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Dive into the research topics where Steven Middleton is active.

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Featured researches published by Steven Middleton.


Lancet Oncology | 2012

Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study

Isabelle Ray-Coquard; Jean-Yves Blay; Antoine Italiano; Axel Le Cesne; Nicolas Penel; Jianguo Zhi; Florian Heil; Ruediger Rueger; Bradford Graves; Meichun Ding; David Geho; Steven Middleton; Lyubomir T. Vassilev; Gwen Nichols; Binh Bui

BACKGROUND We report a proof-of-mechanism study of RG7112, a small-molecule MDM2 antagonist, in patients with chemotherapy-naive primary or relapsed well-differentiated or dedifferentiated MDM2-amplified liposarcoma who were eligible for resection. METHODS Patients with well-differentiated or dedifferentiated liposarcoma were enrolled at four centres in France. Patients received up to three 28-day neoadjuvant treatment cycles of RG7112 1440 mg/m(2) per day for 10 days. If a patient progressed at any point after the first cycle, the lesion was resected or, if unresectable, an end-of-study biopsy was done. The primary endpoint was to assess markers of RG7112-dependent MDM2 inhibition and P53 pathway activation (P53, P21, MDM2, Ki-67, macrophage inhibitory cytokine-1 [MIC-1], and apoptosis). All analyses were per protocol. This trial is registered with EudraCT, number 2009-015522-10. RESULTS Between June 3, and Dec 14, 2010, 20 patients were enrolled and completed pretreatment and day 8 biopsies. 18 of 20 patients had TP53 wild-type tumours and two carried missense TP53 mutations. 14 of 17 assessed patients had MDM2 gene amplification. Compared with baseline, P53 and P21 concentrations, assessed by immunohistochemistry, had increased by a median of 4·86 times (IQR 4·38-7·97; p=0·0001) and 3·48 times (2·05-4·09; p=0·0001), respectively, at day 8 (give or take 2 days). At the same timepoint, relative MDM2 mRNA expression had increased by a median of 3·03 times (1·23-4·93; p=0·003) that at baseline. The median change from baseline for Ki-67-positive tumour cells was -5·05% (IQR -12·55 to 0·05; p=0·01). Drug exposure correlated with blood concentrations of MIC-1 (p<0·0001) and haematological toxicity. One patient had a confirmed partial response and 14 had stable disease. All patients experienced at least one adverse event, mostly nausea (14 patients), vomiting (11 patients), asthenia (nine patients), diarrhoea (nine patients), and thrombocytopenia (eight patients). There were 12 serious adverse events in eight patients, the most common of which were neutropenia (six patients) and thrombocytopenia (three patients). DISCUSSION MDM2 inhibition activates the P53 pathway and decreases cell proliferation in MDM2-amplified liposarcoma. This study suggests that it is feasible to undertake neoadjuvant biopsy-driven biomarker studies in liposarcoma. FUNDING F Hoffmann-La Roche.


Journal of Clinical Oncology | 2012

Phase I Study of RO4929097, a Gamma Secretase Inhibitor of Notch Signaling, in Patients With Refractory Metastatic or Locally Advanced Solid Tumors

Anthony W. Tolcher; Wells A. Messersmith; Stanislaw M. Mikulski; Kyriakos P. Papadopoulos; Eunice L. Kwak; Darlene Gibbon; Amita Patnaik; Gerald S. Falchook; Arvind Dasari; Geoffrey I. Shapiro; John Frederick Boylan; Zhi Xin Xu; Ka Wang; Astrid Koehler; James Song; Steven Middleton; Jonathan Deutsch; Mark DeMario; Razelle Kurzrock; Jennifer J. Wheler

