Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial

PURPOSE Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents. METHODS SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: ). RESULTS Two hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P = .011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P < .0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P = .001). CONCLUSION Patients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted. (C) 2022 by American Society of Clinical Oncolog

Anxiolytic effects of nicotine in a rodent test of approach–avoidance conflict

Nicotine has been reported to produce both anxiolytic and/or anxiogenic effects in humans and animals. This study examined whether pretreatment with nicotine would alter anxiety in a unique runway model of approach–avoidance conflict. Food-restricted rats were trained to run a straight alley once a day to obtain food upon goal-box entry. Beginning on trial 11, food reward was followed by a series of five foot shocks (0.3–0.4 mA, 0.5 s) in the goal box. Non-shocked control rats continued to run for food only. The resulting association of the goal box with both a positive (food) and negative (foot shock) stimulus produced an approach–avoidance conflict (subjects exhibited “retreat behaviors” in which they would approach the goal box, stop, and then retreat back towards the start box). Once retreats were established, their sensitivity to nicotine pretreatment (0.0, 0.03, 0.045, 0.06, or 0.075 mg/kg, i.v.) was compared to saline. In subsequent tests, the effects of nicotine (0.06 or 0.03 mg/kg) were examined on spontaneous activity (locomotion) and center-square entries in an open field (anxiety). Doses of 0.06 and 0.075 mg/kg, but not lower doses of nicotine, reduced the number of runway retreats, and 0.06 mg/kg nicotine increased the number of open-field center entries relative to saline. No effects on locomotion were observed. Nicotine reduced approach–avoidance conflict and increased the rats’ willingness to enter the center of an open field, suggesting that the drug can produce anxiolytic properties and that such effects may serve as an important factor in the persistence of smoking behavior

Anxiolytic effects of nicotine in a rodent test of approach–avoidance conflict

Nicotine has been reported to produce both anxiolytic and/or anxiogenic effects in humans and animals. This study examined whether pretreatment with nicotine would alter anxiety in a unique runway model of approach–avoidance conflict. Food-restricted rats were trained to run a straight alley once a day to obtain food upon goal-box entry. Beginning on trial 11, food reward was followed by a series of five foot shocks (0.3–0.4 mA, 0.5 s) in the goal box. Non-shocked control rats continued to run for food only. The resulting association of the goal box with both a positive (food) and negative (foot shock) stimulus produced an approach–avoidance conflict (subjects exhibited “retreat behaviors” in which they would approach the goal box, stop, and then retreat back towards the start box). Once retreats were established, their sensitivity to nicotine pretreatment (0.0, 0.03, 0.045, 0.06, or 0.075 mg/kg, i.v.) was compared to saline. In subsequent tests, the effects of nicotine (0.06 or 0.03 mg/kg) were examined on spontaneous activity (locomotion) and center-square entries in an open field (anxiety). Doses of 0.06 and 0.075 mg/kg, but not lower doses of nicotine, reduced the number of runway retreats, and 0.06 mg/kg nicotine increased the number of open-field center entries relative to saline. No effects on locomotion were observed. Nicotine reduced approach–avoidance conflict and increased the rats’ willingness to enter the center of an open field, suggesting that the drug can produce anxiolytic properties and that such effects may serve as an important factor in the persistence of smoking behavior

Cocaine Self-Administration Elevates GluN2B within dmPFC Mediating Heightened Cue-Elicited Operant Responding.

Cue-elicited drug-craving correlates with hyperactivity within prefrontal cortex (PFC), which is theorized to result from dysregulated excitatory neurotransmission. The NMDA glutamate receptor is highly implicated in addiction-related neuroplasticity. As NMDA receptor function is regulated critically by its GluN2 subunits, herein, we assayed the relation between incubated cue-elicited cocaine-seeking following extended access to intravenous cocaine (6 h/d; 0.25 mg/infusion for 10 d) and the expression of GluN2A/B receptor subunits within PFC sub regions during early versus late withdrawal (respectively, 3 vs. 30 days). Cocaine-seeking rats exhibited elevated GluN2B expression within the dorsomedial aspect of the PFC (dmPFC); this effect was apparent at both 3 and 30 days withdrawal and occurred in cocaine-experienced rats, regardless of experiencing an extinction test or not. Thus, elevated dmPFC GluN2B expression appears to reflect a pharmacodynamic response to excessive cocaine intake that is independent of the duration of drug withdrawal or re-exposure to drug-taking context. The functional relevance of elevated dmPFC GluN2B expression for drug-seeking was assessed by the local infusion of the prototypical GluN2B-selective antagonist ifenprodil (1.0 µg/side). Ifenprodil did not alter cue-elicited responding in animals with a history of saline self-administration. In contrast, ifenprodil lowered cue-elicited cocaine-seeking, while potentiating cue-elicited sucrose-seeking. Thus, the effects of an intra-dmPFC ifenprodil infusion upon cue reactivity are reinforcer-specific, arguing in favor of targeting GluN2B-containing NMDA receptors as a pharmacological strategy for reducing behavioral reactivity to drug-associated cues with the potential benefit of heightening the reinforcing properties of cues associated with non-drug primary rewards

