Evaluation of ABT-751 against childhood cancer models in vivo

Morton, Christopher L.; Favours, Edward; Mercer, Kimberly; Boltz, Claire R.; Crumpton, Jeri Carol; Tucker, Chandra L.; Billups, Catherine A.; Houghton, Peter J.

doi:10.1007/s10637-007-9042-y

Cited by 28 publications

(27 citation statements)

References 19 publications

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“…These are human Wilms tumors propagated subcutaneously in SCID (severe combined immunodeficiency) mice that have been successfully used as a model for sporadic Wilms tumor (41,42). These tumors were removed from the mice, dissociated, separated from host cells, and loaded with Fura-2 to measure changes in cytosolic Ca 2ϩ concentration.…”

Section: Resultsmentioning

confidence: 99%

“…Ca 2ϩ measurements were made using a Leica DMI 6000B fluorescence microscope controlled by Slidebook software (Intelligent Imaging Innovations, Denver, CO). Fluorescence emission at 505 nm was monitored while alternating between 340-and 380-nm excitation wavelengths at a frequency of 0.67 Hz; intracellular Ca 2ϩ measurements are shown as 340/380 nm ratios obtained from groups (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45) of single cells.…”

Section: Methodsmentioning

confidence: 99%

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Wilms Tumor Suppressor 1 (WT1) and Early Growth Response 1 (EGR1) Are Regulators of STIM1 Expression

Ritchie

Yue

Zhou

et al. 2010

Journal of Biological Chemistry

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Store-operated calcium entry (SOCE) is a key evolutionarily conserved process whereby decreases in endoplasmic reticulum Ca 2؉ content lead to the influx of Ca 2؉ across the plasma membrane. How this process is regulated in specific tumor cell types is poorly understood. In an effort to address this concern, we obtained and tested primary Wilms tumor cells, finding no detectable SOCE in this cell type. Analysis of the expression levels of STIM1 and ORAI1 (the molecular mediators of SOC) revealed poor STIM1 expression. Analysis of the STIM1 promoter using the TESS search system (University of Pennsylvania) revealed four putative response elements to the zinc-finger proteins WT1 (Wilms tumor suppressor 1) and EGR1 (early growth response 1). Either overexpression of WT1 or knockdown of EGR1 resulted in loss of STIM1 expression and a resultant decrease in SOCE. Furthermore, examination of Egr1 knock-out animals revealed loss of STIM1 expression in multiple tissues. Finally, using chromatin immunoprecipitation, we reveal direct binding of both WT1 and EGR1 to putative response elements located within 500 bp of the transcriptional start site of STIM1. Considering that WT1 and EGR1 are well described oncogenes and tumor suppressors, these observations may reveal new mechanisms responsible for distinct Ca 2؉ signals in cancer cells. Changes in cytosolic Ca2ϩ levels are a common component of the signal transduction pathways for numerous growth factors and cytokines. Thus, activation of phospholipase C-coupled receptors (primarily via either G protein or tyrosine kinase receptors) results in the generation of the second messenger inositol 1,4,5-trisphosphate (1). Inositol 1,4,5-trisphosphate diffuses rapidly through the cytosol and interacts with its receptor on the endoplasmic reticulum (ER), 2 resulting in both transient ER Ca 2ϩ release and a lengthy increased influx of Ca 2ϩ across the plasma membrane, a process termed capacitative or store-operated Ca 2ϩ entry (SOCE) (2). SOCE has been shown to regulate numerous fundamental processes in cell biology, including migration (3, 4), proliferation (4 -6), and differentiation (7,8). Given the impact of these pathways on cancer cell biology, it is not surprising that altered Ca 2ϩ signaling can be observed in numerous classes of cancer cells. Indeed, inhibition of either the phosphatidylinositol pathway (9) or calcium influx (10, 11) can induce either growth arrest or cell death in a variety of tumor cells. Despite these observations, Ca 2ϩ signals remain poorly utilized therapeutic targets. This is in part because these studies were all performed prior to the discovery of the identities of the molecular mediators of SOCE. Without this insight, it was not possible to link changes in Ca 2ϩ signals with changes in the expression and function of oncogenes and tumor suppressors that cause tumor formation.After nearly 20 years of investigations into the mysteries of SOCE, the identities of the key molecular components of this process have finally been revealed (for recent reviews...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Wilms Tumor Suppressor 1 (WT1) and Early Growth Response 1 (EGR1) Are Regulators of STIM1 Expression

