Abstract 4195: Evaluation of the anti-myeloma effects of high and metronomic selinexor alone and in combination with duvelisib in vitro and in vivo
Authors: Chen Haiming , Behare Stacy , Li Mingjie , Goldwater Marissa , Hekmati Ava , Cao Jasmin , Levin Rocky , Xu Ning , Berenson James 
Published: June 2022

Introduction: Selinexor (Karyopharm Therapeutics) is an FDA-approved oral selective inhibitor of nuclear export (SINE) compound. It specifically blocks XPO1 enforcing the nuclear retention of tumor suppressor proteins restoring their anti-cancer functions. It also attenuates the phosphoinositide-3 kinase (PI3K)-AKT pathway by activating PTEN. Although activation of PI3K signaling is often detected in hematological malignancies, there are no data regarding the combination of selinexor with the PI3K inhibitor duvelisib for MM treatment. Thus, we evaluated the anti-myeloma effects of selinexor in combination with duvelisib in vitro and also studied alternative schedules of selinexor with dexamethasone in vivo using our MM xenograft models LAGκ-2.

Methods: The human MM cell line U266 was obtained from ATCC. Primary MM tumor cells were isolated from MM patients’ bone marrow (BM) aspirates. Cell viability was quantified using the MTS cell proliferation assay. For the in vivo studies, the human myeloma xenograft LAGκ-2 was surgically implanted into SCID mice. Selinexor was administered via oral gavage at 2.5 mg/kg 5x per week, 5 mg/kg 4x per week on consecutive days, or 10 mg/kg 2x per week with one day between treatments. Dexamethasone was administered via intraperitoneal injection at 4 mg/kg 2x per week except the vehicle control.

Results and Discussion: MTS assays showed selinexor induced concentration dependent inhibition of cell viability/proliferation in the MM cell line MM1s at 0.1, 0.4 and 1.6 μM. Selinexor alone at 0.2 μM reduced cell proliferation of primary MM tumor cells obtained from BM mononuclear cells (MCs) from a patient with progressive disease. We next examined cell viability in the presence of selinexor and duvelisib. MM1s or fresh BM mononuclear cells were incubated with a fixed concentration of selinexor (0.1μM) with increasing concentrations of duvelisib (1.5 μM -25 μM) for 48 h. The results showed that duvelisib enhanced the cytotoxic effects of selinexor in a concentration dependent manner. We also evaluated dosing and scheduling of selinexor and dexamethasone in vivo using SCID mice bearing LAGκ-2 MM xenografts. When selinexor was combined with dexamethasone, lower more frequent dosing showed greater inhibition of tumor growth than mid-range and higher less frequent dosing of this SINE. This study illustrates that the combination of selinexor and duvelisib showed enhanced cytotoxic effects in vitro compared with single agent treatment, and we will further evaluate the anti-MM effects of selinexor in combination with duvelisib in vivo using our human MM xenograft models. These studies suggest that the combination of a SINE and PI3K inhibitor may be effective for MM treatment.

Citation Format: Haiming Chen, Stacy Behare, Mingjie Li, Marissa Goldwater, Ava Hekmati, Jasmin Cao, Rocky Levin, Ning Xu, James Berenson. Evaluation of the anti-myeloma effects of high and metronomic selinexor alone and in combination with duvelisib in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4195.