Faculty Bibliography

The Wnt/β-catenin signaling pathway is aberrantly activated in colorectal (CRC) and many other cancers, and novel strategies for effectively targeting it may be needed due to its complexity. In this report, SM08502, a novel small molecule in clinical development for the treatment of solid tumors, was shown to reduce Wnt pathway signaling and gene expression through potent inhibition of CDC-like kinase (CLK) activity. SM08502 inhibited serine and arginine rich splicing factor (SRSF) phosphorylation and disrupted spliceosome activity, which was associated with inhibition of Wnt pathway-related gene and protein expression. Additionally, SM08502 induced the generation of splicing variants of Wnt pathway genes, suggesting that its mechanism for inhibition of gene expression includes effects on alternative splicing. Orally administered SM08502 significantly inhibited growth of gastrointestinal tumors and decreased SRSF phosphorylation and Wnt pathway gene expression in xenograft mouse models. These data implicate CLKs in the regulation of Wnt signaling and represent a novel strategy for inhibiting Wnt pathway gene expression in cancers. SM08502 is a first-in-class CLK inhibitor being investigated in a Phase 1 clinical trial for subjects with advanced solid tumors (NCT03355066).

Introduction: Apremilast demonstrated efficacy in the treatment of the oral ulcers (OU) of Behcet's syndrome in a phase III, multicenter, randomized, double-blind, placebo-controlled study (RELIEF).
Objective(s): To assess apremilast efficacy in patients with Behcet's syndrome for OU, OU pain, disease activity, and QoL, as well as their relationship.
Material(s) and Method(s): 207 patients were randomized (1:1) to apremilast 30 mg BID or placebo for 12 weeks, followed by a 52-week active treatment extension. Patients had active Behcet's syndrome, with >=3 OU at randomization or >=2 OU at screening and randomization, without active major organ involvement. The primary endpoint was area under the curve for number of OU through 12 weeks (AUCWk0-12). Clinical improvement of OU was evaluated by OU pain assessments (100-mm VAS) and measures of disease activity using the Behcet's Syndrome Activity Score (BSAS), Behcet's Disease Current Activity Form (BDCAF), and Behcet's Disease QoL (BDQoL). Pearson's correlation coefficients and associated P values assessed the relationship in change from baseline scores at 12 weeks among BSAS, BDCAI, and BDQoL with OU number and change in OU pain.
Result(s): AUCWk0-12 was significantly lower in apremilast vs. placebo (P<0.0001). This treatment effect is supported by significant improvements in OU number and pain (both P<0.0001), disease activity using BSAS (P<0.0001), BDCAI (P=0.0335), and BDQoL (P=0.0003) at Week 12. With apremilast, significant correlations were observed between numbers of OU vs. change in BSAS (P<0.0001) and BDCAI (P=0.0081); change in OU pain vs. BSAS (P<0.0001), BDQoL (P=0.0036), and BDCAI (P=0.0146); and change in BSAS vs. BDQoL (P=0.0237) and BDCAI (P=0.0007).
Conclusion(s): Apremilast demonstrated significant improvements in number and pain of OU, measures of disease activity and QoL. Significant correlations between improvements in OU number and pain, disease activity, and QoL in apremilast-treated patients suggest that beneficial effects of apremilast are internally consistent

PURPOSE OF REVIEW/OBJECTIVE:New treatment options have been studied over the last several years, with a recent approval, a first for Behcet syndrome, in the United States. New management guidelines have also been published, helping with this nowadays more commonly recognized condition's management. The goal of this review is to summarize the most important and potentially clinically relevant recent developments and discuss their impact in the management of patients with Behcet syndrome. RECENT FINDINGS/RESULTS:Apremilast is now approved for the treatment of oral ulcer of Behcet syndrome in the United States. It's possible benefits in controlling nonoral ulcer features of the syndrome are awaited. Long-term use of tumor necrosis factor inhibitors for the treatment of especially eye disease in Behcet syndrome seems to be safe and efficacious. New treatment options such as ustekinumab, secukinumab, tocilizumab and others have early promising data but more studies are needed to better clarify their role in Behcet management. SUMMARY/CONCLUSIONS:The last 2 years have not only seen the approval of the first drug specifically labeled for the treatment of Behcet syndrome in the case of apremilast, many groups have also presented and published their findings on promising new therapeutic agents, which may soon be added to our tools in treating this condition. We also know more about other drugs, such as tumor necrosis factor inhibitors as many patients have been on these for long periods of time, and long-term follow-up data seem to confirm their role in Behcet treatment. Lack of placebo controlled, randomized trials, for the most part, are still outstanding issues.