Ritchie

Yue

Zhou

et al. 2010

Journal of Biological Chemistry

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“…81 Pre-clinical studies of this agent found it to be most effective in neuroblastoma models and a phase I study showed it to be safe. 82,83 The results of a recently concluded phase II trial of ABT-751 in children with relapsed or refractory neuroblastoma are pending publication.…”

Section: New Treatment Strategiesmentioning

confidence: 99%

Neuroblastoma

Davidoff

2012

Seminars in Pediatric Surgery

161

115

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Neuroblastoma is a heterogeneous disease; tumors can spontaneously regress or mature, or display an aggressive, therapy-resistant phenotype. Increasing evidence indicates that the biologic and molecular features of neuroblastoma significantly influence and are highly predictive of clinical behavior. Because of this, neuroblastoma has served as a paradigm for biological risk assessment and treatment assignment. Most current clinical studies of neuroblastoma base therapy and its intensity on a risk stratification that takes into account both clinical and biologic variables predictive of relapse. For example, surgery alone offers definitive therapy with excellent outcome for patients with low-risk disease, while patients at high-risk for disease relapse are treated with intensive multimodality therapy. In this review recent advances in the understanding of the molecular genetic events involved in neuroblastoma pathogenesis are discussed, and how they are impacting the current risk stratification and providing potential targets for new therapeutic approaches for children with neuroblastoma. In addition, the results of significant recent clinical trials for the treatment of neuroblastoma are reviewed.

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“…ABT-751 is a novel oral anti-mitotic agent that binds to the colchicine binding site rather than the vincristine binding site on b-tubulin, and inhibits polymerization of microtubules. Importantly, ABT-751 is active against tumor models that are otherwise resistant to vincristine and doxorubicin [Morton et al, 2007]. A COG Phase II study of this compound is currently underway, based on Phase I results showing an encouraging median time-to-progression of 16 weeks in 35 children with relapsed neuroblastoma [Fox et al, 2008].…”

Section: Antimitoticsmentioning

confidence: 99%

New therapeutic targets for the treatment of high‐risk neuroblastoma

Wagner

Danks

2009

J of Cellular Biochemistry

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High-risk neuroblastoma remains a major problem in pediatric oncology, accounting for 15% of childhood cancer deaths. Although incremental improvements in outcome have been achieved with the intensification of conventional chemotherapy agents and the addition of 13-cis-retinoic acid, only one-third of children with high-risk disease are expected to be long-term survivors when treated with current regimens. In addition, the cost of cure can be quite high, as surviving children remain at risk for additional health problems related to long-term toxicities of treatment. Further advances in therapy will require the targeting of tumor cells in a more selective and efficient way so that survival can be improved without substantially increasing toxicity. In this review we summarize ongoing clinical trials and highlight new developments in our understanding of the molecular biology of neuroblastoma, emphasizing potential targets or pathways that may be exploitable therapeutically.

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Evaluation of ABT-751 against childhood cancer models in vivo

Cited by 28 publications

References 19 publications

Wilms Tumor Suppressor 1 (WT1) and Early Growth Response 1 (EGR1) Are Regulators of STIM1 Expression

Wilms Tumor Suppressor 1 (WT1) and Early Growth Response 1 (EGR1) Are Regulators of STIM1 Expression

Neuroblastoma

New therapeutic targets for the treatment of high‐risk neuroblastoma

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