Morphoproteomics Provides Further Insight into the Biology of Metastatic Osteosarcoma and Identifies Potential Therapeutic Targets.
Sanda Alexandrescu, Pete Anderson, Jamie Buryanek, Robert E Brown. University of Texas- Medical School, Houston; MD Anderson Cancer Center, Houston, TX
Background: Metastasis in osteosarcoma decreases the survival to 10-25%. Establishing a targeted therapeutic protocol for these patients is challenging, because of genetic instability. However, these tumors have common biologic components that might be targets for therapy (expression of c-Met, TRAIL (DR4), and activation of insulin-like growth factor-1 receptor (IGF1R) signaling pathway).
Design: Three consulting pathologists examined tissue from four MD Anderson Cancer Center patients (age range 11-16) with multiple sites of metastatic osteosarcoma unresponsive to treatment. A morphoproteomic analysis of signaling pathways, cell cycle analytes, antiapoptotic/tumorigenic/angiogenic/chemoresistance factors, proapoptotic proteins and stem cell markers was performed.
Results: We observed: variable activation of ras/Raf kinase/extracellular signal regulated-kinase (ERK) pathway, evident by nuclear translocation of p-ERK1/2 (Thr202/Tyr204) in a majority of the tumor cells; activation of the mammalian target of rapamycin (mTOR) pathway in many tumor cells with p-mTOR(Ser 2448) in both cytoplasmic and nuclear compartments (consistent with variable mTORC1 and mTORC2 activation); brisk cell cycle progression;expression of tumorigenic proteins, heat shock protein (Hsp)90, p-p38MAPK (Thr 180/Tyr182)and fatty acid synthase (FAS); proapoptotic TRAIL-DR4 expression; and a CD133 and nestin stem cell immunophenotype. EGFRvIII/wild type, HER-2 and VEGF-A were absent or weakly expressed in a minority of cells.
Conclusions: This consultative study provides an explanation for the limited efficacy of some of the agents used in these patients (bevacizumab, rapamycin, anti-EGFR antibody), and suggests new targeted therapies.Sorafenib and aminobisphosphonates act to downregulate the ras/Raf kinase/ERK pathway. Metformin inhibits IGF-1R signaling pathway at the level of IRS-1, induces TRAIL-mediated apoptosis in osteosarcoma and contributes to cell cycle arrest. It also inhibits fatty acid synthase, representing a convenient substitute for c-MET inhibitor. Doxorubicin sensitizes osteosarcoma cells, but not normal bone cells to Apo2L/TRAIL-induced apoptosis and targets mitotically active tumor. Melatonin inhibits cell cycle progression and augments chemotherapy while minimizing toxic side effects.
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 220, Monday Morning