Pediatric Anaplastic Ependymoma: Morphoproteomics and Biomedical Analytics Identify Hypoxia Pathway Signaling and Provide Targeted Therapeutic Options
Alyaa Q Al-Ibraheemi, Mary F McGuire, Robert E Brown. UT Health-Medical School, Houston, TX
Background: Relapsed, anaplastic ependymoma carries a poor prognosis, eventuating in death in approximately 90% of patients. Such tumors are largely chemoradioresistant. New therapeutic strategies will require defining the biology of anaplastic ependymoma. Objective: To profile pediatric anaplastic ependymomas using morphoproteomic techniques in an effort to identify pathogenetic commonalities amenable to therapeutic intervention and to employ biomedical analytics to translate such findings into targeted therapies. Study Population: Six (6) pediatric patients (ages 3 to 10 years)with recurrent/progressive anaplastic ependymoma were included in this IRB approved study using morphoproteomic analysis.
Design: Morphoproteomics and biomedical analytics. Representative sections from formalin-fixed, paraffin-embedded sections of histopathologically proven cases of anaplastic ependymoma were received for morphoproteomic analysis.
Results: Hypoxia-inducible factor (HIF)-1 alpha expression with nuclear translocation was identified in four out of six tumors and showed correlative expression of:phosphorylated (p)insulin-like growth factor receptor; p-mammalian target of rapamycin (mTOR)[Ser2448] with nuclear translocation (favoring mTORC2); cyclo-oxygenase (COX)-2; p-p38 mitogen-activated protein kinase (MAPK)[Thr180/Tyr182]; secreted protein acidic and rich in cysteine (SPARC);and hypoxia/stemness markers to include CD133 and nestin.These coincided with the presence of ischemic-type coagulative necrosis in the same four cases. Biomedical analytics were then applied to the morphoproteomic analysis data. For each case, a scored profile was computed and used to generate the most likely biological pathway network model. The models revealed interactions with therapeutic agents that modulate hypoxia pathways including metformin, a histone deacetylase inhibitor (valporic acid), melatonin, celecoxib and doxorubicin
Conclusions: The application of morphoproteomics to recurrent/progressive anaplastic ependymoma cases reveals protein correlates of hypoxia pathway signaling which also accord with coagulative type necrosis in 4 out of 6 cases. This represents an adaptive pathway in such tumors to allow the emergence of chemoradioresistant populations and recurrent disease. Morphoproteomic analysis and biomedical analytics provide therapeutic options designed to target this adaptive pathway in cases in which the hypoxia pathway is identified.
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 285, Monday Morning