Project 467245

The nuclear export protein Exportin 1 (XPO1), which carries proteins, ribosomal subunits, and RNA into the cytoplasm, is overexpressed in almost all patients with solid and hematological cancers. Selinexor, a selective inhibitor of nuclear export (SINE), has demonstrated strong anti-cancer activity with minimal effects on normal cells, leading to its accelerated FDA approval for diffuse large B cell lymphoma (DLBCL) and multiple myeloma (MM). However, there are large knowledge gaps in understanding what XPO1 exports in DLBCL and how this is affected by Selinexor. This lack of understanding means that there is no grasp on who may benefit from Selinexor treatment, who may not respond to it, and what drugs it can be combined with effectively. My research project aims to fill this knowledge gap by identifying cargo of XPO1 and how its affected by Selinexor using proximity-dependent labelling via BioID. Due to the complex role of XPO1, I predict that it will carry specific cargo in DLBCL that is relevant to cancer progression and treatment resistance in this lymphoma, and that Selinexor can modulate this process in ways that promote anti-cancer activity both as a single agent and in combination with other drugs. By identifying cargo of XPO1 and the effects of Selinexor, I will discover which downstream pathways are involved in oncogenic nuclear export, thus allowing identification of drugs that can be used in combination for strong anti-cancer effects. This will inspire sound preclinical and clinical trials for Selinexor combination therapies, which may result in effective anti-cancer therapies for DLBCL.