Ponatinib is a multi-targeted third generation tyrosine kinase inhibitor (TKI) used in the treatment of chronic myeloid leukemia (CML) patients harboring the Abelson (Abl)-breakpoint cluster region (Bcr) T315I mutation. In spite of having superb clinical efficacy, ponatinib triggers severe vascular adverse events (VAEs) that significantly limit its therapeutic potential. On vascular endothelial cells (ECs), ponatinib promotes EC dysfunction and apoptosis, and inhibits angiogenesis. Furthermore, ponatinib-mediated anti-angiogenic effect has been suggested to play a partial role in systemic and pulmonary hypertension via inhibition of vascular endothelial growth factor receptor 2 (VEGFR2). Even though ponatinib-associated VAEs are well documented, their etiology remains largely unknown, making it difficult to efficiently counteract treatment-related adversities. Therefore, a better understanding of the mechanisms by which ponatinib mediates VAEs is critical. In cultured human aortic ECs (HAECs) treated with ponatinib, we found an increase in nuclear factor NF-kB/p65 phosphorylation and NF-kB activity, inflammatory gene expression, cell permeability, and cell apoptosis. Mechanistically, ponatinib abolished extracellular signal-regulated kinase 5 (ERK5) transcriptional activity even under activation by its upstream kinase mitogen-activated protein kinase kinase 5α (CA-MEK5α). Ponatinib also diminished expression of ERK5 responsive genes such as Krüppel-like Factor 2/4 (klf2/4) and eNOS. Because ERK5 SUMOylation counteracts its transcriptional activity, we examined the effect of ponatinib on ERK5 SUMOylation, and found that ERK5 SUMOylation is increased by ponatinib. We also found that ponatibib-mediated increased inflammatory gene expression and decreased anti-inflammatory gene expression were reversed when ERK5 SUMOylation was inhibited endogenously or exogenously. Overall, we propose a novel mechanism by which ponatinib up-regulates endothelial ERK5 SUMOylation and shifts ECs to an inflammatory phenotype, disrupting vascular homeostasis.

The treatment of spine metastases continues to pose a significant clinical challenge, requiring the integration of multiple therapeutic modalities to address the multifactorial aspects of this disease process. Radiofrequency ablation (RFA) and vertebral cement augmentation (VCA) are 2 less invasive modalities compared to open surgery that have emerged as promising strategies, offering the potential for both pain relief and preservation of vertebral stability. The utility of these approaches, however, remains uncertain and subject to ongoing investigation. This systematic review and meta-analysis evaluates the available evidence and synthesize the results of studies that have investigated the combination of RFA and VCA for the treatment of spinal metastases, with the goal of providing a comprehensive and up-to-date assessment of the efficacy and safety of this therapeutic approach. A literature search was conducted using the electronic databases PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus from their inception to May 4th, 2022 in accordance with PRISMA guidelines. Studies were included if they met the following criteria: 1) spine metastases treated with RFA in combination with VCA, 2) available data on at least one outcome (i.e., pain palliation, complications, local tumor control), 3) prospective or retrospective studies with at least 10 patients, and 4) English language. Meta-analyses were conducted in R (R Foundation for Statistical Computing; Vienna, Austria), using the meta package. In the 25 included studies, a total of 947 patients (females=53.9%) underwent RFA + VCA for spinal metastatic tumors. Out of 1,163 metastatic lesions, the majority were located in the lumbar region (585/1,163 [50.3%]) followed by thoracic (519/1,163 [44.6%]), sacrum (39/1,163 [3.4%]), and cervical (2/1,163 [0.2%]). 48/72 [66.7%] metastatic lesions expanded into the posterior elements. Preoperative pathologic vertebral fractures were identified in 115/176 [65.3%] patients. Between pre-procedure pain scores and postprocedure pain scores, average follow-up (FU) was 4.41±2.87 months. Pain scores improved significantly at a short-term FU (1-6 months), with a pooled mean difference (MD) from baseline of 4.82 (95% CI, 4.48–5.16). The overall local tumor progression (LTP) rate at short-term FU (1–6 months) was 5% (95% CI, 1%–8%), at mid-term FU (6–12 months) was 22% (95% CI, 0%–48%), and at long-term FU (>12 months) was 5% (95% CI, 0%–11%). The pooled incidence of total complications was 1% (95% CI, 0%–1%), the most frequent of which were transient radicular pain and asymptomatic cement extravasation. The findings of this meta-analysis reveal that the implementation of RFA in conjunction with VCA for the treatment of spinal metastatic tumors resulted in a significant short-term reduction of pain, with minimal total complications. The LTP rate was additionally low. The clinical efficacy and safety of this technique are established, although further exploration of the long-term outcomes of RFA+VCA is warranted.

Background: Surgical resection remains the preferred treatment in spine giant cell tumors (SGCTs), but it is not always feasible. Conservative strategies have been studied for inoperable cases. We systematically reviewed the literature on inoperable SGCTs treated with denosumab, radiotherapy or selective arterial embolization (SAE). Methods: PubMed, Scopus, Web-of-Science, Ovid-EMBASE, and Cochrane were searched following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to include studies of inoperable SGCTs treated with denosumab, radiotherapy or SAE. Treatment outcomes were analyzed and compared with a random-effect model meta-analysis. Results: Among the 17 studies included, 128 patients received denosumab, 59 radiotherapy, and 43 SAE. No significant differences in baseline patient characteristics were found between the three groups. All strategies were equally effective in providing symptom improvement (p = 0.187, I² = 0%) and reduction in tumor volume (p = 0.738, I² = 56.8%). Rates of treatment-related complications were low (denosumab: 12.5%; radiotherapy: 8.5%; SAE: 18.6%) and comparable (p = 0.311, I² = 0%). Patients receiving denosumab had significantly lower rates of local tumor recurrence (10.9%) and distant metastases (0%) compared to patients receiving radiotherapy (30.5%; 8.5%) or SAE (35.6%; 7%) (p = 0.003, I² = 32%; p = 0.002, I² = 47%). Denosumab was also correlated with significantly higher overall survival rates at 18 months (99.2%) and 24 months (99.2%) compared to radiotherapy (91.5%; 89.6%) and SAE (92.5%; 89.4%) (p = 0.019, I² = 8%; p = 0.004, I² = 23%). Mortality was higher in patients receiving SAE (20.9%) or radiotherapy (13.6%) compared to denosumab (0.8%) (p < 0.001), but deaths mostly occurred for unrelated diseases. Conclusions: Denosumab, radiotherapy, and SAE are safe and effective for inoperable SGCTs. Clinical and radiological outcomes are mostly comparable, but denosumab may provide superior tumor control.