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Inhibition of Neuroblastoma Cell Growth by Difluoromethylornithine (DFMO) and Bortezomib through Suppression of LIN28 and MYCN
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作者 Maria E. Rich Ping Zhao +2 位作者 Abhinav B. Nagulapally Jeffrey Bond Giselle L. Saulnier Sholler 《Journal of Cancer Therapy》 2017年第6期561-578,共18页
Neuroblastoma (NB) is the most common childhood cancer arising from the nervous system. Many high-risk neuroblastoma (HRNB) patients develop relapse after initial response to induction treatment and overall long term ... Neuroblastoma (NB) is the most common childhood cancer arising from the nervous system. Many high-risk neuroblastoma (HRNB) patients develop relapse after initial response to induction treatment and overall long term survival remains poor (less than 60%), emphasizing the need for new therapeutic approaches and more effective treatments. Combination therapies present a favorable approach to improve efficacy, decrease toxicity, and reduce development of drug resistance. Difluoromethylornithine (DFMO) has shown promise in recent clinical trials as a therapeutic agent in treating HRNB. Proteasomes are known to play an important role in tumor cell growth. Bortezomib was the first proteasome inhibitor shown to have anticancer activity clinically. In this study we explore the mechanistic and therapeutic effects of the novel drug combination of DFMO and bortezomib in NB. Cell proliferation studies demonstrated synergistic inhibition of NB cell growth. Bortezomib induced cleaved caspase-3 apoptotic pathway whereas DFMO induced a cytostatic effect on NB cells. Western blot analyses demonstrated down regulation of MYCN, LIN28 and NF-kB in response to DFMO and bortezomib, pathways that are important in cancer stem cells. A decrease in ATP-per-cell when treated with combination therapy suggests inhibition of glycolytic metabolism in NB cells. DFMO as a single agent or in combination with bortezomib significantly reduced tumor growth in xenograft mice. Given the lack of effective treatments, DFMO coupled with bortezomib offers a potential new therapeutic treatment for children with NB. 展开更多
关键词 NEUROBLASTOMA DFMO BORTEZOMIB LIN28B Glycolytic METABOLISM
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YM155 Inhibits Neuroblastoma Cell Migration and Survival <i>in Vitro</i>and Tumor Growth and Metastatic Burden in a Pre-Clinical Model
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作者 Heather M. Calderone Akshita Dutta +3 位作者 Lauren Smith Alexandra Eckardt Ping Zhao Giselle Saulnier Sholler 《Journal of Cancer Therapy》 2014年第13期1289-1302,共14页
Background: Neuroblastoma exhibits a high incidence of chromosomal translocations, the most common being the gain of a portion of the long arm of chromosome 17. This region includes the gene BIRC5/survivin, which is h... Background: Neuroblastoma exhibits a high incidence of chromosomal translocations, the most common being the gain of a portion of the long arm of chromosome 17. This region includes the gene BIRC5/survivin, which is highly upregulated in neuroblastoma and correlates with poor prognosis. Survivin is a member of the inhibitor of apoptosis family of proteins and is involved in tumor cell survival and migration. YM155 is a small molecule inhibitor of survivin transcription and has shown efficacy in several cancer model systems both?in vitro?and?in vivo. Procedure: Cells were treated with YM155 and effects on migration, invasion, and apoptosis signaling were investigated?in vitro. Tumor burden was assessed in xenografted mice by measuring tumor volume and liver metastases. Results: Treatment with YM155 caused a dose-dependent decrease in survivin expression and induction of apoptosis. Lower concentrations of YM155 reduced cell migration and invasion by 15% - 50% which varied by cell line. In a xenograft model, YM155 treatment inhibited tumor growth by 25% - 70%, reduced metastatic burden in the liver by 50%, and prolonged animal survival. Conclusion: The data suggest YM155 as a possible therapeutic agent for metastatic neuroblastoma. 展开更多
关键词 NEUROBLASTOMA YM155 Survivin Metastasis Apoptosis
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Challenges and opportunities identifying therapeutic targets for chemotherapy-induced peripheral neuropathy resulting from oxidative DNA damage
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作者 Mark R.Kelley Jill C.Fehrenbacher 《Neural Regeneration Research》 SCIE CAS CSCD 2017年第1期72-74,共3页
Background on chemotherapy-induced peripheral neuropathy(CIPN)Incidence,prevalence,and consequences:Up to 90%of cancer patients experience CIPN at some point during or after anticancer treatment(Seretny et al.,201... Background on chemotherapy-induced peripheral neuropathy(CIPN)Incidence,prevalence,and consequences:Up to 90%of cancer patients experience CIPN at some point during or after anticancer treatment(Seretny et al.,2014). 展开更多
关键词 neuropathy chemotherapy consequences anticancer identifying oxidative prevalence DNA incidence repair
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A Pilot Trial Testing the Feasibility of Using Molecular-Guided Therapy in Patients with Recurrent Neuroblastoma
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作者 Giselle L. Saulnier Sholler William Ferguson +16 位作者 Genevieve Bergendahl Erika Currier Shannon R. Lenox Jeffrey Bond Marni Slavik William Roberts Deanna Mitchell Don Eslin Jacqueline Kraveka Joel Kaplan Nehal Parikh Suman Malempati Gina Hanna Emily Eugster David Cherba Jeremy Miller Craig Webb 《Journal of Cancer Therapy》 2012年第5期602-612,共11页
Background: Neuroblastoma is the most common extracranial solid tumor in children, and treatment options for recurrent neuroblastoma are limited. Using molecular profiling to target the molecular vulnerabilities of ne... Background: Neuroblastoma is the most common extracranial solid tumor in children, and treatment options for recurrent neuroblastoma are limited. Using molecular profiling to target the molecular vulnerabilities of neuroblastoma with existing therapeutic agents may result in a rational, data-driven approach with potential to improve clinical outcomes. Methods: The primary objective of this pilot study was to evaluate the feasibility of supporting real-time treatment decisions through predictive modeling of genome-wide mRNA gene expression data from neuroblastoma tumor biopsies. Feasibility was defined as completion of tumor biopsy, histopathological evaluation, RNA extraction and quality control, gene expression profiling within a CLIA-certified laboratory, bioinformatic analysis, generation of a drug predicttion report, molecular tumor board review yielding a formulated treatment plan, and independent medical monitor review within a 2-week period. Results: Five patients with multiply relapsed or refractory neuroblastoma were enrolled between April and June 2010. All biopsies passed histopathology and RNA quality control. Generation of gene expression data and its analysis (3-7 days), reports which linked this data into medically actionable drug candidates (1-5 days), molecular tumor board (1-3 days) and independent medical monitor review (1 day) were all completed in real-time. The average time was 10.5 days for all patients. Conclusion: This study shows that it is feasible to create therapeutic treatment plans based on genomic profiling in less than 12 days. This warrants further testing in a Phase I study to determine safety of predicted treatments and evaluate whether the information obtained in these analyses would result in patient benefit. 展开更多
关键词 NEUROBLASTOMA MOLECULAR GUIDED THERAPY Predictive THERAPIES MOLECULAR PROFILING Genomic PROFILING Pediatric Cancer
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