortholog, Sdccag1 (Serologically defined colon cancer antigen gene 1), is inactive in all five NCSLC lines examined (Bi et al. 2005). Furthermore, we have demonstrated that expression of the fly Caliban gene in these human NCSLC lines blocks or reverts many of the tumor properties of these lung cancer cells, including their ability to grow in the absence of serum, colony formation on soft agar and invasiveness. This suggests that it might be possible to develop Caliban/Sdccag1 as a potential gene therapy for the treatment of lung cancer.
In addition, we have developed a biomarker assay for both fly and human Caliban/Sdccag1 function. This assay consists of following the subcellular localization of a green fluorescent protein tagged biomarker, which is exported from the nucleus to the cytoplasm by the activity of Caliban/Sdccag1 but remains in the nucleus when Caliban/Sdccag1 is inactive. This biomarker can be used to identify cells with impaired Caliban/Sdccag1 function and to monitor the restoration of its activity. It therefore can be used in high throughput drug discovery for compounds that restore or enhance Caliban/Sdccag1 activity, which will have the implied property that they are candidates for therapeutic agents for lung and possibly other cancers.
The Hursh lab is using the fruit fly as a genetic model organism to study developmental models of human disease. We have collaborated on the establishment of the fly to study the normal function of Caliban. This will identify the normal pathway(s) affected by Caliban during development and elucidate potential targets responsible for the tumorigenesis seen in mutant human lung cells. A knockout fly has been created and will be used in these studies. In addition, a knockout mouse model is being developed.
Proposed project for IOTF fellow:
Fellows will study several aspects of Caliban function. First, fly developmental genetics will be used to characterize the normal function of Caliban. Second, a mouse model system will be established to confirm and expand on our results obtained in the fly. This will be a two-fold approach: one, to examine the developmental effects in a knockout mouse and two, to test the tumor suppression properties of Caliban in a mammalian model. Third, the biomarker assay will be used in human tissue culture cells to both identify and validate potential drugs for modulating Sdccag1 function.
Regulatory Activity:
At the FDA, Dr. Hursh is product reviewer who regulates clinical trials in cell therapy, gene therapy, and tumor vaccines, many for the treatment of lung cancer. Under the mentorship of Dr. Hursh, fellows will gain experience by working as part of an interdisciplinary team to evaluate potential therapeutics and biomarkers for lung cancer.
Reference(s):
Stultz, B.G., Jackson, D., Xiang Yang, Beachy, P.A., Mortin, M.A., and Hursh D.A. Transcriptional activation by extradenticle in the Drosophila visceral mesoderm. Dev. Biol. In press
Stultz, B.G., Ray, R.P., and Hursh, D.A. (2005) Analysis of the Shortvein Cis-Regulatory Region of the decapentaplegic Gene of Drosophila melanogaster. Genesis 42:181-192.
Bi, X., Jones, T., Abbasi, F., Lee, H., Stultz, B., Hursh, D.A., Mortin, M.A. (2005) Drosophila caliban, a nuclear export mediator, can function as a tumor suppressor in human lung cancer cells. Oncogene 24: 8229-8239
