Integrative genomics reveals hypoxia inducible genes that are associated with a poor prognosis in neuroblastoma patients

Applebaum, Mark A.; Jha, Aashish R.; Kao, Clara; Hernandez, Kyle M.; DeWane, Gillian; Salwen, Helen R.; Chlenski, Alexandre; Dobratic, Marija; Mariani, Christopher J.; Godley, Lucy A.; Prabhakar, Nanduri R.; White, Kevin P.; Stranger, Barbara Elaine; Cohn, Susan L.

doi:10.18632/oncotarget.12713

Cited by 32 publications

(30 citation statements)

References 46 publications

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“…Patients were categorized as having high or low expression of MELK using a sliding window to include at least 10% of patients similar to prior reports (27). The log-rank test was used to calculate the P value of the survival difference between high-and low-expression groups in each window.…”

Section: Survival Analysismentioning

confidence: 99%

Maternal Embryonic Leucine Zipper Kinase (MELK), a Potential Therapeutic Target for Neuroblastoma

Chlenski

Park

Dobratic

et al. 2019

Molecular Cancer Therapeutics

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Maternal embryonic leucine zipper kinase (MELK) activates pathways that mediate aggressive tumor growth and therapy resistance in many types of adult cancers. Pharmacologic and genomic inhibition of MELK impairs tumor growth and increases sensitivity to radiation and chemotherapy. On the basis of these promising preclinical studies, early-phase adult clinical trials testing the MELK inhibitor OTS167 are ongoing. To investigate whether MELK is also a therapeutic target in neuroblastoma, we analyzed MELK expression in primary tumors and cell lines, and examined the effects of OTS167 on neuroblastoma growth. In primary tumors, high levels of MELK were associated with advanced stage disease and inferior survival. Higher levels of MELK were also detected in tumorigenic versus nontumorigenic neuroblastoma cell lines, and cells with higher levels of MELK expression were more sensitive to OTS167 than low-MELK expressing cells. OTS167 suppressed the growth of neuroblastoma xenografts, and in a preclinical model of minimal residual disease, survival was prolonged with MELK inhibition. OTS167 treatment downregulated MELK and its target enhancer of zeste homolog 2 (EZH2), a component of the polycomb repressive complex 2 (PRC2) that is known to modulate the DNA damage response. We also show that OTS167 reduced the formation of collapsed replication forks induced by camptothecin or radiation. Taken together, our results indicate that MELK indirectly mediates efficient processing of replication-associated DNA lesions in neuroblastoma, and that OTS167 sensitizes cells to DNA-damaging agents by abrogating this process. Further studies evaluating the activity of combination treatment regimens with OTS167 in neuroblastoma are warranted.

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Section: Survival Analysismentioning

confidence: 99%

Maternal Embryonic Leucine Zipper Kinase (MELK), a Potential Therapeutic Target for Neuroblastoma

Chlenski

Park

Dobratic

et al. 2019

Molecular Cancer Therapeutics

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“…Tumor hypoxia is well recognized in oncology as a key factor resulting in treatment failure and poor prognosis 19 - 21 . Hypoxia is thought to play a pivotal role in accelerating tumor progression by both inducting EMT of tumor cells and polarization of TAMs 11 .…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible factor-1 alpha Correlates with Tumor-Associated Macrophages Infiltration, Influences Survival of Gastric Cancer Patients

Zhang

Chen

Zhou³

et al. 2017

J. Cancer

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Background: Hypoxia was a common feature for accelerating tumor metastasis by both inducting epithelial-mesenchymal transition (EMT) of tumor cells and polarization of tumor-associated macrophages (TAMs). The association and roles between hypoxia, EMT and TAMs in the biological behavior of gastric cancer (GC) for the time being recurrence is unclear.Material and methods: hypoixa by expression of hypoxia-inducible factor-1 alpha (HIF-1α), polarized functional status of infiltrated TAMs by immunohistochemical staining of CD68 and CD163, and the expression of E-cadherin as EMT property had been evaluated in 236 patients consecutive with histologically confirmed GC. Clinical significance was assessed for all these patients.Results: High expression of HIF-1α was found in patients with aggressive features, especially for recurrent patients. High infiltration of TAMs and abnormal expression of EMT-marker were also related to aggressive characteristics and predicted poor prognosis in GC. Meanwwhile, there existed a significant correlation among expression of HIF-1α, infiltration of TAMs and EMT marker in GC tissues. Multivariate Cox analysis revealed that high expression of HIF-1α combined TAMs infiltration were independent prognostic factors for disease-specific survival rate.Conclusion: HIF-1α is an unfavorable indicator for prognosis, may promote tumor progression through the induction of EMT and establishment of a pro-tumor immunosuppressive microenvironment. Further investigation into the therapeutic effects of blocking hypoxia is possible a potential strategy for GC treatment.

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“…Global gene expression analysis has also been used to investigate the relationship between hypoxia and NB progression, particularly analysing the role of HIF-2α. In support of the induction by hypoxia of immature stem-cell-like features contributing to a malignant phenotype in NB, Applebaum et al integrated diverse transcriptomics datasets from NB tumours and cell lines, identifying a hypoxia-upregulated signature correlated with poor patient outcome in three independent cohorts [49]. The signature included the expression of LCO4A1, ENO1, HK2, PGK1, MTFP1, HILPDA, VKORC1, TPI1, and HIST1H1C.…”

Section: Neuroblastoma Differentiation and Stemness In Hypoxic Contextsmentioning

confidence: 99%

Hypoxia in the Initiation and Progression of Neuroblastoma Tumours

Castaño

Gómez-Muñoz

Pardal

et al. 2019

IJMS

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Neuroblastoma is the most frequent extracranial solid tumour in children, causing 10% of all paediatric oncology deaths. It arises in the embryonic neural crest due to an uncontrolled behaviour of sympathetic nervous system progenitors, giving rise to heterogeneous tumours. Low local or systemic tissue oxygen concentration has emerged as a cellular stimulus with important consequences for tumour initiation, evolution and progression. In neuroblastoma, several evidences point towards a role of hypoxia in tumour initiation during development, tumour cell differentiation, survival and metastatic spreading. However, the heterogeneous nature of the disease, its developmental origin and the lack of suitable experimental models have complicated a clear understanding of the effect of hypoxia in neuroblastoma tumour progression and the molecular mechanisms implicated. In this review, we have compiled available evidences to try to shed light onto this important field. In particular, we explore the effect of hypoxia in neuroblastoma cell transformation and differentiation. We also discuss the experimental models available and the emerging alternatives to study this problem, and we present hypoxia-related therapeutic avenues being explored in the field.

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Integrative genomics reveals hypoxia inducible genes that are associated with a poor prognosis in neuroblastoma patients

Cited by 32 publications

References 46 publications

Maternal Embryonic Leucine Zipper Kinase (MELK), a Potential Therapeutic Target for Neuroblastoma

Maternal Embryonic Leucine Zipper Kinase (MELK), a Potential Therapeutic Target for Neuroblastoma

Hypoxia-inducible factor-1 alpha Correlates with Tumor-Associated Macrophages Infiltration, Influences Survival of Gastric Cancer Patients

Hypoxia in the Initiation and Progression of Neuroblastoma Tumours

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