In vivo drug screening in Drosophila for cancer stem cells
Drug screen for cancer stem cells
Chemotherapeutic treatments for cancer can effectively reduce tumor mass, but the disease often relapses. To explain this phenomenon, the cancer stem cell (CSC) hypothesis suggests that tumors contain a small number of tumor-forming, self-renewing, CSCs within a population of non-tumor-forming cancer cells. Unlike most cells within the tumor, CSCs are resistant to well-defined chemotherapy, and after treatment they can regenerate all the cell types in the tumor through their stem cell-like behavior. For this reason, drugs that selectively target CSCs offer great promise for more complete cancer treatment, although none are known at present. For this reason, drugs that selectively target CSCs offer great promise for more complete cancer treatment; however, finding such drugs remains a great challenge.
A major challenge in cancer therapeutics is to identify drugs that target cancer stem cells. The Perrimon laboratory has developed novel methods and approaches which will identify drugs that cause cancer stem cells to die or differentiate into non-dividing daughter cells. This technology can be used for the following applications:
• Drug screening to identify and validate compounds which target cancer stem cells
• Characterize the novel hit compounds discovered by the Perrimon lab to identify potential novel cancer therapeutics
Innovations and Advantages
Traditional high-throughput screening approaches for drugs that target CSCs are problematic because the complex cellular interactions underlying stem cell biology are difficult to recapitulate in vitro. Researchers in the Perrimon laboratory have therefore used the well-characterized stem cell biology of the adult Drosophila gut as a vehicle to develop novel methods and approaches to screen in vivo for anti-cancer drugs that target CSCs:
• Transgenic fly models for stem cell cancer: A series of tumor models that use a promoter to drive the expression of a number of oncogenes in gut stem cells.
• Novel method to screen cancer growth in vivo: A screening method that uses a luciferase reporter to measure changes in tumor size from whole-animal homogenates.
• Novel platform for drug screening: An assay to feed adult flies drugs in a 96-well plate format. Using this screen, the Perrimon lab identified 25 hits which demonstrated a 50% or greater reduction in luciferase following drug treatment. The initial hits include novel compounds as well as several FDA approved anti-cancer therapies. Further confirmation of the hits was then assessed by dissecting and imaging cells in the gut. The researchers found that many hits specifically block tumor stem cells with no change in the number of wild type stem cells. Paradoxically, some other compounds were shown to block stem cell tumor growth while promoting wild type stem cell growth.
• Assay to determine cell specificity of drugs: An assay which differentiates between a stem cell autonomous effect versus a drug which has a stronger effect on neighboring cells such as daughter cells. Hits from the drug screening assay that promote wild type stem cell growth were found to induce the expression of evolutionarily conserved signal transduction pathway reporters in daughter cells. Thus, this assay will enable the detection of drugs that kill tumor stem cells with or without activating stress pathways in daughter cells.
Intellectual Property Status: Patent(s) pending
This technology is available for worldwide, exclusive licensing and/or a collaborative research program with the Perrimon laboratory.
Perrimon, Norbert J.
For further information, please contact:
Grant Zimmermann, Director of Business Development
Reference Harvard Case #4020