Posted August 25, 2015
Xiao-Nan Li, M.D., Ph.D., Baylor College of Medicine
DIPG is the most lethal childhood cancer. Approximately 300 children are diagnosed with DIPG each year, and less than 1% of those children will live 5 years beyond diagnosis. DIPG is a tumor found in the pons, the region that joins the spinal cord to the brain. The pons controls critical functions such as breathing, blood pressure, and heart rate. As the name suggests, DIPG is so devastating because the tumor cells grow through healthy tissue, making surgical recession impossible. Until recently, little progress had been made toward developing effective treatments due to a lack of experimental model systems.
In fiscal year 2010, Dr. Xiao-Nan Li from Baylor College of Medicine utilized a Peer Reviewed Cancer Research Program Concept Award to investigate the feasibility of using autopsied DIPG tissues to develop a mouse xenograft model (i.e., injecting DIPG cells into a mouse to form a new tumor). Dr. Li challenged the prevailing dogmas that insufficient viable tumor cells could be harvested from autopsied tissue to establish models and that, even if viable cells were recovered, the mouse brain stem was so fragile that injection of DIPG cells would incapacitate or kill the mouse. Early in the award, Dr. Li established that indeed, a population (~10% of the total cells) of the cells from an autopsy sample still consisted of viable tumor cells. Furthermore, these DIPG cells were tumorigenic and formed xenograft tumors in the brain stems of mice that replicated the relevant histopathological features of the original patient tumors. A characteristic important for the development of this as an experimental model, the xenografts could be propagated by serial subtransplantation. A few xenografts were even adapted to culture conditions—a first for DIPG cells. Finally, novel dysregulated and mutated genes were identified after sequencing the genetic material of two xenograft models and four autopsied DIPG tumor samples.
This work provides critically needed, and clinically relevant, DIPG animal models. These model systems form the foundation for studies searching for potential therapeutic targets. Once targets are identified, the models can then be used to test the safety and efficacy of potential therapeutics.
One such study using Dr. Li's model system can be found in a recently published article in Nature Medicine. Drs. Charles Keller and Michelle Monje led a large, collaborative effort to identify and develop effective treatments for DIPG. The mice with DIPG xenografts established by Dr. Li were treated with a putative therapeutic agent identified from a panel of 83 potential candidates. Furthermore, collaborators on this study utilized this model to define a potential therapeutic strategy for DIPG. This is a crucial step toward finding a treatment for a disease that is currently untreatable.
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