Novel therapy for neuroblastoma : focus on prostaglandin E2 and microsomal prostaglandin E synthases-1

Abstract

Cancer is a major public health problem and to date cancer is one of the leading causes of death worldwide. Neuroblastoma is a malignant pediatric tumor of the sympathetic nervous system. Neuroblastoma is one of the most common and deadliest extra cranial tumors of childhood. During the last decades, the survival rate has increased for children with neuroblastoma. However, this mainly accounts for children with favorable tumor biology while only 40-50% of children with high-risk neuroblastoma survive their disease despite very intensive treatment regimen. This demands a better understanding of high-risk neuroblastoma biology to enable novel therapeutic approaches.

Solid tumors are composed by a variety of cellular components including malignant cells and non-transformed stromal cells. The complex interaction between these cells creates the tumor microenvironment and contributes to tumor growth and initiation. Prostaglandin E2 (PGE2) regulates tumor inflammation and immune suppression, angiogenesis, metastasis, tumor progression and therapy resistance.

PGE2 production is conducted via the conversion of arachidonic acid (AA) by the cyclooxygenase enzymes (COX-1 and COX-2) into the intermediate prostaglandin H2 (PGH2), subsequently converted by microsomal prostaglandin E synthase-1 (mPGES-1), the terminal enzyme responsible for induced PGE2 formation. Inhibitors of the COX enzymes are potent preventive agents in several malignancies. However, clinical use of COX inhibitors in oncology has been hampered due to side effects caused by unselective inhibition of all products downstream of PGH2 that are important for normal cellular functions. In this thesis we improve the biological understanding of PGE2 in neuroblastoma and investigate if inhibition of mPGES-1 in neuroblastoma could maintain the anti-carcinogenic effect of COX targeting without the severe side effects. Investigation of neuroblastoma tissues and cell lines revealed an abundant expression of all PGE2 receptors and PGE2 increased neuroblastoma cell growth and induced activation of survival signaling cascades. Inhibition of PGE2 receptor signaling reduced cell survival.

Investigation of aggressive high-risk neuroblastoma subsets revealed a highly activated PGE2 synthesis pathway with elevated levels of PGE2 in tumors due to high mPGES-1 expression and low expression of 15-PGDH, responsible of PGE2 degradation. Compared to adult malignancies little is known of the role of inflammation in childhood cancers. Analysis of the microenvironment of the high-risk tumors showed a higher infiltration of immunosuppressive macrophages compared to low-risk tumors indicating a tumor-promoting inflammatory local milieu. Furthermore, we could show that infiltrating cancer-associated fibroblasts (CAFs) in the neuroblastoma microenvironment was the major source of mPGES-1 expression. Pharmacological inhibition of mPGES-1 in preclinical in vivo models modulated the microenvironment towards a less tumor-promoting state and significantly reduced tumor growth. In an established in vitro model recapitulating in vivo features of neuroblastoma, inhibition of mPGES-1 augmented the cytotoxic effect of conventional chemotherapeutics.

In this thesis it is concluded that mPGES-1 targeting represents a promising novel therapy in neuroblastoma. Further, the importance of deepened understanding of the complex interactions and heterogeneity within the neuroblastoma microenvironment is underlined.