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Immunomodulatory drugs (IMiDs) are important for the treatment of multiple myeloma and myelodysplastic syndrome. Binding of IMiDs to Cereblon (CRBN), the substrate receptor of the CRL4 CRBN E3 ubiquitin ligase, induces cancer cell death by targeting key neo-substrates for degradation. Despite this clinical significance, the physiological regulation of CRBN remains largely unknown. Herein we demonstrate that Wnt, the extracellular ligand of an essential signal transduction pathway, promotes the CRBN-dependent degradation of a subset of proteins. These substrates include Casein kinase 1α (CK1α), a negative regulator of Wnt signaling that functions as a key component of the β-Catenin destruction complex. Wnt stimulation induces the interaction of CRBN with CK1α and its resultant ubiquitination, and in contrast with previous reports does so in the absence of an IMiD. Mechanistically, the destruction complex is critical in maintaining CK1α stability in the absence of Wnt, and in recruiting CRBN to target CK1α for degradation in response to Wnt. CRBN is required for physiological Wnt signaling, as modulation of CRBN in zebrafish and Drosophila yields Wnt-driven phenotypes. These studies demonstrate an IMiD-independent, Wnt-driven mechanism of CRBN regulation and provide a means of controlling Wnt pathway activity by CRBN, with relevance for development and disease. Cereblon (CRBN) is an E3 ubiquitin ligase substrate receptor that is involved in cancer cell death, although its regulation is poorly understood. Here, the authors show that Wnt ligand increases CRBN-dependent protein degradation and demonstrate CRBN’s importance in physiological Wnt signaling.

Most children with medulloblastoma (MB) achieve remission, but some face very aggressive metastatic tumors. Their dismal outcome highlights the critical need to advance therapeutic approaches that benefit such high-risk patients. Minnelide, a clinically relevant analog of the natural product triptolide, has oncostatic activity in both preclinical and early clinical settings. Despite its efficacy and tolerable toxicity, this compound has not been evaluated in MB. Utilizing a bioinformatic data set that integrates cellular drug response data with gene expression, we predicted that Group 3 (G3) MB, which has a poor 5-year survival, would be sensitive to triptolide/Minnelide. We subsequently showed that both triptolide and Minnelide attenuate the viability of G3 MB cells ex vivo. Transcriptomic analyses identified MYC signaling, a pathologically relevant driver of G3 MB, as a downstream target of this class of drugs. We validated this MYC dependency in G3 MB cells and showed that triptolide exerts its efficacy by reducing both MYC transcription and MYC protein stability. Importantly, Minnelide acted on MYC to reduce tumor growth and leptomeningeal spread, which resulted in improved survival of G3 MB animal models. Moreover, Minnelide improved the efficacy of adjuvant chemotherapy, further highlighting its potential for the treatment of MYC-driven G3 MB.

Multiple sclerosis (MS) is a chronic progressive neurodegenerative demyelinating disease affecting the central nervous system. Glatiramer acetate (GA; Copaxone®) was the first disease-modifying treatment (DMT) for MS successfully tested in humans (1977) and was approved by the US Food and Drug Administration in December 1996. Since then, there have been numerous developments in the MS field: advances in neuroimaging allowing more rapid and accurate diagnosis; the availability of a range of DMTs including immunosuppressant monoclonal antibodies and oral agents; a more holistic approach to treatment by multidisciplinary teams; and an improved awareness of the need to consider a patient’s preferences and patient-reported outcomes such as quality of life. The use of GA has endured throughout these advances. The purpose of this article is to provide an overview of the important developments in the MS field during the 20 years since GA was approved and to review clinical data for GA in MS, with the aim of understanding the continued and widespread use of GA. Both drug-related (efficacy versus side-effect profile and monitoring requirements) and patient factors (preferences regarding mode of administration and possible pregnancy) will be explored.

Wnt signaling regulates numerous cellular processes during embryonic development and adult tissue homeostasis. Underscoring this physiological importance, deregulation of the Wnt signaling pathway is associated with many disease states, including cancer. Here, we review pivotal regulatory events in the Wnt signaling pathway that drive cancer growth. We then discuss the roles of the established negative Wnt regulator, casein kinase 1α (CK1α), in Wnt signaling. Although the study of CK1α has been ongoing for several decades, the bulk of such research has focused on how it phosphorylates and regulates its various substrates. We focus here on what is known about the mechanisms controlling CK1α, including its putative regulatory proteins and alternative splicing variants. Finally, we describe the discovery and validation of a family of pharmacological CK1α activators capable of inhibiting Wnt pathway activity. One of the important advantages of CK1α activators, relative to other classes of Wnt inhibitors, is their reduced on-target toxicity, overcoming one of the major impediments to developing a clinically relevant Wnt inhibitor. Therefore, we also discuss mechanisms that regulate CK1α steady-state homeostasis, which may contribute to the deregulation of Wnt pathway activity in cancer and underlie the enhanced therapeutic index of CK1α activators.

