Drugging MYCN through an Allosteric Transition in Aurora Kinase A

Gustafson, W. Clay; Meyerowitz, Justin; Nekritz, Erin A.; Chen, Justin; Benes, Cyril H.; Charron, Elise; Simonds, Erin F.; Seeger, Robert C.; Matthay, Katherine K.; Hertz, Nicholas T.; Eilers, Martin; Shokat, Kevan M.; Weiss, William A.

doi:10.1016/j.ccr.2014.07.015

Cited by 238 publications

(259 citation statements)

References 48 publications

(60 reference statements)

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“…[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

115

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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.

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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

115

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“…Interest in Aurora A and its conformational plasticity has recently increased owing to the discovery that inhibiting Aurora A with MLN8054 or CD532, both observed to bind Aurora A in an inactive T‐loop conformation, disrupts the interaction of Aurora A with the proto‐oncogenic transcription factor N ‐Myc. This leads to degradation of N ‐Myc and offers an alternative therapeutic strategy for N ‐Myc‐driven tumors (currently under clinical evaluation with MLN8237/alisertib) 5d, 6. These factors make Aurora A an excellent clinically relevant system for studying the heterogeneity and dynamics of T‐loop conformation underlying the observed structural and catalytic properties of protein kinases.…”

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confidence: 99%

“…MLN8054 and CD532 are both nanomolar inhibitors of Aurora A, and X‐ray structures show that each binds in an inactive T‐loop conformation (Figure S1 c, d) 5b,5d,5g. Although both are referred to as type II inhibitors, neither extends into the allosteric hydrophobic pocket, and neither has been captured binding the kinase with a canonical DFG‐out motif.…”

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confidence: 99%

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Dynamic Equilibrium of the Aurora A Kinase Activation Loop Revealed by Single‐Molecule Spectroscopy

et al. 2017

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The conformation of the activation loop (T‐loop) of protein kinases underlies enzymatic activity and influences the binding of small‐molecule inhibitors. By using single‐molecule fluorescence spectroscopy, we have determined that phosphorylated Aurora A kinase is in dynamic equilibrium between a DFG‐in‐like active T‐loop conformation and a DFG‐out‐like inactive conformation, and have measured the rate constants of interconversion. Addition of the Aurora A activating protein TPX2 shifts the equilibrium towards an active T‐loop conformation whereas addition of the inhibitors MLN8054 and CD532 favors an inactive T‐loop. We show that Aurora A binds TPX2 and MLN8054 simultaneously and provide a new model for kinase conformational behavior. Our approach will enable conformation‐specific effects to be integrated into inhibitor discovery across the kinome, and we outline some immediate consequences for structure‐based drug discovery.

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“…However, MYCN is a transcription factors that was considered a poor drug target, until recent approaches suggested that down-regulation of MYCN could be possible by indirect targeting using Aurora kinase inhibitors or BET inhibitors. These concepts were proven using preclinical models [2][3][4][5][6] and are now entering clinical trials. …”

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confidence: 99%

MYCN-targeting vaccines and immunotherapeutics

Schramm

Lode

2016

Human Vaccines & Immunotherapeutics

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Amplification and concomitant overexpression of the MYCN oncogene is a frequent event in many malignancies including the childhood tumors, neuroblastoma and medulloblastoma. MYCN is only expressed in a defined time frame during early developmental processes, 1 which is beneficial for approaches combatting tumor-specific MYCN. However, MYCN is a transcription factors that was considered a poor drug target, until recent approaches suggested that down-regulation of MYCN could be possible by indirect targeting using Aurora kinase inhibitors or BET inhibitors. These concepts were proven using preclinical models [2][3][4][5][6] and are now entering clinical trials. KEYWORDS DNA vaccination; minigene; MYCN; neuroblastomaIn neuroblastoma (NB), a common solid tumor of childhood, the MYCN oncogene is amplified in~20 % of cases. 7 Following induction chemotherapy and consolidation with high dose chemotherapy and stem cell rescue, maintenance treatment regimens focus on passive immunotherapy by targeting NB-specific expression of the disialoganglioside GD2 with GD2-specific monoclonal antibodies (MAbs). As GD2 is devoid of any intracellular signal transduction component, the mechanism of action of this approach is the induction of complement-dependent (CDC) and antibody-dependent cellular cytotoxicity (ADCC). In this context, treatment with mouse-human chimeric Mab ch14.18 showed superior survival rates when used as a single agent approach 8 or in combination with IL-2 and GM-CSF. 9 These two studies from independent cooperative groups demonstrated the potential of targeted immunotherapies in neuroblastoma. Ongoing clinical trials in the context of passive immunotherapy address the role of cytokines as well as the potential of novel delivery methods by long term continuous infusion. The specific components of ch14.18 were also used to design GD2-specific chimeric antigen receptor-engineered (CAR) T cells. These were generated and administered to NB patients in the context of a phase I study. Complete remission was achieved in 3/11 patients with active disease and persistence of CARs in vivo > 6 weeks was found to correlate with clinical outcome. 10 One disadvantage of passive immunotherapy is the absence of long lasting and persistent immunity against the malignancy. Based on the high relapse rate in NB combined with limited strategies for therapeutic intervention new approaches are urgently needed. 11 Globally, neuroblastomas escape from destruction by the immune system using a combinatorial strategy involving MYCN-dependent downregulation of MHC molecules 12 and inhibition of NKT cells, which in turn causes up-regulation of tumor-associated macrophages (TAMs, 13,14 Earlier reports also indicated that MYCN-specific cytotoxic T cells (CTLs) are present in neuroblastoma patients harboring tumor-specific MYCN amplification. 15 Surprisingly, little is known on the usefulness of MYCN as a target for cancer immunotherapy. 16 Peptide vaccination using a HLA-A2 restricted peptide derived from MYCN has been shown to effecti...

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Drugging MYCN through an Allosteric Transition in Aurora Kinase A

Cited by 238 publications

References 48 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

Dynamic Equilibrium of the Aurora A Kinase Activation Loop Revealed by Single‐Molecule Spectroscopy

MYCN-targeting vaccines and immunotherapeutics

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