Gene Targeting of Stem Cells: Cancer Therapy

Research has recently uncovered the presence of so-called cancer stem cells in a number of human malignancies.  These cells have the potential to re-initiate and propagate tumor formation even after the primary tumor has been removed. Further, they tend to be resistant to chemotherapy.  Fundamental questions remain concerning the genesis of these cancer stem cells and what strategies might be employed to eradicate them. Trainees in this area will be coadvised by IGERT faculty with expertise in three-dimensional in vitro glioma models (C. Roth, BME), a combination of molecular and systems biology measurements (R. Hart, BMB and S. Gunderson, BMB), and advanced data mining methodologies (G. Bhanot, BioMAPS), to discover regulatory pathways contributing to the cancer stem cell phenotype.

Fig. 12 Stem Cells for Cancer Therapy:  Mesenchymal stem cells engineered with interferons IFNaA caused killing of B16/F0 melanoma cancer cells compared to controls (left).  Flow cytometry confirms decreased counts on the right (see red arrow) indicating inhibition of growth of cancer cells.

Identification of central molecular players in this process will provide new therapeutic targets that exploit the unique properties of the cancer stem cell niche.  Another exciting project area comes from the lab of S. Pestka (MB), a renowned scientist who developed interferons, a widely used family of cytokine drugs (see Fig. 12).  Despite their promise in treating cancers, at higher levels, interferons injected into patient's blood stream can have debilitating side effects and cannot be tolerated. Given that stem cells home toward tumors, IGERT Trainees will genetically engineer stem cells to produce these interferons near the site of tumor, thus improving efficacy and reducing the side effects of chemotherapy. IGERT Trainees will also research several challenging questions in collaboration with C. Roth (BME): To what extent do stem cells alter the profiles of chemotherapeutic drugs?  How does one resolve the challenge of delivery/fate of stem cells to tumor microenvironments ?