SINE compounds have been studied as a novel anticancer strategy in multiple preclinical trials of hematologic malignancies. Higher levels of XPO1 are associated with poor prognosis in acute leukemia [
65]. Earlier preclinical work demonstrated that KPT-185 inhibited proliferation and induced G1 phase cell cycle arrest in AML cell lines and primary AML blasts
in vitro[
25]. Nucleophosmin 1 (NPM1) is a nucleolar TSP that shuttles between the nucleolus and cytoplasm via the XPO1-RanGTP pathway and regulates p53 dependent cell death [
66]. NPM1 mutations in AML cells were seen in 25% to 35% cases [
67]. These mutations cause increased XPO1 binding and localization of NPM1 in the cytoplasm [
68]. SINEs block this export of mutant NPM1 and induce antileukemic effects in AML cell lines and primary AML blasts. AML blasts with NPM1 mutations were very responsive to KPT-185 and had an IC
50 of 100 nmol/L. However, wild type (WT) NPM1 in AML cells were also sensitive to SINEs, indicating that other TSPs like p53 also have a role in the antileukemic effects of SINE. Kojima
et al. further established that p53 is a major determinant in SINE induced cytotoxicity in AML, independent of NPM1. Mutant p53 samples were less sensitive to KPT-185 [
65]. XPO1 inhibition by SINE also resulted in blast differentiation, likely due to upregulation by p53 and CEBPA [
69], a protein essential for myeloid granulocytic differentiation via activation of several necessary genes [
70],[
71]. SINEs were also shown to downregulate FLT3 and cKIT tyrosine kinase proteins [
25]. FLT3 gene mutation may coexist with NPM1 mutations [
72]. SINE downregulated FLT3 and NPM1. Thus, SINEs can potentially target 2 critical pathways. cKIT mutations or overexpression also confer a worse prognosis in AML [
73],[
74]. Kojima
et al. demonstrated synergistic activity using the combination of SINE with MDM2 inhibitor Nutlin-3a. MDM2, frequently overexpressed in AML, is a p53-specific ligase, promoting p53 degradation [
75]. Nutlin-3a is a selective MDM2 inhibitor, shown to increase nuclear and cytoplasmic p53 and induces p53 mediated apoptosis [
75]. The addition of SINE to Nutlin-3a led to higher p53 nuclear level than by using either agent alone
in vitro[
65]. This combination strategy can be potentially effective not only in AML but in several other malignancies. Furthermore, SINEs are not shown to induce apoptosis in normal hematopoietic cells [
23],[
65],[
76].
Philadelphia chromosome positive ALL remains a challenge even with availability of multiple tyrosine kinase inhibitors [
80],[
81]. Walker
et al. demonstrated successful use of KPT-185
in vitro and KPT-330
in vivo in Philadelphia chromosome positive ALL (Ph + ALL) and chronic myeloid leukemia blast crisis (CML-BC). Combination with imatinib led to synergistic effects [
82]. SINE treatment was associated with significant reduction in BCR-ABL + cells in mice, likely by reactivation of the tumor suppressor proteins PP2A, p53, p21 and FOXO3a [
82].
The preliminary results of an ongoing phase I trial using KPT-330 in relapsed/refractory AML were presented Yee
et al. recently. They showed that KPT-330 treatment given to heavily pretreated, refractory/relapsed AML patients had no DLT. Out of the 32 evaluable patients, 4 (12%) showed complete response (CR) with hematological recovery, 1 (3%) showed marrow CR (mCR), mCR without hematological recovery was seen in 1 (3%) patient. Partial response (PR) was seen in 2 patients (6%). Eleven patients (34%) showed progression while 12 (37%) experienced stable disease after 30 days [
83].