Small Molecule Inhibitors of Aurora-A Induce Proteasomal Degradation of N-Myc in Childhood Neuroblastoma

Brockmann, Markus; Poon, Evon; Berry, Teeara; Carstensen, Anne; Deubzer, Hedwig E.; Rycak, Lukas; Jamin, Yann; Thway, Khin; Robinson, Simon P.; Roels, Frederik; Witt, Olaf; Fischer, Matthias; Chesler, Louis; Eilers, Martin

doi:10.1016/j.ccr.2013.05.005

Cited by 261 publications

(214 citation statements)

References 40 publications

Supporting

Mentioning

207

Contrasting

Order By: Relevance

“…[12][13][14] Additional lines of evidence support further evaluation of Aurora A kinase inhibition in neuroblastoma. Increased expression of Aurora A kinase correlates with inferior outcomes in neuroblastoma.…”

Section: Introductionmentioning

confidence: 80%

Phase I Study of the Aurora A Kinase Inhibitor Alisertib in Combination With Irinotecan and Temozolomide for Patients With Relapsed or Refractory Neuroblastoma: A NANT (New Approaches to Neuroblastoma Therapy) Trial

DuBois

Marachelian

Fox

et al. 2016

JCO

117

View full text Add to dashboard Cite

Purpose Alisertib is an oral Aurora A kinase inhibitor with preclinical activity in neuroblastoma. Irinotecan and temozolomide have activity in patients with advanced neuroblastoma. The goal of this phase I study was to determine the maximum tolerated dose (MTD) of alisertib with irinotecan and temozolomide in this population. Patients and Methods Patients age 1 to 30 years with relapsed or refractory neuroblastoma were eligible. Patients received alisertib tablets at dose levels of 45, 60, and 80 mg/m2 per day on days 1 to 7 along with irinotecan 50 mg/m2 intravenously and temozolomide 100 mg/m2 orally on days 1 to 5. Dose escalation of alisertib followed the rolling six design. Samples for pharmacokinetic and pharmacogenomic testing were obtained. Results Twenty-three patients enrolled, and 22 were eligible and evaluable for dose escalation. A total of 244 courses were administered. The MTD for alisertib was 60 mg/m2, with mandatory myeloid growth factor support and cephalosporin prophylaxis for diarrhea. Thrombocytopenia and neutropenia of any grade were seen in the majority of courses (84% and 69%, respectively). Diarrhea in 55% of courses and nausea in 54% of courses were the most common nonhematologic toxicities. The overall response rate was 31.8%, with a 50% response rate observed at the MTD. The median number of courses per patient was eight (range, two to 32). Progression-free survival rate at 2 years was 52.4%. Pharmacokinetic testing did not show evidence of drug-drug interaction between irinotecan and alisertib. Conclusion Alisertib 60 mg/m2 per dose for 7 days is tolerable with a standard irinotecan and temozolomide backbone and has promising response and progression-free survival rates. A phase II trial of this regimen is ongoing.

show abstract

Section: Introductionmentioning

confidence: 80%

Phase I Study of the Aurora A Kinase Inhibitor Alisertib in Combination With Irinotecan and Temozolomide for Patients With Relapsed or Refractory Neuroblastoma: A NANT (New Approaches to Neuroblastoma Therapy) Trial

DuBois

Marachelian

Fox

et al. 2016

JCO

117

View full text Add to dashboard Cite

show abstract

“…Oncogenic functions of Aurora A in neuroblastoma are well established (11). Akt and Aurora A are partners and important targets for neuroblastoma treatment (13,39). Akt was shown to transduce signal to chemorestistance induced via TRKB/BDNF (40) and to participate in signaling network from Aurora A that drives tumor growth (35).…”

Section: Discussionmentioning

confidence: 99%

“…In neuroblastoma, the most common extra-cranial tumor of childhood, Aurora A (encoded by AURKA) and MYCN are partners in driving the malignancy and negative prognostic factors (11,12). Importantly, this interaction provides an opportunity to target high risk MYCN-amplified neuroblastoma tumors with Aurora A inhibitors (13,14), as MYCN due to its function of a transcription factor is viewed as 'undruggable' (15).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of the PHLDA1 gene in IMR-32 neuroblastoma cells increases levels of Aurora A, TRKB and affects proteins involved in apoptosis and autophagy pathways

