Discontinuation of surgical versus nonsurgical clinical trials: an analysis of 88,498 trials.

BACKGROUND: It has been previously reported that over 20% of surgical trials will be discontinued prematurely raising ethical and financial concerns. Previous studies have been limited in scope owing to the need for manual review of selected trials. To date, there has been no broad analysis comparing surgical and nonsurgical registered clinical trials. MATERIALS AND METHODS: ClinicalTrials.gov was queried October 7, 2017 for all US trials from 2005 to 2017. Trials were assigned to surgical or nonsurgical groups by automated sorting. The sorting algorithm was validated by comparison with manual assignments made by blinded investigators. Comparisons were made between trial status, funding sources, and trial design. The reasons for discontinuation were examined and tabulated. RESULTS: The database search yielded 82,719 nonsurgical and 5779 surgical trials after automatic assignment. The algorithm for assignments had an overall accuracy of 87.99% and a positive likelihood ratio of 6.09 and negative likelihood ratio of 0.093. Significant differences existed in trial status (nonsurgical versus surgical: completed: 55.51% versus 39.49%, P < 0.001 and discontinued: 11.07% versus 15.97%, P < 0.001). Discontinuation due to poor recruitment was more commonly cited by surgical trials (44.65% versus 34.74% P < 0.001). Industry funding predicted discontinuation for all trials (odds ratio 1.63 P < 0.001) and surgical trials independently (OR 1.25 P = 0.041). Patient enrollment, reporting results, and NIH funding were all protective against discontinuation. CONCLUSIONS: Surgical trials are more likely to prematurely discontinue than nonsurgical trials. Industry funding independently predicts trial discontinuation. Poor recruitment is a major cause of early trial discontinuation for all trials and is more pronounced in surgical trials.

NF-κB-induced IL-6 ensures STAT3 activation and tumor aggressiveness in glioblastoma.

Glioblastoma (GBM) is the most aggressive, neurologically destructive and deadly tumor of the central nervous system (CNS). In GBM, the transcription factors NF-κB and STAT3 are aberrantly activated and associated with tumor cell proliferation, survival, invasion and chemoresistance. In addition, common activators of NF-κB and STAT3, including TNF-α and IL-6, respectively, are abundantly expressed in GBM tumors. Herein, we sought to elucidate the signaling crosstalk that occurs between the NF-κB and STAT3 pathways in GBM tumors. Using cultured GBM cell lines as well as primary human GBM xenografts, we elucidated the signaling crosstalk between the NF-κB and STAT3 pathways utilizing approaches that either a) reduce NF-κB p65 expression, b) inhibit NF-κB activation, c) interfere with IL-6 signaling, or d) inhibit STAT3 activation. Using the clinically relevant human GBM xenograft model, we assessed the efficacy of inhibiting NF-κB and/or STAT3 alone or in combination in mice bearing intracranial xenograft tumors in vivo. We demonstrate that TNF-α-induced activation of NF-κB is sufficient to induce IL-6 expression, activate STAT3, and elevate STAT3 target gene expression in GBM cell lines and human GBM xenografts in vitro. Moreover, the combined inhibition of NF-κB and STAT3 signaling significantly increases survival of mice bearing intracranial tumors. We propose that in GBM, the activation of NF-κB ensures subsequent STAT3 activation through the expression of IL-6. These data verify that pharmacological interventions to effectively inhibit the activity of both NF-κB and STAT3 transcription factors must be used in order to reduce glioma size and aggressiveness.

Activation of the NF-κB pathway by the STAT3 inhibitor JSI-124 in human glioblastoma cells.

Glioblastoma tumors are characterized by their invasiveness and resistance to therapies. The transcription factor signal transducer and activator of transcription 3 (STAT3) was recently identified as a master transcriptional regulator in the mesenchymal subtype of glioblastoma (GBM), which has generated an increased interest in targeting STAT3. We have evaluated more closely the mechanism of action of one particular STAT3 inhibitor, JSI-124 (cucurbitacin I). In this study, we confirmed that JSI-124 inhibits both constitutive and stimulus-induced Janus kinase 2 (JAK2) and STAT3 phosphorylation, and decreases cell proliferation while inducing apoptosis in cultured GBM cells. However, we discovered that before the inhibition of STAT3, JSI-124 activates the nuclear factor-κB (NF-κB) pathway, via NF-κB p65 phosphorylation and nuclear translocation. In addition, JSI-124 treatment induces the expression of IL-6, IL-8, and suppressor of cytokine signaling (SOCS3) mRNA, which leads to a corresponding increase in IL-6, IL-8, and SOCS3 protein expression. Moreover, the NF-κB-driven SOCS3 expression acts as a negative regulator of STAT3, abrogating any subsequent STAT3 activation and provides a mechanism of STAT3 inhibition after JSI-124 treatment. Chromatin immunoprecipitation analysis confirms that NF-κB p65 in addition to other activating cofactors are found at the promoters of IL-6, IL-8, and SOCS3 after JSI-124 treatment. Using pharmacological inhibition of NF-κB and inducible knockdown of NF-κB p65, we found that JSI-124-induced expression of IL-6, IL-8, and SOCS3 was significantly inhibited, showing an NF-κB-dependent mechanism. Our data indicate that although JSI-124 may show potential antitumor effects through inhibition of STAT3, other off-target proinflammatory pathways are activated, emphasizing that more careful and thorough preclinical investigations must be implemented to prevent potential harmful effects.

An NF-κB p65-cIAP2 link is necessary for mediating resistance to TNF-α induced cell death in gliomas.

Malignant gliomas are diffusively infiltrative and remain among the deadliest of all cancers. NF-κB is a transcription factor that mediates cell growth, migration and invasion, angiogenesis and resistance to apoptosis. Normally, the activity of NF-κB is tightly regulated by numerous mechanisms. However, in many cancers, NF-κB is constitutively activated and may function as a tumor promoter. Herein, we show that in gliomas, NF-κB is constitutively activated and the levels of cIAP2, Bcl-2, Bcl-xL and Survivin are elevated. These genes are regulated by NF-κB and can inhibit apoptosis. To understand the potential role of NF-κB p65 in suppressing apoptosis, we generated human glioma cell lines that inducibly express shRNA molecules specific for p65. We demonstrate that in the absence of p65, TNF-α induced cIAP2 expression is significantly reduced while the levels of Bcl-2, Bcl-xL and Survivin are not affected. These data suggest that of these genes, only cIAP2 is a direct target of p65, which was confirmed using RT-PCR and chromatin immunoprecipitation (ChIP) assays. By reducing the levels of p65 and/or cIAP2 levels, we demonstrate that the levels of RIP poly-ubiquitination are reduced, and that p65-deficient glioma cells are more sensitive to the cytotoxic effects of TNF-α. Specifically, in the presence of TNF-α glioma cells lacking p65 and/or cIAP2 showed cellular proliferation defects and underwent cell death. These data suggest that NF-κB and/or cIAP2 may be therapeutically relevant targets for the treatment of malignant gliomas.