Cocaine Self-Administration Elevates GluN2B within dmPFC Mediating Heightened Cue-Elicited Operant Responding.

Cue-elicited drug-craving correlates with hyperactivity within prefrontal cortex (PFC), which is theorized to result from dysregulated excitatory neurotransmission. The NMDA glutamate receptor is highly implicated in addiction-related neuroplasticity. As NMDA receptor function is regulated critically by its GluN2 subunits, herein, we assayed the relation between incubated cue-elicited cocaine-seeking following extended access to intravenous cocaine (6 h/d; 0.25 mg/infusion for 10 d) and the expression of GluN2A/B receptor subunits within PFC sub regions during early versus late withdrawal (respectively, 3 vs. 30 days). Cocaine-seeking rats exhibited elevated GluN2B expression within the dorsomedial aspect of the PFC (dmPFC); this effect was apparent at both 3 and 30 days withdrawal and occurred in cocaine-experienced rats, regardless of experiencing an extinction test or not. Thus, elevated dmPFC GluN2B expression appears to reflect a pharmacodynamic response to excessive cocaine intake that is independent of the duration of drug withdrawal or re-exposure to drug-taking context. The functional relevance of elevated dmPFC GluN2B expression for drug-seeking was assessed by the local infusion of the prototypical GluN2B-selective antagonist ifenprodil (1.0 µg/side). Ifenprodil did not alter cue-elicited responding in animals with a history of saline self-administration. In contrast, ifenprodil lowered cue-elicited cocaine-seeking, while potentiating cue-elicited sucrose-seeking. Thus, the effects of an intra-dmPFC ifenprodil infusion upon cue reactivity are reinforcer-specific, arguing in favor of targeting GluN2B-containing NMDA receptors as a pharmacological strategy for reducing behavioral reactivity to drug-associated cues with the potential benefit of heightening the reinforcing properties of cues associated with non-drug primary rewards

Prefrontal Homer imbalance in cocaine relapse

Withdrawal from a history of extended access to self-administered cocaine produces a time-dependent intensification of drug seeking, which might relate to a cocaine-induced imbalance in the relative expression of constitutively expressed Homer1 versus Homer2 isoforms within the ventromedial aspect of the prefrontal cortex (vmPFC). Thus, we employed immunoblotting to examine the relation between cue-reinforced lever pressing at 3- versus 30-day withdrawal from a 10-day history of extended access (6 hours/day) to intravenous cocaine (0.25 mg/infusion) or saline (Sal6h), and the expression of Homer1b/c and Homer2a/b within the vmPFC versus the more dorsomedial aspect of this structure (dmPFC). Behavioral studies employed adeno-associated virus (AAV) vectors to reverse cocaine-elicited changes in the relative expression of Homer1 versus Homer2 isoforms and tested animals for cocaine prime-, and cue-induced responding following extinction training. Cocaine self-administration elevated both Homer1b/c and Homer2a/b levels within the vmPFC at 3-day withdrawal, and the rise in Homer2a/b persisted for at least 30 days. dmPFC Homer levels did not change as a function of self-administration history. Reversing the relative increase in Homer2 versus Homer1 expression via Homer1c overexpression or Homer2b knockdown failed to influence cue-reinforced lever pressing when animals were tested in a drug-free state, but both AAV treatments prevented cocaine-primed reinstatement of lever-pressing behavior. These data suggest that a cocaine-elicited imbalance in the relative expression of constitutively expressed Homer2 versus Homer1 within the vmPFC is necessary for the capacity of cocaine to reinstate drug-seeking behavior, posing drug-induced changes in vmPFC Homer expression as a molecular trigger contributing to drug-elicited relapse