Characterization of B7-H3: A target for monoclonal antibody therapy of human solid tumors.
Monoclonal antibody (mAb) 8H9 radioimmunotherapy has shown promise in patients with central nervous system (CNS) relapse. It is specific for cell surface glycoprotein gp58. This project was initiated with the biochemical characterization of gp58, which was purified from the extract of neuroblastoma cell line LAN-1 by 8H9-affinity chromatography and was unequivocally identified by mass spectrometry as 4Ig-B7-H3, the long and principal form of B7-H3, an immune modulator which is known to inhibit immune cell attack by natural killer (NK) and T-cells. While B7-H3 transcript was ubiquitously expressed in solid tumors and normal human tissues, B7-H3 protein was detected by 8H9 only in human solid tumors, and not in most normal tissues, including normal CNS tissues tested. Currently the research focuses on: (1) investigating the mechanism behind B7-H3 overexpression in solid tumors, especially the role of microRNAs in its regulation. Modulating B7-H3 protein expression may improve therapeutic potential of mAbs like 8H9, especially for patients with metastatic solid tumors; (2) identifying the putative B7-H3 receptor(s) on activated NK/T cells, and determining which receptor(s) functions primarily as a coinhibitory molecule. Unraveling the role of B7-H3 coinhibitory receptor(s) may help in developing more efficient, innovative NK/T cell-based therapeutic approaches in neuroblastoma and other solid tumors.
Effects of Chk1 inhibitor on neuroblastoma cells and its potential for combination therapy in neuroblastoma.
Although rare at diagnosis, aberrations in p53/MDM2/p14ARF pathway are frequently found at relapse in patients with advanced neuroblastoma (NB). These aberrations probably account for chemoresistance after an initial treatment response. Selective inhibitors of checkpoint kinase Chk1 can enhance the action of DNA-damaging agents in carcinomas, especially those with p53 mutations. By expression array, Chk1 expression is high in NB cell lines and a subset of NB tumors. But effects of Chk1 inhibition on tumors with aberrations in p53 pathway (p53 mutations, p14ARF methylation, p14ARF deletion, and MDM2 amplification) have never been systematically studied in NB. Our preliminary studies have shown that NB cell lines are highly sensitive to Chk1 inhibitor in vitro, which synergizes with conventional DNA-damaging agents, particularly in chemoresistant NB cells with p53 mutations. Now the project focuses on: (1) establishing which aberrations other than p53 mutations result in chemoresistance; (2) determining whether Chk1 inhibitor synergizes in vitro with DNA-damaging agents in cell lines with those aberrations; (3) determining whether Chk1 inhibitor potentiates in vivo anti-tumor efficacy of DNA-damaging agents in mouse xenograft model with those aberrations.
Xu H, Cheung IY, Guo HF, Cheung NK. MicroRNA miR-29 Modulates Expression of Immunoinhibitory Molecule B7-H3: Potential Implications for Immune Based Therapy of Human Solid Tumors. Cancer Research 2009 69(15):6275-81.