Daclizumab, a humanised monoclonal antibody, reduced multiple sclerosis disease activity in previous non-randomised studies. We aimed to assess whether daclizumab reduces disease activity in patients with active relapsing multiple sclerosis who are receiving interferon beta treatment. We did a phase 2, randomised, double-blind, placebo-controlled study at 51 centres in the USA, Canada, Germany, Italy, and Spain. Patients with active relapsing multiple sclerosis who were taking interferon beta were randomly assigned to receive add-on subcutaneous daclizumab 2 mg/kg every 2 weeks (interferon beta and high-dose daclizumab group), daclizumab 1 mg/kg every 4 weeks (interferon beta and low-dose daclizumab group), or interferon beta and placebo for 24 weeks. The randomisation scheme was generated by Facet Biotech. All patients and assessors were masked to treatment with the exception of Facet Biotech bioanalysts who prepared data for the data safety monitoring board or generated pharmacokinetic or pharmacodynamic data, a drug accountability auditor, and the site pharmacist. The primary endpoint was total number of new or enlarged gadolinium contrast-enhancing lesions measured on brain MRI scans every 4 weeks between weeks 8 and 24. Effects of daclizumab on prespecified subsets of lymphocytes and quantitative T-cell proliferative response were assessed in an exploratory pharmacodynamic substudy. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00109161. From May, 2005, to March, 2006, 288 patients were assessed for eligibility, and 230 were randomly assigned to receive interferon beta and high-dose daclizumab (n=75), interferon beta and low-dose daclizumab (n=78), or interferon beta and placebo (n=77). The adjusted mean number of new or enlarged gadolinium contrast-enhancing lesions was 4·75 in the interferon beta and placebo group compared with 1·32 in the interferon beta and high-dose daclizumab group (difference 72%, 95% CI 34% to 88%; p=0·004) and 3·58 in the interferon beta and low-dose daclizumab group (25%, −76% to 68%; p=0·51). In the pharmacodynamic substudy, daclizumab was not associated with significant changes in absolute numbers of T cells, B cells, or natural killer cells, or T-cell proliferative response compared with interferon beta alone. The number of CD56 bright natural killer cells was seven to eight times higher in both daclizumab groups than in the interferon beta and placebo group (interferon beta and low-dose daclizumab group p=0·002; interferon beta and high-dose daclizumab group p<0·0001). Common adverse events were equally distributed across groups. Add-on daclizumab treatment reduced the number of new or enlarged gadolinium contrast-enhancing lesions compared with interferon beta alone and might reduce multiple sclerosis disease activity to a greater extent than interferon beta alone. Facet Biotech and Biogen Idec.

Alemtuzumab is a humanised monoclonal antibody that depletes lymphocytes, causing long-term immunomodulation. In a 3-year, rater-blinded phase 2 study (the CAMMS223 study) in patients with relapsing-remitting multiple sclerosis (RRMS), alemtuzumab reduced relapse rate and the risk of sustained accumulation of disability compared with subcutaneous interferon beta-1a, and the mean expanded disability status scale (EDSS) score of the alemtuzumab cohort improved compared with baseline. Adverse events included infusion-associated reactions, predominantly mild to moderate infections, thyroid disorders, and immune thrombocytopenia. In this study, we further analysed the CAMMS223 data with the aim of determining whether demographic and baseline disease-related characteristics affect the beneficial effects of alemtuzumab. Additionally, we aimed to describe a new outcome measure in multiple sclerosis research: sustained reduction in disability. 334 treatment-naive patients with active, early RRMS were randomly assigned in a 1:1:1 ratio to receive interferon beta-1a (44 μg subcutaneously three times per week), or 24 mg per day or 12 mg per day alemtuzumab intravenously for 2 or 3 annual cycles. We analysed freedom from clinical disease activity (CDA; defined as no relapses and no sustained accumulation of disability) and occurrence of sustained reduction in disability (SRD; a ≥1 point decrease on the EDSS sustained for 6 consecutive months for patients with a baseline EDSS ≥2), and analysed efficacy outcomes for subgroups based on age, sex, geographic region, MRI-T1 brain volume, MRI-T2 lesion volume, disease duration, number of previous relapses within 2 years, and EDSS. 322 patients were analysed. 161 of 215 patients treated with alemtuzumab were free of CDA at 36 months (Kaplan-Meier estimate 71·8%, 95% CI 63·1–78·8%) compared with 52 of 107 patients treated with interferon beta-1a (42·6%, 32·4–52·4%; hazard ratio [HR]=0·31, 0·20–0·46; p<0·0001). For the 199 patients with a baseline EDSS score greater than or equal to 2, SRD was more likely (HR=2·61, 1·54–4·43; p=0·0004) among patients treated with alemtuzumab (66 of 133 patients, Kaplan-Meier estimate 51·6%, 95% CI 43·2–60·7%) than patients treated with interferon beta-1a (15 of 66 patients, 27·2%, 17·2–41·4%). All disability and relapse outcomes showed evidence of beneficial effects of alemtuzumab compared with interferon beta-1a across all analysed patient subsets, and no subgroup of patients consistently responded better than others to alemtuzumab. Alemtuzumab reduced disease activity compared with interferon beta-1a in most of the analysed subgroups. Significantly greater numbers of patients experienced sustained improvement in disability after treatment with alemtuzumab than interferon beta-1a. The efficacy offered by alemtuzumab is a substantial advance in the treatment of multiple sclerosis. Genzyme and Bayer Schering Pharma.

