The identification of alternative splice variants of Survivin that possess distinct functions from those originally identified for the main Survivin isoform has greatly increased the complexity of ...our understanding of the role of Survivin in different cells. Previous functional studies of the Survivin splice variants have been performed almost exclusively in cancer cells. However, Survivin has increasingly been implicated in other normal physiologic and pathophysiologic processes, including angiogenesis. In this study, we dissect the involvement of Survivin ΔEx3 in angiogenesis. We show by confocal microscopy that a pool of endothelial Survivin ΔEx3 is localized to membrane ruffles. We also demonstrate that Survivin ΔEx3 is the Survivin splice variant responsible for modulating angiogenesis in vitro, in tube formation assays, and in vivo, in an in vivo angiogenesis assay. Our data indicate that Survivin ΔEx3 may regulate angiogenesis via several mechanisms including cell invasion, migration, and Rac1 activation. Our findings identify a novel pathway regulating angiogenesis through Survivin ΔEx3 and a novel mechanism for Rac1 activation during angiogenesis. In conclusion, our results provide new insights into the regulation of endothelial cell homeostasis and angiogenesis by the Survivin proteins.
Selumetinib, a highly specific mitogen-activated protein kinase 1/2 inhibitor, is approved for children older than 2 years of age with neurofibromatosis 1 who have inoperable plexiform neurofibromas. ...By selectively binding to mitogen-activated protein kinase 1/2 proteins, selumetinib can arrest the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway that regulates critical cellular responses. Selumetinib has shown promising results as a single agent or in combination with conventional chemotherapy and other targeted therapies both preclinically and clinically, in multiple cancers including pediatric low-grade glioma, non-small cell lung cancer, and melanoma, among others. The pharmacokinetic profiles of selumetinib and its active metabolite N-desmethyl selumetinib have been well characterized in both adults and children. Both compounds exhibited rapid absorption and mean terminal elimination half-lives of about 7.5 h, with minimal accumulation at steady state. Three population pharmacokinetic models have been developed in adults and children, characterizing large inter- and intra-patient variabilities, and identifying significant covariates including food intake on selumetinib absorption, weight metrics, age, co-administration of cytochrome modulators, and Asian ethnicity on selumetinib apparent oral clearance. The most common side effects associated with selumetinib are dermatologic, gastrointestinal toxicities, and fatigue. Most toxicities are mild or moderate, generally tolerated and manageable. Cardiovascular and ocular toxicities remain less frequent but can be potentially more severe and require close monitoring. Overall, selumetinib exhibits a favorable safety profile and pharmacokinetic properties, with promising activity in multiple solid tumors, supporting current and further evaluation in combination with conventional chemotherapy and other targeted agents.
Paediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; ...however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients.
The Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3–21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549–BRAF fusion or the BRAFV600E Val600Glu mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m2 twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101.
Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% 95% CI 18–57) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72–45·59). In stratum 3, ten (40% 21–61) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14–51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five 10%) and maculopapular rash (five 10%). No treatment-realted deaths were reported.
Selumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children's Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1.
National Cancer Institute Cancer Therapy Evaluation Program, the American Lebanese Syrian Associated Charities, and AstraZeneca.
Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric low-grade gliomas (LGGs). The aim of this study was to determine the recommended phase II dose (RP2D) ...and the dose-limiting toxicities (DLTs) of the MEK inhibitor selumetinib in children with progressive LGG.
Selumetinib was administered orally starting at 33 mg/m2/dose b.i.d., using the modified continual reassessment method. Pharmacokinetic analysis was performed during the first course. BRAF aberrations in tumor tissue were determined by real-time polymerase chain reaction and fluorescence in situ hybridization.
Thirty-eight eligible subjects were enrolled. Dose levels 1 and 2 (33 and 43 mg/m2/dose b.i.d.) were excessively toxic. DLTs included grade 3 elevated amylase/lipase (n = 1), headache (n = 1), mucositis (n = 2), and grades 2-3 rash (n = 6). At dose level 0 (25 mg/m2/dose b.i.d, the RP2D), only 3 of 24 subjects experienced DLTs (elevated amylase/lipase, rash, and mucositis). At the R2PD, the median (range) area under the curve (AUC0-∞) and apparent oral clearance of selumetinib were 3855 ng*h/mL (1780 to 7250 ng × h/mL) and 6.5 L × h-1 × m-2 (3.4 to 14.0 L × h-1 × m-2), respectively. Thirteen of 19 tumors had BRAF abnormalities. Among the 5 (20%) of 25 subjects with sustained partial responses, all at the RP2D, 4 had BRAF aberrations, 1 had insufficient tissue. Subjects received a median of 13 cycles (range: 1-26). Fourteen (37%) completed all protocol treatment (26 cycles n = 13, 13 cycles n = 1) with at least stable disease; 2-year progression-free survival at the RP2D was 69 ± SE 9.8%.
Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.
Abstract BACKGROUND ACNS1123 was a Phase 2 study to determine whether irradiation could be safely reduced without impacting survival in a subgroup of NGGCT patients. METHODS Patients with localized ...disease who achieved a complete (CR) or partial response (PR) to induction chemotherapy were eligible to receive reduced dose/volume of irradiation to 30.6Gy whole ventricular field with 54Gy tumor-bed boost. RESULTS 107 eligible NGGCT patients were accrued. The median age of patients at enrollment was 11 years (3.7-21.6). Eighty patients (75%) were male. Location was pineal in 58 (55%), suprasellar in 37 (35%), ventricles in 6 (6%), and bifocal in 6 patients (6%). Sixty-six (61.7%) patients achieved a CR/PR post-induction and were eligible and evaluable for the primary objective and received reduced dose and volume of irradiation. Eight patients progressed; 6 had a distant spinal relapse (outside the irradiation field) and 2 had a local plus distant relapse. As of December 31, 2023, the median follow-up time for eligible and evaluable patients was 5.6 years (0.9-7.9) from enrollment. Except for an unrelated death due to SARS-CoV-2 at 5.5 years from enrollment, there were no grade 3 or higher adverse events at the 60-month follow-up timepoint and no disease progressions beyond 2 years. The 5-year progression-free and overall survival for all eligible and evaluable patients are 87.9% (95% CI:79%-94.8%) and 92.4% (95% CI:82.8%- 96.8%), respectively. CONCLUSION Although the study was closed prematurely due to the concern of increased spinal relapse, the current data suggest that most patients with localized NGGCT and a CR/PR to chemotherapy will survive long-term, and, in fact, have similar survival (PFS and OS) to patients enrolled on ACNS0122 who received full dose craniospinal irradiation. The key to future biologic studies and clinical trials is identifying at diagnosis those patients at high risk for relapse.
Paediatric low-grade gliomas (also known as pLGG) are the most common type of CNS tumours in children. In general, paediatric low-grade gliomas show clinical and biological features that are distinct ...from adult low-grade gliomas, and the developing paediatric brain is more susceptible to toxic late effects of the tumour and its treatment. Therefore, response assessment in children requires additional considerations compared with the adult Response Assessment in Neuro-Oncology criteria. There are no standardised response criteria in paediatric clinical trials, which makes it more difficult to compare responses across studies. The Response Assessment in Pediatric Neuro-Oncology working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. We established a subcommittee to develop consensus recommendations for response assessment in paediatric low-grade gliomas. Final recommendations were based on literature review, current practice, and expert opinion of working group members. Consensus recommendations include imaging response assessments, with additional guidelines for visual functional outcomes in patients with optic pathway tumours. As with previous consensus recommendations, these recommendations will need to be validated in prospective clinical trials.
Abstract
BACKGROUND: Focal Areas of Signal Intensity (FASI) are T2 hyperintense benign lesions in children with NF1. They can mimic the appearance of low-grade glioma (LGG). Selumetinib has shown ...efficacy in treatment of NF1-associated LGG but treatment effects on FASI have not yet been described. METHODS: Patients with NF1-associated LGG treated with selumetinib on Stratum 3 of PBTC-029B were compared to age-matched untreated children with NF1-associated LGG at Cincinnati Children’s Hospital Medical. FASI were defined by published criteria as T2 hyperintense lesions lacking mass effect, enhancement or T1 hypointensity. Lesion size was determined by cross-product of perpendicular measures in LGG and 1-3 FASI per subject. When multiple FASI were present, the sum of FASI cross-products was used. Change between baseline and the latest available measure within 4 months of control was assessed, insuring that selumetinib-treated subjects were still receiving therapy. RESULTS: Fifteen age-matched pairs were assessed (2.8-16.9 years and 60% were male). Initial FASI size was not different between groups (p=0.98; median IQR: 138.7mm2 88.4-182.0 for treated subjects versus 121.6mm2 79.6-181.9 for untreated subjects). Lesion change was measured over mean follow up of 18.9 + 5.9 months. Spider plots show decreased LGG size over time during treatment, but there was no consistent change in size among treated or untreated FASI. Comparing FASI size between paired timepoints showed no difference in change from baseline for treated subjects versus for untreated subjects (two-sided test; p=0.08). In subjects who received selumetinib, there was no correlation between change in LGG and change in FASI (r=-0.04, p=0.88). Using RANO criteria for FASI lesions, 2/30 (6.7%) subjects had partial response, 26/30 (86.7%) subjects had stable disease, and 2/30 (6.7%) subjects had progressive disease. CONCLUSIONS: While the sample size was limited, treatment with selumetinib did not reduce overall FASI size in children with NF1 and LGG.
