| PROJECT DESCRIPTION:
Pediatric solid tumors are a heterogeneous group of diseases in which cure rates remain unsatisfactory. The prognosis is particularly poor in patients who relapse or have metastatic disease at diagnosis, as tumors in this setting are often refractory to therapy. There is now substantial evidence that some human cancers contain a subpopulation of tumor-initiating cells, which has been designated Cancer Stem Cells (CSCs). It has been hypothesized that CSCs may play an important role in tumor refractoriness or recurrence after therapy. We, therefore, propose to isolate tumor-initiating cells from pediatric solid tumors, especially those for which current therapy is inadequate such as metastatic osteosarcoma or neuroblastoma; to characterize “stemness” genes related in self-renewal; and to develop a preclinical murine model.
Established cell lines and tumor specimens will be obtained and sorted into subpopulations by flow cytometry using known stem/progenitor cell surface markers. CSCs and non-stem cells will be analyzed for genes associated with stem cell behavior, including ABC transporter proteins, polycomb genes, cyclin dependent kinase inhibitors and members of the Wnt/Hh and Notch pathways. Finally, tumors will be transplanted into NOD/SCID or athymic mice for in vivo study of the “stemness” properties. An independent grant from the St. Baldrick’s Foundation for this project has been awarded to Dr. Rainusso to develop this project in the next years.
We strongly believe that these studies will be of critical importance in the future for the development of new therapeutic strategies to improve the outcome of pediatric patients with solid malignancies.
|
