The findings by the research group of Dr. Päivi Ojala (University of Helsinki) in collaboration with the groups of Professor Marikki Laiho (University of Helsinki), Dr. Pirjo Laakkonen (University of Helsinki), and Dr. Jürgen Haas (Max von Pettenkofer Institute, Munich & University of Edinburgh) open new options for exploiting reactivation of p53 as a novel and highly selective treatment modality for this virally-induced lymphoma. The project involves scientists from two Academy of Finland National Centre of Excellence Programs, the Translational Genome-Scale Biology and Cancer Biology.
The study will be published 15.3.2007 in the Journal of Clinical Investigation.
TP53 gene encodes a transcription factor (p53) that plays a central role in protecting cells from tumor development by inducing cell-cycle arrest or apoptosis via a complex signal transduction network referred to as the p53 pathway. TP53 gene is mutated or deleted in 50% of all malignant tumors. A recently discovered strategy for p53 activation targets the interaction of p53 with its negative regulator MDM2. This is based on a potent and selective small-molecule inhibitor of the p53–MDM2 interaction, the Nutlin-3a, originally discovered by Dr Lyubomir T Vassilev (Roche Research Center, Nutley, NJ., USA). Nutlin-3a has been suggested to be a potential treatment option for cancers with wt p53.
PEL is a non-Hodgkin type lymphoma latently infected with KSHV, and it manifests as an effusion malignancy in Kaposi’s sarcoma patients. There are no current therapies effective against the aggressive KSHV-induced PEL. KSHV displays two patterns of infection: latent and lytic phase. During latency, only a restricted set of viral genes is expressed. The KSHV genome encodes several homologues of cellular proteins, which engage cellular signaling pathways, govern cell proliferation and modulate apoptosis.
Majority of the PELs appear to have an intact TP53 gene suggesting that genetic alterations are not selected for during PEL tumorigenesis. The results of this study demonstrate binding of the KSHV latency associated antigen LANA to both p53 and MDM2, and that the MDM2 inhibitor Nutlin-3a disrupts the p53-MDM2-LANA complex and selectively induces massive apoptosis in PEL cells. The cytotoxic effect of Nutlin-3a was specific for the KSHV-infected cells since Nutlin-3a did not induce apoptosis in lymphoblastoid cell lines transformed with another human tumor virus, the Epstein-Barr virus, despite of their wt p53 status.
Moreover, the researchers show that Nutlin-3a has striking anti-tumor activity in vivo in a mouse xenograft model for the PEL. Nutlin-3a treatment resulted in a marked regression of all tumors in the treated animals in two weeks. These results demonstrate that p53 reactivation via Nutlin-3a is an efficient treatment for KSHV-lymphomas in mice and suggest a novel therapeutic strategy for treatment of these fatal virus-induced malignancies also in humans.
This work was supported by grants from the Academy of Finland including also Centres of Excellence in Translational Genome-Scale Biology and Cancer Biology, and additional funds have been obtained from the University of Helsinki, Academy of Finland research program for Systems Biology and Bioinformatics, Finnish Cancer Foundations, Sigrid Juselius Foundation, and from the European Union (FP6 INCA project LSHC-CT-2005-018704).
Paivi Lehtinen | alfa
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