Pediatric Solid Tumor Metabolism [A Prospective Study Exploring Metabolism of Solid Tumors in Pediatrics]

Summary

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The principal objective of this study is the metabolic characterization of pediatric solid tumors, with a particular focus on neuroblastoma (NBL) and fusion positive sarcoma (FPS), which will allow the detection of tumor specific metabolic alterations that can be exploited with the aim of developing...

The principal objective of this study is the metabolic characterization of pediatric solid tumors, with a particular focus on neuroblastoma (NBL) and fusion positive sarcoma (FPS), which will allow the detection of tumor specific metabolic alterations that can be exploited with the aim of developing novel therapeutic strategies and biomarkers. The rationale behind this study and the reasons for its clinical significance are described below: Neuroblastoma: Neuroblastoma, a malignancy of the sympathetic nervous system, is the most common extra-cranial solid tumor in children, accounting for 7% of childhood cancers and 15% of childhood cancer related deaths. Neuroblastoma has a wide range of clinical outcomes ranging from spontaneous maturation with regression, to death from widespread metastatic disease. The outcomes and prognoses for children with neuroblastoma depend on their specific risk group classification. Risk stratification is dependent on subject age, tumor histology and tumor genetic characteristics and leads to vastly different therapies and outcomes. Currently the therapy for low risk disease includes surgery and possibly chemotherapy with a 5 year EFS >85%. However, despite intensive cytotoxic chemotherapy, double autologous stem cell transplantation, and targeted radiopharmaceutical delivery of methyl-iodo-benzyl-guanidine (MIBG), children with high risk disease have a 5 year EFS <50%. The relevance of neuroblastoma genotype to clinical outcome is well established, as evidenced by the poor prognosis in children with MYCN amplification. An important mechanism by which oncogenes promote tumorigenesis, including increased proliferation and decreased differentiation, is by regulating cellular metabolism. While non-malignant cells typically generate cellular energy through use of oxidative phosphorylation, malignant cells emphasize aerobic glycolysis (Warburg Effect) as a source of cellular energy since this process also provide substrates for macromolecule synthesis and redox pathways. More specifically, in the presence of oxygen, differentiated, non-malignant, cells metabolize glucose through oxidative phosphorylation, creating an increased amount of energy, specifically 36 molecules of ATP. However, in malignant cells, the majority of glucose is converted to lactate despite the presence of oxygen, resulting in less energy and ATP production (2 molecules). More recent research suggests that in fact both processes are increased in malignant cells. This finding has been identified in cell-based neuroblastoma systems with MYCN amplification. MYNC amplified tumors have alterations in mitochondrial metabolism that cause cells to be dependent on glutamine for survival. If glutamine is depleted, these cells undergo apoptosis leading to cell death. Studies are currently underway looking at the use of Fenretinide, a synthetic retinoid, and its ability to cause a glutamine deplete environment leading to apoptosis of these cells. Altered metabolism, in cell-based neuroblastoma systems, is also evidenced by reduced activity of the metabolic enzyme succinate dehydrogenase (SDH) in correlation to loss of heterozygosity (LOH) of 1p36 and increased expression of multiple genes involved in glycolysis, glutamine, fatty acid and mitochondrial metabolism in correlation to MYCN expression. However, MYCN amplification is only present in about 20% of neuroblastoma tumors and there are multiple other genetic mutations whose metabolic consequences at yet to be determined. When NBL occurs in a hereditary fashion, there is classically a mutation in the ALK oncogene or more rarely a mutation in PHOX2B. When neuroblastoma occurs sporadically, it is associated with amplification of MYCN (50% of high-risk patients), LOH of 1p36 (35% of primary NBL), LOH of 11q (35-40% of newly diagnosed patients), and gains at 17q. Therefore, the investigators feel it is imperative to continue to explore the metabolism of neuroblastoma to discover further alterations in their metabolism and possible links to these genetic alterations. Fusion Positive Sarcoma: Fusion positive sarcoma, including Ewing sarcoma (EWS), Ewing-like sarcoma, alveolar rhabdomyosarcoma (aRMS) and many childhood non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), occurs in approximately 1,100 children in the United States annually. Eighty percent of those with metastatic or recurrent FPS will die of disease, and only 55-75% of those with more favorable risk can expect long-term survival. Juxtaposition of the EWS gene to ETS-family FLI-1 gene occurs in 85% of patients with EWS, while alternate ETS family