Pilot Award – Final Report
- Kepal N. Patel. M.D.
- Memorial Sloan-Kettering Cancer Center
- Title: Anti-MUC1 Targeting in Aggressive Thyroid Cancer
Our preliminary data demonstrated a strong relationship between MUC1 aberrations and aggressive clinical behavior in thyroid cancer (TC). However, this evidence was associative. To establish MUC1 as a potential therapeutic target, direct assessment of MUC1 biologic activity in TC was required.
Multiple human TC cell lines were obtained and screened for MUC1 expression. Similar to expression patterns in primary tumors, increased MUC1 expression was found only in aggressive TC cell lines. A plasmid containing full length MUC1 cDNA was cloned and stably transfected into low MUC1 expressing cells, resulting in increased MUC1 expression. A variety of tumorigenicity assays were performed using the transformed cells. Conversely, a recombinant retroviral short hairpin RNAi (shRNA) delivery system against MUC1 was developed. Efficacy and optimal dosing of shRNA against MUC1 was determined. MUC1 over-expressing human TC cells were stably treated, resulting in decreased MUC1 expression. Tumorigenicity assays were repeated.
Increasing the expression of MUC1 in TC cells resulted in increased cell proliferation, anchorage independent growth and invasive capacity. We found increased activity of matrix metalloproteinase 9 (MMP-9) in these cells. MMP-9 inhibition reversed the increased invasive phenotype, suggesting MUC1 induced MMP-9 activation as a potential mechanism of action. RNAi mediated decrease in the expression of MUC1 resulted in decreased cell proliferation, anchorage independent growth and invasive capacity. Our experimental data corroborates our preliminary data. This is the first report which provides direct evidence implicating MUC1 in the pathogenesis of thyroid carcinoma with MMP-9 activation as a potential mechanism of action. In vivo studies are currently being performed.
We wish to thank the AHNS for their kind and generous support of our research. We were able to perform and complete a majority of the experiments proposed and have had very encouraging results. We have been pleased with our progress and hopefully these results will help us launch into the next phase of our investigations.
Abstracts and Manuscripts:
Patel KN, Maghami E, Yu Z, Wreesmann VB, Ghossein R, Singh B. Anti-MUC1 targeting leads to growth inhibition in aggressive thyroid carcinoma. (For submission, Cancer Res)
Patel KN, Maghami E, Wreesmann VB, Shaha AR, Shah JP, Ghossein R, Singh B. MUC1 plays a role in tumor maintenance in aggressive thyroid carcinomas. Surgery. (in press)
Expenditures (one year grant period 6/04 – 5/05):
Laboratory supplies and core services, experimental reagents, additional antibodies: $3200
Research assistant support: $5000
Fringe Benefits: $1800