Abstract
Background
Pediatric low-grade gliomas (pLGGs) are the most common childhood brain tumor. Progression-free survival (PFS) is much lower than overall survival, emphasizing the need for ...alternative treatments. Sporadic (without neurofibromatosis type 1) optic pathway and hypothalamic gliomas (OPHGs) are often multiply recurrent and cause significant visual deficits. Recently, there has been a prioritization of functional outcomes.
Methods
We present results from children with recurrent/progressive OPHGs treated on a PBTC (Pediatric Brain Tumor Consortium) phase II trial evaluating efficacy of selumetinib (AZD6244, ARRY-142886) a MEK-1/2 inhibitor. Stratum 4 of PBTC-029 included patients with sporadic recurrent/progressive OPHGs treated with selumetinib at the recommended phase II dose (25mg/m2/dose BID) for a maximum of 26 courses.
Results
Twenty-five eligible and evaluable patients were enrolled with a median of 4 (1-11) previous therapies. Six of 25 (24%) had partial response, 14/25 (56%) had stable disease, and 5 (20%) had progressive disease while on treatment. The median treatment courses were 26 (2-26); 14/25 patients completed all 26 courses. Two-year PFS was 78 ± 8.5%. Nineteen of 25 patients were evaluable for visual acuity which improved in 4/19 patients (21%), was stable in 13/19 (68%), and worsened in 2/19 (11%). Five of 19 patients (26%) had improved visual fields and 14/19 (74%) were stable. The most common toxicities were grade 1/2 CPK elevation, anemia, diarrhea, headache, nausea/emesis, fatigue, AST and ALT increase, hypoalbuminemia, and rash.
Conclusions
Selumetinib was tolerable and led to responses and prolonged disease stability in children with recurrent/progressive OPHGs based upon radiographic response, PFS, and visual outcomes.
Abstract BACKGROUND Diffuse Leptomeningeal Glioneuronal Tumors (DLGT) typically have a clinical course with slow progression; however, there have been cases of anaplastic transformation. We describe ...the clinical presentation, radiographic features, and molecular characteristics in 2 pediatric DLGT cases that underwent aggressive transformation. METHODS Patient 1: A 20 y/o male with DLGT with BRAF-KIAA1549 fusion and loss of 1p who was first diagnosed at 2.5 y/o. Over the course of 17 years, he was treated with numerous therapies due to multiple progressions, including temozolomide, carboplatin/vincristine, selumetinib, and vinblastine. At age 17, he developed significant growth of a posterior fossa mass with solid and cystic characteristics. Resection revealed new anaplastic pathologic features. Patient 2: He was diagnosed with DLGT at age 2 y/o. Imaging demonstrated intramedullary spinal nodules at T4 and T5 with abnormal thickening and enhancement over the cerebral leptomeningeal space. A biopsy revealed DLGT with a BRAF-KIAA1549 fusion, 1p loss and Ki67 5%. He received multiple therapies including carboplatin/vincristine, vinblastine, and selumetinib. RESULTS Patient 1: Molecular characterization revealed new ATRX mutation, and CDKN2A/B homozygous deletion. Over the following 2 years, he had multiple treatments, progressions, and surgeries. Final pathology revealed significant anaplasia with Ki67 90%, ATRX loss, and mutation of PPM1D and ARID1A. He rapidly declined. Patient 2: Approximately 2.5 years after diagnosis, he developed rapid progression in the 4th and lateral ventricles. Pathology confirmed recurrent DLGT, but with high-grade transformation, H3K27M (-), H3k27m3 loss, ATRX (+), Ki67 40%. He was treated with focal irradiation followed by temozolomide/CCNU. CONCLUSION In rare cases, DLGT can undergo anaplastic transformation. Once this occurs, it behaves clinically like a high-grade glioma. Understanding the molecular underpinnings and prognostic features that lead to this transformation are important for future study.
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