PIM Kinases Are a Potential Prognostic Biomarker and Therapeutic Target in Neuroblastoma.

The majority of high-risk neuroblastoma patients are refractory to, or relapse on, current treatment regimens, resulting in 5-year survival rates of less than 50%. This emphasizes the urgent need to identify novel therapeutic targets. Here, we report that high PIM kinase expression is correlated with poor overall survival. Treatment of neuroblastoma cell lines with the pan-PIM inhibitors AZD1208 or PIM-447 suppressed proliferation through inhibition of mTOR signaling. In a panel of neuroblastoma cell lines, we observed a marked binary response to PIM inhibition, suggesting that specific genetic lesions control responses to PIM inhibition. Using a genome-wide CRISPR-Cas9 genetic screen, we identified NF1 loss as the major resistance mechanism to PIM kinase inhibitors. Treatment with AZD1208 impaired the growth of NF1 wild-type xenografts, while NF1 knockout cells were insensitive. Thus, our data indicate that PIM inhibition may be a novel targeted therapy in NF1 wild-type neuroblastoma. Mol Cancer Ther; 17(4); 849-57. ©2018 AACR.

Clinical Dosing Regimen of Selinexor Maintains Normal Immune Homeostasis and T-cell Effector Function in Mice: Implications for Combination with Immunotherapy.

Selinexor (KPT-330) is a first-in-class nuclear transport inhibitor currently in clinical trials as an anticancer agent. To determine how selinexor might affect antitumor immunity, we analyzed immune homeostasis in mice treated with selinexor and found disruptions in T-cell development, a progressive loss of CD8 T cells, and increases in inflammatory monocytes. Antibody production in response to immunization was mostly normal. Precursor populations in bone marrow and thymus were unaffected by selinexor, suggesting that normal immune homeostasis could recover. We found that a high dose of selinexor given once per week preserved nearly normal immune functioning, whereas a lower dose given 3 times per week did not restore immune homeostasis. Both naïve and effector CD8 T cells cultured in vitro showed impaired activation in the presence of selinexor. These experiments suggest that nuclear exportins are required for T-cell development and function. We determined the minimum concentration of selinexor required to block T-cell activation and showed that T-cell-inhibitory effects of selinexor occur at levels above 100 nmol/L, corresponding to the first 24 hours post-oral dosing. In a model of implantable melanoma, selinexor treatment at 10 mg/kg with a 4-day drug holiday led to intratumoral IFNγ+, granzyme B+ cytotoxic CD8 T cells that were comparable with vehicle-treated mice. Overall, selinexor treatment leads to transient inhibition of T-cell activation, but clinically relevant once and twice weekly dosing schedules that incorporate sufficient drug holidays allow for normal CD8 T-cell functioning and development of antitumor immunity. Mol Cancer Ther; 16(3); 428-39. ©2017 AACRSee related article by Farren et al., p. 417.