The Hedgehog signaling pathway functions in both embryonic development and adult tissue homeostasis. Importantly, its aberrant activation is also implicated in the progression of multiple types of cancer, including basal cell carcinoma and medulloblastoma. GLI transcription factors function as the ultimate effectors of the Hedgehog signaling pathway. Their activity is regulated by this signaling cascade via their mRNA expression, protein stability, subcellular localization, and ultimately their transcriptional activity. Further, GLI proteins are also regulated by a variety of non-canonical mechanisms in addition to the canonical Hedgehog pathway. Recently, with an increased understanding of epigenetic gene regulation, novel transcriptional regulators have been identified that interact with GLI proteins in multi-protein complexes to regulate GLI transcriptional activity. Such complexes have added another layer of complexity to the regulation of GLI proteins. Here, we summarize recent work on the regulation of GLI transcriptional activity by these novel protein complexes and describe their relevance to cancer, as such GLI regulators represent alternative and innovative druggable targets in GLI-dependent cancers.

The AFFIRM and SENTINEL studies showed that natalizumab was effective both as monotherapy and in combination with interferon beta (IFNβ)-1a in patients with relapsing multiple sclerosis (MS). Further analyses of AFFIRM and SENTINEL data were conducted to determine the efficacy of natalizumab in prespecified patient subgroups according to baseline characteristics: relapse history 1 year before randomization (1, 2, ≥ 3), Expanded Disability Status Scale score (≤ 3.5, > 3.5), number of T2 lesions (< 9, ≥ 9), presence of gadolinium-enhancing (Gd+) lesions (0, ≥ 1), age (< 40, ≥ 40) and gender (male, female). A post hoc analysis was conducted to determine the efficacy of natalizumab in patients with highly active disease (i. e., ≥ 2 relapses in the year before study entry and ≥ 1 Gd+ lesion at study entry). In both AFFIRM and SENTINEL studies natalizumab reduced the annualized relapse rates across all subgroups (except the small subgroups with < 9 baseline T2 lesions) over 2 years. In AFFIRM, natalizumab significantly reduced the risk of sustained disability progression in most subgroups. In SENTINEL, natalizumab significantly reduced the risk of sustained disability progression in the following subgroups: ≥ 9 T2 lesions at baseline, ≥ 1 Gd+ lesions at baseline, female patients and patients < 40 years of age. Natalizumab reduced the risk of disability progression by 64 % and relapse rate by 81 % in treatment- naive patients with highly active disease and by 58 % and 76 %, respectively, in patients with highly active disease despite IFNβ-1a treatment. These results indicate that natalizumab is effective in reducing disability progres- sion and relapses in patients with relapsing MS, particularly in patients with highly active disease.

Background: Interleukins 12 and 23 (IL-12/23) have been implicated in multiple sclerosis (MS) pathogenesis. This study assessed the efficacy and safety of ABT-874, a monoclonal anti-IL-12/23 antibody, in active relapsing–remitting MS (RRMS) or secondary progressive MS (SPMS). Methods: In this 24-week study, patients with RRMS or SPMS received ABT-874 200 mg every other week (EOW), ABT-874 200 mg every week (EW), or placebo. The cumulative number of gadolinium-enhanced lesions, relapse rate, disability progression, and adverse events were measured. Results: 215 patients were randomized (ABT-874 200 mg EOW, N = 76; ABT-874 200 mg EW, N = 70; placebo, N = 69). At week 24, gadolinium-enhanced lesions were statistically significantly reduced with ABT-874 200 mg EOW vs. placebo (mean number [SD]: 5.4 [8.1] vs. 7.6 [14.4], p = 0.003), but not with ABT-874 200 mg EW (6.8 [11.3], p = 0.134). Mean relapse rate (relapses/y) was significantly lower for ABT-874 200 mg EW vs. placebo (0.1 [95% CI −0.0, 0.3] vs. 0.5 [0.2, 0.8], p = 0.007). Changes from baseline in disability scores and incidences of adverse events were not significantly different across treatment groups, although a numerically greater percentage of serious adverse events was reported for ABT-874 treatment groups. Conclusions: Although rates of adverse events were not significantly different between ABT-874 treatment groups and placebo, the magnitude of ABT-874 efficacy was less than that observed with other agents currently in development for MS treatment. Anti-IL-12/23 monotherapy does not appear to warrant further testing as monotherapy treatment for MS.

In two parallel randomized trials in patients with MS, ublituximab resulted in lower relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not affect disability.