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249, KPT-251, KPT-276 and KPT-330 (Selinexor). As summarized in Tables 3 and 4, SINE compounds have
been extensively tested in preclinical models of many different hematological malignancies [80,82,83,100,101,137-157]
and solid tumors [89,95,97,158-188] . In these models, SINEs have demonstrated potent in vitro and in vivo activity
against cancer cells (including growth inhibition, induction of apoptosis, and cell cycle arrest), with only
minor toxic effects on normal cells. Importantly, several SINEs (most prominently Selinexor) have been
shown to increase the sensitivity of cancer cells to currently used drugs, such as doxorubicin or the protea-
some inhibitors bortezomib and carfilzomib, and also to synergize with other targeted therapeutic agents,
such as ibrutinib (an inhibitor of Bruton tyrosine kinase) or linsitinib (an inhibitor of insulin-like growth
factor receptor-1). A more extensive and detailed discussion of the preclinical results obtained with SINEs
in specific tumor settings can be found in recent reviews [9,10,79,133,189] .

In general terms, the anticancer effect of XPO1 inhibition is thought to rely on the relocation of mislocal-
ized XPO1 cargos with tumor-suppressive and growth-regulatory functions (e.g., p53) to the nucleus, where
they carry out their normal activity. In our opinion, this may be an overly simplistic view. Given the large
number of potential XPO1 cargos with a role in cancer, the export-independent roles of XPO1, and the
complex nature of the tumorigenesis process, the specific molecular and cellular mechanisms underlying
the anticancer effect of SINEs may differ in different tumor settings. In this regard, as indicated in Tables
3 and 4, preclinical studies are providing important information on tumor context-specific proteins and
signaling pathways that may mediate SINE activity, such as the BCR-ABL oncoprotein in CML mentioned
[176]
above, or the NF-κB pathway in lung cancer .
Intriguingly, there is emerging evidence that, in addition to cancer, other conditions, such as demyelinat-
[190]
[191]
ing diseases or viral infections might be amenable to treatment with SINEs.
Evaluation of Selinexor in clinical trials
In preclinical studies, Selinexor compared favorably to other “first-generation” SINEs in terms of the bal-
ance between potency and tolerability. Selinexor, an orally available drug, is the only compound of the
series that has advanced into clinical development for human cancer.

The ClinicalTrials.gov site (https://clinicaltrials.gov/, accessed on 11 Jun 2018) registers 60 clinical studies
on different tumor types with Selinexor as single agent or in combination with other drugs. In addition,
there are isolated clinical trials registered for other XPO1 inhibitors, such as the “second-generation” SINE
compound KPT-8602 (Eltanexor) or the non-SINE compound SL-801.

Interim data from some clinical studies with Selinexor have been reported as meeting proceedings (some
of these data are reviewed by Mahipal and Malafa ). Here, we will limit our discussion to the results of
[192]
phase I and II trials that have undergone full peer-reviewed publication as PubMed-indexed articles (sum-
marized in Table 5).

Abdul Razak et al. evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of Selinexor
[193]
in 189 patients with advanced solid tumors, testing several doses and administration schedules. The most
common grade 3 or 4 toxicities in this series were thrombocytopenia, fatigue, and hyponatremia. One
hundred and fifty seven patients were evaluable for response. Seven patients achieved partial or complete
response, and 27 patients achieved stable disease for ≥ 4 months. The authors concluded that Selinexor is
a safe therapeutic with broad antitumor activity, and proposed a recommended phase II dose (RP2D) of
35 mg/m with a twice-a-week dosing schedule.
2

Gounder et al. [194] carried out a phase I study on 54 patients with advanced soft tissue or bone sarcoma.
2
2
Selinexor was administered twice per week at doses of 30 mg/m , 50 mg/m , or 60 mg flat dose. The most