Durbas

Horwacik

Boratyn

et al. 2016

International Journal of Oncology

View full text Add to dashboard Cite

Abstract.We have recently shown that mRNA and protein of PHLDA1 (pleckstrin-homology-like domain family A, member 1) were by far the most upregulated molecules upon treatment of IMR-32 cells with the anti-GD2 ganglioside monoclonal antibody 14G2a. Hence, we decided to study functions of PHLDA1 using human neuroblastoma IMR-32 cells as a model. Here, we show that constitutive expression of mRNA and protein of the PHLDA1 gene in IMR-32 cells was inversely correlated with transcript of the AURKA gene and Aurora A oncoprotein. Next, we silenced PHLDA1 expression in IMR-32 cells using an shRNA interference method. We report that IMR-32 cells with stable downregulation of PHLDA1 showed enhanced cellular ATP levels and an increase in mitochondrial membrane potential, as compared to control and non-transduced cells. We demonstrated that downregulation of PHLDA1 leads to a significant increase in expression of Aurora A and TRKB that are markers of poor prognosis in neuroblastoma. Also, we measured an increase in Aurora A and Akt kinases phosphorylation in the cells. Most importantly, PHLDA1-silenced cells were less susceptible to apoptosis than control cells, as shown by the lower expression of cleaved caspase-3 and PARP as well as a decreased activity of caspase-3 and -7. Our study negatively correlates expression of PHLDA1 and Aurora A in IMR-32 cells and sheds new light on functions of PHLDA1 in the neuroblastoma tumor cells, suggesting its role as a pro-apoptotic protein. Additionally, our results show possible links of the protein to regulation of features of mitochondria and formation of autophagosomes. IntroductionPHLDA1 was identified as a gene involved in Fas (CD95) expression and apoptosis induced after an anti-TCR antibody binding to mouse T cell hybridoma cells (1). In humans the gene is located on the long arm of the chromosome 12 [12q15 (2)] and encodes a 401 amino acid (aa) protein (45 kDa) named pleckstrin-homology-like domain family A, member 1 (PHLDA1, synonyms include: DT1P1B11, PHRIP, 'prolinehistidine rich protein', TDAG51, based on www.genecards. org).Several research groups have aimed to characterize involvement of PHLDA1 in biology of cancer cells, including its function in apoptosis. Thus, Neef et al measured levels of mRNA of PHLDA1 in three sets of cell lines, derived from paired samples of primary and metastatic melanoma tumors, and reported that PHLDA1 was downregulated in the latter. PHLDA1 was detected by the authors in benign melanocytic nevi, and its level was shown to decrease with progression of malignant melanomas. Also, constitutive expression of the PHLDA1 protein in a melanoma cell line Mel Rif has led to cell growth reduction along with an increase in basal apoptosis and sensitivity to doxorubicin and camptothecin (3). In 2006, Hayashida et al showed that PHLDA1 is a heat shock inducible gene regulated by HSF1 and when overexpressed in HeLa cells has pro-apoptotic functions (4). In yet another report, Nagai et al have reported that downregulation of PHLDA1 is a strong predictor of ...

show abstract

“…Some of the available inhibitors of AURKA induce an unusually distorted conformation of its kinase domain, thus impairing its interaction with N-myc (87). AURKA inhibitors have shown preclinical activity in N-myc-amplified neuroblastoma and neuroendocrine prostate cancer (35,66,88), and are now undergoing phase II evaluation for these diseases. Recently, Bjerke and colleagues carried out a synthetic lethal screen to identify kinases that could represent a therapeutic target in N-myc-amplified pediatric glioblastoma multiforme (24).…”

Section: Targeting N-mycmentioning

confidence: 99%

The N-myc Oncogene: Maximizing its Targets, Regulation, and Therapeutic Potential

Beltran

2014

Molecular Cancer Research

124

116

View full text Add to dashboard Cite

N-myc (MYCN), a member of the Myc family of basic-helix-loop-helix-zipper (bHLHZ) transcription factors, is a central regulator of many vital cellular processes. As such, N-myc is well recognized for its classic oncogenic activity and association with human neuroblastoma. Amplification and overexpression of N-myc has been described in other tumor types, particularly those of neural origin and neuroendocrine tumors. This review outlines N-myc's contribution to normal development and oncogenic progression. In addition, it highlights relevant transcriptional targets and mechanisms of regulation. Finally, the clinical implications of N-Myc as a biomarker and potential as a target using novel therapeutic approaches are discussed. Mol Cancer Res; 12(6); 815-22. Ó2014 AACR. IntroductionThe N-myc gene was first reported in 1983, when Schwab and colleagues (1) and Kohl and colleagues (2) discovered that there were a subset of human neuroblastoma cell lines harboring multiple copies of a DNA sequence related to the C-myc oncogene (MYC), and this region was designated Nmyc (MYCN). Genomic amplification of N-myc resulted in overexpression of N-myc at the mRNA level, and rat embryo cells transfected with N-myc demonstrated oncogenic properties. These findings were first to bring attention to N-myc as a putative oncogene.

show abstract

Small Molecule Inhibitors of Aurora-A Induce Proteasomal Degradation of N-Myc in Childhood Neuroblastoma

Cited by 261 publications

References 40 publications

Phase I Study of the Aurora A Kinase Inhibitor Alisertib in Combination With Irinotecan and Temozolomide for Patients With Relapsed or Refractory Neuroblastoma: A NANT (New Approaches to Neuroblastoma Therapy) Trial

Phase I Study of the Aurora A Kinase Inhibitor Alisertib in Combination With Irinotecan and Temozolomide for Patients With Relapsed or Refractory Neuroblastoma: A NANT (New Approaches to Neuroblastoma Therapy) Trial

Downregulation of the PHLDA1 gene in IMR-32 neuroblastoma cells increases levels of Aurora A, TRKB and affects proteins involved in apoptosis and autophagy pathways

The N-myc Oncogene: Maximizing its Targets, Regulation, and Therapeutic Potential

Contact Info

Product

Resources

About