Daniel Birnbaum

XPO1, therapeutic … and prognostic target in sarcomas

In a recent issue of Oncotarget [1], Nakayama et al. showed the anti-tumor activity of selinexor, an inhibitor of exportin 1, against a wide variety of sarcoma preclinical models, including several pathological subtypes of soft tissue sarcomas (STS). STS, which amount to less than 2% of adult cancers are a heterogeneous disease with ∼50 different pathological subtypes [2]. Surgery is the main treatment of patients with early stage STS. Despite surgery, more than 40% of cases will experience metastatic relapse. The survival benefit of adjuvant anthracycline- based chemotherapy remains unproven today, perhaps in part because of the absence of accurate prognostic features and predictors of response to chemotherapy. Identifying new prognostic features, complementary and/ or more accurate than the current ones, is crucial. These may be molecular, such as the gene expression signature CINSARC [3]. In patients with metastasis not amenable to curative-intent surgery, the first-line treatment involves palliative chemotherapy, which has not changed over the three past decades and remains based on doxorubicin with or without ifosfamide. After intolerance or failure, the currently approved second-line therapies include chemotherapies (trabectedin, ifosfamide, dacarbazine) and a recently approved targeted therapy (pazopanib). Clearly, the improvement of systemic therapies is needed. The Nakayamas study represents a promising new avenue of research. Selinexor is a novel and safe oral small-molecule inhibitor of exportin 1 (XPO1/CRM1) with broad antitumor activity [4]. Exportin 1 is a karyopherin that mediates the nuclear export (and subsequent inactivation) of tumor suppressors such as P53, P73, BRCA, and P21. Exportin 1 is also involved in the activation of oncogenic pathways, through enhanced nuclear export of EIF4E, the sole transporter of guanine-capped mRNAs, including mRNAs for oncogenes such as MYC, cyclin D1, and MDM2. Thus, XPO1 inhibition provides a novel and promising anticancer strategy able to prevent inactivation of tumor suppressors and the translation of several key mRNAs and proteins by preventing their export and restricting them to the nucleus. XPO1 overexpression has been reported in different solid cancers and is associated with poor prognosis [5,6]. To our knowledge, XPO1 expression has never been assessed in clinical samples of STS.