Targeting Ovarian Carcinoma Stem Cells
Revised final rept. 1 may 2009-30 Apr 2012
JOHNS HOPKINS UNIV BALTIMORE MD
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Background Many cancers appear to arise from rare, primitive self-renewing cancer cells, that are biologically distinct from their more numerous differentiated progeny characterizing the malignancy. Although the clinical significance of these cancer stem cells CSC has been uncertain, our data suggest that they are responsible for many of the relapses that follow anticancer therapy. ObjectiveHypothesis We hypothesize that the dramatic initial response rates in ovarian carcinoma represent therapeutic effectiveness against the differentiated cancer cells making up the bulk of the tumor, while the high rate of relapses represent rare, resistant CSC. The overall objectives of these studies are to identify and characterize ovarian CSC, and to develop novel therapies that target these cells. Shared stem cell characteristics and pathways will be key elements of both the characterization and therapeutic investigations. Specific Aims 1 Identify, isolate, and characterize ovarian CSC, and 2 Develop clinical approaches for eliminating ovarian CSC. Study Design. Using a spontaneously developing rat ovarian carcinoma FNAR that mimics the human disease, strategies will be developed to isolate and characterize ovarian CSC. These results will be used to guide similar studies using human ovarian cell lines, and ultimately primary human ovarian carcinoma. Our preliminary data show that aldehyde dehydrogenase ALDH expression marks FNAR cells which initiate tumors in rats. These cells highly CD24, CD44 and CD47 when compared to the bulk tumor cells. Preliminary data demonstrate human ovarian cancer cell lines contain a parallel ALDH-expressing cell population. Potential therapeutic strategies will also be initially tested in the rat model and human cell lines those with activity in these models will be evaluated against ovarian CSC from clinical specimens.
- Medicine and Medical Research