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targeting the midkine / anaplastic lymphoma kinase axis as a therapeutic strategy in GBM

Israel López-Valero, Deparment of Biochemistry and Molecular Biology I, School of Biology, Complutense University and Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC); David Dávila, Deparment of Biochemistry and Molecular Biology I, School of Biology, Complutense University; Mar Lorente, Deparment of Biochemistry and Molecular Biology I, School of Biology, Complutense University; Sonia Hernández-Tiedra, Deparment of Biochemistry and Molecular Biology I, School of Biology, Complutense University; Sofía Torres, Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC); José González, Deparment of Biochemistry and Molecular Biology I, School of Biology, Complutense University; Aurelio Hernández Laín, Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, Madrid; Pilar Sánchez-Gómez, Neuro-Oncology Unit, Instituto de Salud Carlos III-UFIEC, Madri; Juan Sepúlveda, Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, Madrid and Guillermo Velasco, Deparment of Biochemistry and Molecular Biology I, School of Biology, Complutense University.


Introduction:

Glioblastoma multiforme (GBM) is the most common and lethal form of primary brain tumor. Thus, median survival after diagnosis is usually just 12 to 15 months. These tumors exhibit a high resistance to standard chemotherapy and radiotherapy which has been proposed to be due, at least in part, to the presence within these tumors of a population of cells with stem-like characteristics, named glioma initiating cells (GICs). Thus, GICs may be potential key target for novel GBM therapies.

Previous data published by our group have shown that increased expression of Midkine (Mdk), a growth factor involved in resistance to anti-cancer therapies and in stem cell regulation, correlates with decreased survival in GBM patients. Furthermore, high levels of Midkine and subsequent activation of Anaplasic Lymphoma Kinase (ALK) receptor are critically involved in the promotion of glioma resistance to the antitumoral action of cannabinoid (a novel family of potential anticancer agents derived from Cannabis sativa).

Objectives:

The aim of this work is to analyse the role of the Mdk/ALK axis in GICs and to investiugate the effect of strategies based on combination of cannabinoids with inhibitors of the Mdk/ALK via.

Results:

Our data show that both pharmacologic and genetic inhibition of the MK/ALK axis inhibits the self-renewal capacity of GICs and sensitizes these cells to THC-induced cell death in vitro. Moreover, genetic depletion of Mdk levels prevented the growth of GICs-derived tumor xenografts in mice. We also found that Mdk overexpression in neural progenitors (Nestin+ cells) promotes the growth of Platelet-derived growth factor B (PDGFB)-induced gliomas in the nestin TVA transgenic mouse model.

In addition, the combined administration of cannabinoids and inhibitors of the MK/ALK axis triggers a sustained activation of autophagy that leads to the apoptotic death of GICs, and the almost complete elimination of the GIC population in vitro.

Conclusion:

In summary, our findings support that the Mdk/ALK axis plays a pivotal role in the regulation of GICs and that its blockade could be a potential therapeutic strategy to eliminate the GIC population in GBM patients.

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