Servicio de Información Comunitario sobre Investigación y Desarrollo - CORDIS


MalOnco Informe resumido

Project ID: 615905
Financiado con arreglo a: FP7-IDEAS-ERC
País: Denmark

Periodic Report Summary 2 - MALONCO (Targeting cancer using evolutionary refined pathogen derived antigens)

As an immune evasion survival strategy the P. falciparum malaria parasite has evolved a protein named VAR2CSA, which mediates parasite binding in the placenta through interaction with uniquely sulfated Chondroitin Sulfate A (CSA) proteoglycans on the throphoblast cells, thereby avoiding circulation in the blood. The background for our project was the finding that these unique placental type CSA molecules were also present on a number of cancer cells. In the ERC project we started out by consolidating these finding by testing a very large and wide range of cancer cell lines and tissue biopsies. We demonstrate that VAR2CSA binds with high affinity and specificity to the vast majority of the cells (>95%) with no binding to primary non-cancer cells and VAR2CSA tissue staining correlations with progression of cancer. Pull down experiments and mass spectrophotometry demonstrate that this secondary CSA modification is present on at least 15 well defined (cancer expressed) proteoglycans. Functional studies demonstrate that VAR2CSA binding to CSA on cancer cells hinders growth, migration and invasion by hindering focal adhesion. In vivo data show that IV treatment of animals with VAR2CSA hinders metastasis formation. Intra venous injected VAR2CSA rapidly locates to the tumor tissue, in several tested models including melanoma, prostate cancer and glioblastoma. A drug conjugate has been made by adding a toxin to VAR2CSA. This drug conjugate has been tested in a wide range of cancer models (Glioblastoma, Melanoma, Metastatic breast cancer, Prostate cancer, Lymphoma and Cisplatin resistant bladder cancer). In all models we observe a dramatic effect on tumor growth, and in several of the models animals were cured from the engrafted cancer. We are now working towards being able to test a VAR2CSA treatment in cancer patients. Focus will be on pharmacokinetics, immunogenicity, increased efficacy as well as on manufacturing procedures.

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