selinexor and Hematologic-Neoplasms

Exportin 1 (XPO1), also known as chromosome maintenance 1 protein (CRM1), is the main transporter for hundreds of proteins like tumor suppressors, growth regulatory factors, oncoprotein mRNAs and others. Its upregulation leads to the inactivation of the tumor suppressor anti-neoplastic function in many cancers and logically is associated with poor prognosis. Selective inhibitors of nuclear export (SINE) are a new generation of XPO1 inhibitors that are being investigated as a promising targeted anti-cancer therapy. Selinexor is the first generation of SINE compounds that is being evaluated in many clinical trials involving solid tumors and hematological malignancies with its two approved indications for relapsed multiple myeloma and relapsed diffuse large B-cell lymphoma. Here, we comprehensively review the current knowledge of selinexor and next generations of the SINE compounds in lymphoid and myeloid malignancies.

Topics: Active Transport, Cell Nucleus; Antineoplastic Agents; Disease Management; Exportin 1 Protein; Hematologic Neoplasms; Humans; Hydrazines; Karyopherins; Molecular Targeted Therapy; Prognosis; Receptors, Cytoplasmic and Nuclear; Treatment Outcome; Triazoles

Exportin 1 (XPO1), also known as chromosome region maintenance protein 1, plays a crucial role in maintaining cellular homeostasis via the regulated export of a range of cargoes, including proteins and several classes of RNAs, from the nucleus to the cytoplasm. Dysregulation of this protein plays a pivotal role in the development of various solid and haematological malignancies. Furthermore, XPO1 is associated with resistance to several standard-of-care therapies, including chemotherapies and targeted therapies, making it an attractive target of novel cancer therapies. Over the years, a number of selective inhibitors of nuclear export have been developed. However, only selinexor has been clinically validated. The novel mechanism of action of XPO1 inhibitors implies a different toxicity profile to that of other agents and has proved challenging in certain settings. Nonetheless, data from clinical trials have led to the approval of the XPO1 inhibitor selinexor (plus dexamethasone) as a fifth-line therapy for patients with multiple myeloma and as a monotherapy for patients with relapsed and/or refractory diffuse large B cell lymphoma. In this Review, we summarize the progress and challenges in the development of nuclear export inhibitors and discuss the potential of emerging combination therapies and biomarkers of response.

Topics: Antineoplastic Agents; Cell Line, Tumor; Dexamethasone; Drug Resistance, Neoplasm; Exportin 1 Protein; Hematologic Neoplasms; Humans; Hydrazines; Karyopherins; Lymphoma, Large B-Cell, Diffuse; Molecular Targeted Therapy; Receptors, Cytoplasmic and Nuclear; Triazoles

Recent measures to classify novel molecular targets with therapeutic potential across multiple hematologic tumors have identified the eukaryotic nuclear exporter, exportin 1 (XPO1), as a promising candidate. Molecular agents termed 'Selective Inhibitors of Nuclear Export' (SINEs) have been developed to selectively inhibit the essential regulatory functions of XPO1 in the eukaryotic cell and have been extensively studied in pre-clinical and clinical tumor models. Recently, selinexor (XPOVIO™), a first-in-class oral SINE molecule, was granted accelerated approval by the United States FDA for penta-refractory multiple myeloma. To establish a complete profile of this emerging drug candidate, this article reviews evidence collected from recent clinical studies against both solid and liquid tumors, describing selinexor as a promising new anti-cancer pharmaceutic against late-stage and highly aggressive tumors. With management of well-defined and predictable adverse effects, selinexor can be a life-saving therapeutic option in cancer patients with few alternatives.

Topics: Cell Line, Tumor; Hematologic Neoplasms; Humans; Hydrazines; Triazoles

XPO1 (Exportin-1) is the nuclear export protein responsible for the normal shuttling of several proteins and RNA species between the nucleocytoplasmic compartment of eukaryotic cells. XPO1 recognizes the nuclear export signal (NES) of its cargo proteins to facilitate its export. Alterations of nuclear export have been shown to play a role in oncogenesis in several types of solid tumour and haematologic cancers. Over more than a decade, there has been substantial progress in targeting nuclear export in cancer using selective XPO1 inhibitors. This has resulted in recent approval for the first-in-class drug selinexor for use in relapsed, refractory multiple myeloma and diffuse large B-cell lymphoma (DLBCL). Despite these successes, not all patients respond effectively to XPO1 inhibition and there has been lack of biomarkers for response to XPO1 inhibitors in the clinic. Using haematologic malignancy cell lines and samples from patients with myelodysplastic neoplasms treated with selinexor, we have identified XPO1, NF-κB(p65), MCL-1 and p53 protein levels as protein markers of response to XPO1 inhibitor therapy. These markers could lead to the identification of response upon XPO1 inhibition for more accurate decision-making in the personalized treatment of cancer patients undergoing treatment with selinexor.

Topics: Active Transport, Cell Nucleus; Hematologic Neoplasms; Humans; Karyopherins; Multiple Myeloma