Outcomes from a mechanistic biomarker multi-arm and randomised study of liposomal MTP-PE (Mifamurtide) in metastatic and/or recurrent osteosarcoma (EuroSarc-Memos trial)
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ABSTRACT:
PROVIDER: PRJEB53234 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR10222439_1.fastq.gz | Fastqsanger.gz | |||
| ERR10222439_2.fastq.gz | Fastqsanger.gz | |||
| ERR10222440_1.fastq.gz | Fastqsanger.gz | |||
| ERR10222440_2.fastq.gz | Fastqsanger.gz | |||
| ERR10222441_1.fastq.gz | Fastqsanger.gz |
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Project description:The phase III clinical study of adjuvant liposomal muramyl tripeptide (MTP-PE) in resected high-grade osteosarcoma (OS) documented positive results that have been translated into regulatory approval, supporting initial promise for innate immune therapies in OS. There remains, however, no new approved treatment such as MTP-PE for either metastatic or recurrent OS. Whilst the addition of different agents, including liposomal MTP-PE, to surgery for metastatic or recurrent high-grade osteosarcoma has tried to improve response rates, a mechanistic hiatus exists in terms of a detailed understanding the therapeutic strategies required in advanced disease. Here we report a Bayesian designed multi-arm, multi-centre, open-label phase II study with randomisation in patients with metastatic and/or recurrent OS, designed to investigate how patients with OS might respond to liposomal MTP-PE, either given alone or in combination with ifosfamide. Despite the trial closing because of poor recruitment within the allocated funding period, with no objective responses in eight patients, we report the design and feasibility outcomes for patients registered into the trial. We demonstrate the feasibility of the Bayesian design, European collaboration, tissue collection with genomic analysis and serum cytokine characterisation. Further mechanistic investigation of liposomal MTP-PE alone and in combination with other agents remains warranted in metastatic OS.
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Project description:Osteosarcoma, the most frequent malignant primary bone tumor in pediatric patients is characterized by osteolysis promoting tumor growth. Lung metastasis is the major bad prognosis factor of this disease. Zoledronic Acid (ZA), a potent inhibitor of bone resorption is currently evaluated in phase III randomized studies in Europe for the treatment of osteosarcoma and Ewing sarcoma. The beneficial effect of the liposomal form of Muramyl-TriPeptide-Phosphatidyl Ethanolamine (L-mifamurtide, MEPACT®), an activator of macrophage populations has been demonstrated to eradicate lung metastatic foci in osteosarcoma. The objective of this study was to evaluate the potential therapeutic benefit and the safety of the ZA and L-mifamurtide combination in preclinical models of osteosarcoma, as a prerequisite before translation to patients. The effects of ZA (100 μg/kg) and L-mifamurtide (1 mg/kg) were investigated in vivo in xenogeneic and syngeneic mice models of osteosarcoma, at clinical (tumor proliferation, spontaneous lung metastases development), radiological (bone microarchitecture by microCT analysis), biological and histological levels. No interference between the two drugs could be observed on ZA-induced bone protection and on L-mifamurtide-induced inhibition of lung metastasis development. Unexpectedly, ZA and L-mifamurtide association induced an additional and in some cases synergistic inhibition of primary tumor progression. L-mifamurtide has no effect on tumor proliferation in vitro or in vivo, and macrophage population was not affected at the tumor site whatever the treatment. This study evidenced for the first time a significant inhibition of primary osteosarcoma progression when both drugs are combined. This result constitutes a first proof-of-principle for clinical application in osteosarcoma patients.
