The manuscript, in which the CNIO groups of Dr. Mariano Barbacid and Dr. Manuel Hidalgo, as well as the Group of Dr. Bruno Amati at the Italian FIRC Institute of Molecular Oncology (IFOM) have participated, describes a new strategy that allows a selective killing of cancer cells, given that the tumors present a particular feature. One of the main limitations of current cancer therapy is that the treatment usually is not only toxic for the tumor, but also for the healthy tissue. This is the source of the widely known off-target effects of radio- and chemo-therapy; which may significantly affect the patients health. In this context, many of the current efforts are dedicated to the discovery of chemicals that are particularly toxic for cells harboring cancer-associated mutations. Besides the presence of mutations, another approach is whether the therapy could exploit a more generic feature of cancer cells.
In 2005, several groups reported that a number of cancers present elevated levels of replicative stress, a kind of stress that derives from a deficient DNA replication. During the last 5 years at the CNIO, the group of Dr. Fernandez-Capetillo has focused his research in the understanding of what replicative stress is, and in the investigation of the cellular mechanisms that protect from this stress. In what refers to cancer, the group has been elaborating on a simple idea: “if –and only if- cancers present high levels of replicative stress, then they might be particularly sensitive to chemical inhibitors that eliminate the cellular protection against replicative stress”.
In an article led by Matilde Murga as a first author, the group now describes that tumors harboring high levels of replicative stress are particularly sensitive to the
genetic of chemical inhibition of ATR and Chk1 kinases. These two kinases are the key initiators of the cellular defense against replicative stress, which would explain the high sensitivity of the tumors. As proof of concept, the group shows that Chk1 inhibitors are very effective for the treatment of Burkitt lymphomas, which present high levels of replicative stress. In contrast, this treatment is largely ineffective for the treatment of tumors with no detectable amounts of this stress. In addition to the chemical inhibitor data, the article also shows that limited levels of ATR completely prevent the development of lymphomas and pancreatic tumors initiated by the Myc oncogenes, both of which being characterized with high levels of replicative stress.
Part of the relevance of this work is due to the fact that some of these molecules (i.e. Chk1 inhibitors) were already been tested in the clinic for cancer chemotherapy. However, the results so far were modest and only few patients showed a positive response. The work of Fernandez-Capetillo now helps to understand this poor efficacy, and provides a rationale to identify which patients are most likely to respond to the treatment. The article ends proposing that the use of ATR and Chk1 inhibitors in the clinic should be restricted to the treatment of tumors that present high levels of replication stress.
Related to this same line of work, the group recently reported the development of chemical ATR inhibitors –entirely done at the CNIO- and which showed interesting antineoplastic properties in vitro (Toledo et al Nat Struct Mol Biol 2011). In collaboration with the Experimental Therapeutics Programme of the CNIO, the group is now trying to further develop these molecules into actual drugs that could be tested in the clinic for their antitumoral properties.
The scientific career of Oscar Fernandez-Capetillo has been already recognized nationally and internationally in several occasions, perhaps most notoriously with the Eppendorf Young Investigator Award in 2009, which is the research award coorganized with the prestigious journal Nature and which recognizes the works of
European investigators under 35.
1.- Murga, M., Campaner, S., Lopez-Contreras, A.J., Toledo, L.I., Soria, R., Montaña, M.F., D’Artista, L., Scheckler, T., Guerra, C., Garcia, E., Barbacid, M., Hidalgo, M., Amati, B., Fernandez-Capetillo, O. Exploiting oncogene-induced replicative stress for the selective elimination of Myc-driven tumors. Nat Struct Mol Biol. 10.1038/10.1038/nsmb.2189 2.- Toledo, L.I., Murga, M., Zur, R., Soria, R. Rodriguez, A., Martinez, S., Oyarzabal, J., Pastor, J., Bischoff, J.R., Fernandez-Capetillo, O. A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. (2011) Nat Struct Mol Biol. 18(6):721-7.
About the CNIO:
The Carlos III Health Institute, an institution of the Spanish Ministry of Science and Innovation, established the Spanish National Cancer Research Centre (CNIO) in 1998. The mission of the CNIO is to carry out research of excellence and to offer innovative technologies within the cancer field to the Spanish National Health System. Maria A. Blasco is the CNIO Director since June 2011. For more information: www.cnio.es
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