fusion-partners including ERG, ETV1, E1AF and FEV occur less commonly. More recently a new class of fusion positive Ewing-like sarcoma has been described, with translocations such as CIC:DUX4. Alveolar rhabdomyosarcoma is now characterized as either PAX-FOXO1 fusion positive or fusion negative. The group of malignancies categorized as NRSTS in children, includes many histological subsets driven by oncogenic fusion proteins, such as the SS18-SSX in synovial sarcoma. Genomic studies have revealed critical understanding of FPS disease biology but to date have not laid the foundation for new therapies. In contrast, metabolism studies have the potential to provide new insights. EWS cell lines demonstrate aerobic glycolysis as evidenced by measures of glucose uptake, lactate dehydrogenase activity, ATP, and mitochondrial membrane potential. Alveolar RMS cell lines also display aerobic glycolysis as demonstrated by indirect measures of oxygen consumption and extracellular acidification and by metabolic flux analysis. Cell line verification of aerobic glycolysis in FPS and emerging data demonstrating that metabolic alterations are different in culture and in-vivo renders in-vivo study an essential complement to metabolic studies in cultured cells. Molecular studies in EWS and aRMS have focused on nucleic acid sequencing and identified only rare examples that point toward new therapeutics. In contrast, metabolic studies can identify potential vulnerabilities. A profound example of such a vulnerability relates to 2-hydroxyglutarate (2HG), a putative "onco-metabolite". In 2009, Dang et al. demonstrated the strong correlation between increased 2HG in glioma with mutations in isocitrate dehydrogenase-1 (IDH1). More than 20 studies have confirmed this finding, and investigators in the UTSW Advanced Imaging Research Center developed this finding into a clinical test in which 2HG can be imaged as a non-invasive marker for IDH1/2 mutation and as a response marker for IDH1/2 inhibitors in glioma. There are very few other examples in cancer, similar to IDH-1 in glioma, in which genetic mutations occur in a metabolic enzyme resulting in an onco-metabolite that influences cell activity. However, an early response biomarker, as exemplified by IDH1/2, is essential for modification of therapy in FPS, and may be similarly useful in NBL. Cellular metabolism studies provide insight, in a complementary way to genomics, into processes acting downstream from oncogenes and oncogenic fusion proteins, and such insight may point toward previously unrecognized therapeutic targets or onco-metabolites that are traceable as robust biomarkers for response. The investigator's new approach to use an in-vivo comprehensive analysis of metabolic reprograming in FPS/NBL has never been performed in childhood FPS/NBL and will complement genomics studies for these cancers. For this study the investigators plan to obtain tumor samples at time of surgical biopsy/resection and study their metabolic signatures. They will specifically evaluate the metabolomic profiles and perform metabolic flux analyses of these tumors. Metabolomic profiles provide snapshots of up to 50 metabolites from pathways including glycolysis, the pentose phosphate pathway, the tricarboxylic acid cycle, and both amino acid and nucleotide metabolism, all of which are known to be under oncogenic control in cancer as noted above. Metabolic flux analyses provide dynamic evaluations of glucose entry into major energetic and biosynthetic pathways. Pathway analysis depends on the ability to detect metabolic alterations in these cells. To do this, they will infuse the patient with 13C-glucose pre-operatively. They will then trace the utilization of 13C-glucose of the tumor cells by evaluating the samples with mass spectrometry after obtained at time of biopsy. Biopsies will be performed by either surgeons in the operating room or interventional radiologists in the interventional radiology suites. 13C, a stable, naturally occurring isotope of carbon is uniquely suited for this examination since it does not undergo radioactive decay and has been given to humans safely in prior studies. Some of these analyses may be performed without the concomitant perioperative delivery of 13C-glucose as well. The investigators are ideally positioned to accomplish this here at UT Southwestern, which is one of a very few centers worldwide to have developed intra-operative delivery of stable isotope tracers to characterize metabolic flux in human tumors in children. Furthermore, whenever feasible, patients will undergo preoperative imaging studies, such as PET scan, MIBG, or MRI studies. The results of these imaging studies if obtained will be correlated with the metabolic phenotype to generate a comprehensive non-invasive view of the tumor with the goal of identifying infiltrative, metabolically active solid tumor cells. In addition, a comprehensive molecular profile of the tumor will be reviewed to enable a genotype-metabolic phenotype comparative analysis.

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