Selinexor

Exportin 1 (XPO1), a nuclear export protein frequently overexpressed in multiple myeloma (MM), represents a validated therapeutic target. However, noninvasive imaging approaches capable of assessing XPO1 engagement and pharmacodynamic modulation during therapy remain limited. Here, we present the radiosynthesis and preclinical evaluation of [¹⁸F]selinexor, an XPO1-targeted positron emission tomography (PET) radiotracer derived from the clinically used drug selinexor via an ¹⁸F/¹⁹F isotope exchange method. This labeling approach preserves the parent drug's molecular structure and pharmacological characteristics, enabling in vivo tracking of selinexor. [¹⁸F]Selinexor was synthesized with a radiochemical yield of 23.9 ± 4.1% and molar activity of 0.41 ± 0.08 GBq/μmol. The tracer exhibited favorable stability, XPO1-specific binding, and tumor retention. PET imaging and pharmacokinetic analysis demonstrated rapid systemic distribution followed by slow elimination, closely consistent with known pharmacokinetics of selinexor. Predominant hepatobiliary clearance and prolonged blood retention supported optimal tumor uptake at delayed imaging time points, with tracer uptake peaking at 3 h post-injection in MM.1S (2.92 ± 0.30% ID/g) and NCI-H929 (2.50 ± 0.18% ID/g) xenografts. Uptake was markedly reduced upon blocking, confirming the tracer's in vivo specificity. During therapeutic intervention, repeated selinexor administration effectively suppressed tumor growth and was accompanied by a progressive reduction in tumor uptake from 3.03 ± 0.25% ID/g (day 0) to 0.93 ± 0.13% ID/g (day 15). Notably, this reduction in uptake occurred independently of changes in tumor volume and correlated with decreased XPO1 expression by immunohistochemistry. Conversely, doxorubicin reduced tumor size without affecting uptake, indicating preserved XPO1-associated signal. Together, these findings demonstrate that [¹⁸F]selinexor PET functions as a noninvasive imaging tool for evaluating the in vivo pharmacokinetics and pharmacodynamic behavior of selinexor, and capturing treatment-induced alterations in XPO1 engagement, although further structural optimization will be required prior to potential translation.

Preclinical studies showed a synergistic antileukemia activity with combination of selective XPO1 inhibitor selinexor (SEL) and venetoclax (VEN), with potential to overcome VEN resistance by reducing the anti‐apoptotic protein MCL1. In an investigator‐sponsored, open‐label, phase Ib study (NCT03955783), adult patients with relapsed or refractory acute myeloid leukemia (R/R AML) were enrolled. After the dose‐escalation phase, SEL 80 mg po weekly plus VEN 400 mg/day following ramp‐up was deemed the recommended phase II dose. Responses were assessed with IWG2003 and ELN 2022 criteria. Nineteen patients with R/R AML were enrolled. Median age at enrollment was 67.2 (range, 21.1–83.8) years. Overall, patients received median of 3 (range, 1–5) prior lines of therapy. The most common grade 3–5 treatment emergent adverse events (TEAE) were anemia (39%), neutropenia (33%), febrile neutropenia (28%), and thrombocytopenia (28%). Overall, the response rate with SEL‐VEN was 21%. Two (11%) patients, one with prior allo‐HSCT and one with prior VEN and both treated with SEL 80 mg/week, experienced complete remissions, with duration of response of 7 and 9.1 months, respectively. After a median follow up of 3.0 (range, 0.6–15.4) months, median event‐free survival was 2.4 (95% CI: 1.9–12.1) months and median overall survival was 6.4 (95% CI: 2.5–12.1) months. In conclusion, SEL‐VEN was feasible and active in a heavily pretreated AML cohort, with no new toxicity signal, but survival outcomes remained poor. The second‐generation XPO1‐inhibitor eltanexor, combined with VEN may further improve outcomes in VEN resistant AML in an ongoing study (NCT06399640).