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Project description:BackgroundAcute pulmonary embolism (PE) mortality is linked to abrupt rises in pulmonary artery (PA) pressure due to mechanical obstruction and pulmonary vasoconstriction, leading to right ventricular (RV) dilation, increased RV wall tension and oxygen demand, but compromised right coronary artery oxygen supply. Oxygen is a known pulmonary vasodilator, and in preclinical animal models of PE, supplemental oxygen reduces PA pressures and improves RV function. However, the mechanisms driving these interactions, especially in humans, remain poorly understood. The overall objective of the supplemental oxygen in pulmonary embolism (SO-PE) study is to investigate the mechanisms of supplemental oxygen in patients with acute PE.Methods and analysisThis randomised, double-blind, cross-over trial at Massachusetts General Hospital will include adult patients with acute PE and evidence of RV dysfunction but without hypoxaemia (SaO2 ≥90% on room air). We will enrol 80 patients, each serving as their own control, with 40 randomised to start on supplemental oxygen, and 40 randomised to start on room air. Over 180 min, patients will alternate between supplemental oxygen delivered by non-rebreather mask (60% FiO2) and room air (21% FiO2). The primary outcome will be the difference in pulmonary artery systolic pressure with and without oxygen. Secondary outcomes include additional echocardiographic measures, metabolomic profiles, vital signs and dyspnoea scores. Echocardiographic data will be compared by a paired t-test or Wilcoxon signed-rank test. For metabolomic analyses, we will perform multivariable mixed effects logistic regression models and calculate false discovery rate (q-value ≤0.05) to account for multiple comparisons. Data will be collected in compliance with National Institutes of Health and National Heart Lung and Blood Institute (NHLBI) policies for data and safety monitoring.Ethics and disseminationThe SO-PE study is funded by the NHLBI and has been approved by the Institutional Review Board of Mass General Brigham (no. 2023P000252). The study will comply with the Helsinki Declaration on medical research involving human subjects. All participants will provide prospective, written informed consent.Trial registration numberNCT05891886.
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Project description:Osteosarcoma is the most common primary malignant tumour of bone occurring in children and young adolescents. Osteosarcoma is characterized by considerable phenotypic and genomic heterogeneity, and few recurrent targetable genetic changes have been reported. Osteosarcoma exhibits a complex karyotype with high genomic and chromosomal instability; and harbours multiple rearrangements across the genome, kataegis and chromothripsis as well as epigenetic changes. Here we have performed DNA methylation profiling on 10 osteosarcoma patient samples and four bones using the Infinium HumanMethylation450 BeadChip from Illumina, covering 485,000 CpG sites across the genome.
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Project description:SaOS2 osteosarcoma cells were cultured with or without atorvastatin (10 µM) for 6, 15 or 24h (2 biological replcates). RNA were isolated and hybridized to RNG microarrays. Background Osteosarcoma is the most common primary tumor of bone. The rapid development of metastatic lesions and resistance to chemotherapy remain major mechanisms responsible for the failure of treatments and poor survival rate for patients. Methods We previously showed that the HMGCoA reductase inhibitors statins exhibit anti-tumoral effects on osteosarcoma cells. Here, using microarray analysis, we identify cyr61/CCN1 as a new target of statins. Modulations of expression of cyr61 were performed in human and murine osteosarcoma cell lines to investigate in vitro cell viability, migratory potential and invasiveness. Cyr61 expression was evaluated in 231 tissue cores from osteosarcoma patients using tissue microarray. Tumor behavior and metastases occurence were analysed by IM injection of modified osteosarcoma cells to BALB/c mice. Results Transcriptome comparisons revealed that statins down-regulate cyr61 expression in SaOS2 cells. Cyr61 silencing in human and murine osteosarcoma cell lines enhanced cell death, but reduced cell migration and cell invasion compared to parental cells whereas cyr61 overexpression had opposite effects. Tissue microarray analysis demonstrated that cyr61 protein expression is higher in human osteosarcoma compared to normal bone tissue and is further increased in metastatic tissues. In vivo, cyr61 overexpression in osteosarcoma cells enhanced lung metastases development whereas cyr61 silencing strongly reduced metastases in mice. Conclusion The results reveal that cyr61 expression increases with tumor grade in human osteosarcoma and demonstrate that cyr61 silencing inhibits in vitro osteosarcoma cell invasion and migration as well as in vivo lung metastases in mice. These data provide a novel molecular target for therapeutic intervention in metastatic osteosarcoma.
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