Therapeutic Targeting of Exportin-1 in Childhood Cancer

SIMPLE SUMMARY: Exportin-1 is a nuclear transport protein that is overexpressed in cancer cells and associated with inferior outcomes across a range of malignancies. Selinexor is a novel FDA-approved inhibitor of Exportin-1 (XPO1). Although significant research has focused on integration of selinexor into the treatment regimens of adult cancers, it is increasingly recognized that XPO1-directed therapy may be effective as part of management of childhood cancers. We therefore summarize the history of, and latest knowledge about, the function and therapeutic inhibition of XPO1 as it relates to childhood cancer pathogenesis and treatment. ABSTRACT: Overexpression of Exportin-1 (XPO1), a key regulator of nuclear-to-cytoplasmic transport, is associated with inferior patient outcomes across a range of adult malignancies. Targeting XPO1 with selinexor has demonstrated promising results in clinical trials, leading to FDA approval of its use for multiple relapsed/refractory cancers. However, XPO1 biology and selinexor sensitivity in childhood cancer is only recently being explored. In this review, we will focus on the differential biology of childhood and adult cancers as it relates to XPO1 and key cargo proteins. We will further explore the current state of pre-clinical and clinical development of XPO1 inhibitors in childhood cancers. Finally, we will outline potentially promising future therapeutic strategies for, as well as potential challenges to, integrating XPO1 inhibition to improve outcomes for children with cancer.