Ganglioside and Their Molecular Mechanisms as Targets for Cancer Immunotherapies

The ganglioside N-glycolyl GM3 is considered an attractive target for cancer immunotherapy since it is a tumor-associated antigen with reported presence in several malignancies. A promising anti-ganglioside antibody specific for N-glycolyl GM3 is 14F7, wh ich currently is in phase II clinical trials. This antibody can discriminate N-glycolyl GM3 from the very similar N-acetyl GM3, which is present in both tumor and normal cells. The research proposed here shall foremost elucidate if and how N-glycolyl GM3 affects EGFR signaling and investigate the role of hypoxia in N-glycolyl GM3 expression and tumor development. Modulation of EGFR signaling by 14F7 will also be tested. This will be carried out concurrently with structural studies of the antigen-antibody complex. While the planned proteoliposome work, cell signaling studies and lipid analyses will be performed in Ünal Coskun's lab at the Paul Langerhans Institute in Dresden, hypoxia and structural studies will be undertaken at UiO. The Krengel lab has pre viously solved the crystal structure of 14F7, although not in complex with the ligand, while the Coskun lab established a minimal proteoliposome system containing the EGF receptor (EGFR), which has been studied in detail for modulation by the ganglioside N-acetyl GM3 and forms the ideal basis for our proposed studies. The project will involve the travel of all participants, including three young female researchers, ensuring the transfer of knowledge between the two groups, the establishment of this new co llaboration, and the development of female research talent.