PURPOSE To determine the maximum-tolerated dose (MTD) and assess safety, pharmacokinetics, pharmacodynamics, and evidence of antitumor activity of RO4929097, a gamma secretase inhibitor of Notch signaling in patients with advanced solid malignancies. PATIENTS AND METHODS Patients received escalating doses of RO4929097 orally on two schedules: (A) 3 consecutive days per week for 2 weeks every 3 weeks; (B) 7 consecutive days every 3 weeks. To assess reversible CYP3A4 autoinduction, the expanded part of the study tested three dosing schedules: (B) as above; modified A, 3 consecutive d/wk for 3 weeks; and (C) continuous daily dosing. Positron emission tomography scans with [(18)F]fluorodeoxyglucose (FDG-PET) were used to assess tumor metabolic effects. RESULTS Patients on schedule A (n = 58), B (n = 47), and C (n = 5; expanded cohort) received 302 cycles of RO4929097. Common grade 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. Transient grade 3 hypophosphatemia (dose-limiting toxicity, one patient) and grade 3 pruritus (two patients) were observed at 27 mg and 60 mg, respectively; transient grade 3 asthenia was observed on schedule A at 80 mg (one patient). Tumor responses included one partial response in a patient with colorectal adenocarcinoma with neuroendocrine features, one mixed response (stable disease) in a patient with sarcoma, and one nearly complete FDG-PET response in a patient with melanoma. Effect on CYP3A4 induction was observed. CONCLUSION RO4929097 was well tolerated at 270 mg on schedule A and at 135 mg on schedule B; the safety of schedule C has not been fully evaluated. Further studies are warranted on the basis of a favorable safety profile and preliminary evidence of clinical antitumor activity.


Molecular Pharmacology | 2007

Cellular and in Vivo Activity of JNJ-28871063, A Nonquinazoline Pan-ErbB Kinase Inhibitor That Crosses the Blood-Brain Barrier and Displays Efficacy against Intracranial Tumors

Stuart Emanuel; Terry Vincent Hughes; Mary Adams; Catherine A. Rugg; Angel R. Fuentes-Pesquera; Peter J. Connolly; Niranjan B. Pandey; Sandra Moreno-Mazza; Jeannene Butler; Virna Borowski; Steven Middleton; Robert H. Gruninger; Jennifer R. Story; Cheryl Napier; Beth Hollister; Lee M. Greenberger

JNJ-28871063 is a potent and highly selective pan-ErbB kinase inhibitor from a novel aminopyrimidine oxime structural class that blocks the proliferation of epidermal growth factor receptor (EGFR; ErbB1)- and ErbB2-overexpressing cells but does not affect the growth of non-ErbB-overexpressing cells. Treatment of human cancer cells with JNJ-28871063 inhibited phosphorylation of functionally important tyrosine residues in both EGFR and ErbB2 and blocked downstream signal transduction pathways responsible for proliferation and survival. A single dose of compound reduced phosphorylation of ErbB2 receptors in tumor-bearing mice, demonstrating target suppression in vivo. Tissue distribution studies show that JNJ-28871063 crosses the blood-brain barrier and penetrates into tumors, where it is able to accumulate to higher levels than those found in the plasma. JNJ-28871063 showed oral antitumor activity in human tumor xenograft models that overexpress EGFR and ErbB2. In an intracranial ErbB2-overexpressing tumor model, JNJ-28871063 extended survival relative to untreated animals. The brain is a primary site of metastasis for EGFR-overexpressing lung cancers and ErbB2-overexpressing breast cancers. Therefore, the ability to penetrate into the brain could be an advantage over existing therapies such as trastuzumab (Herceptin) and cetuximab (Erbitux), which are antibodies and do not cross the blood-brain barrier. These results show that JNJ-28871063 is orally bioavailable, has activity against EGFR and ErbB2-dependent tumor xenografts, and can penetrate into the brain and inhibit ErbB2-overexpressing tumor growth.


Haematologica | 2016

Acute myeloid leukemia patients' clinical response to idasanutlin (RG7388) is associated with pre-treatment MDM2 protein expression in leukemic blasts.

Bernhard Reis; Lori Jukofsky; Gong Chen; Giovanni Martinelli; Hua Zhong; W. Venus So; Michael Dickinson; Mark W. Drummond; Sarit Assouline; Maneja Hashemyan; Michel Theron; Steven Blotner; Je-Hwan Lee; Margaret Kasner; Sung-Soo Yoon; Ruediger Rueger; Karen Seiter; Steven Middleton; Kevin R. Kelly; Norbert Vey; Karen Yee; Gwen Nichols; Lin-Chi Chen; William E. Pierceall

In translational research described, we investigated biomarker expression by flow cytometry for MDM2 antagonist clinical response association in relapsed/refractory AML patients treated with idasanutlin-based therapy ( [Clinicaltrials.gov][1] identifier: [NCT01773408][2] ). As MDM2 targets p53 for


British Journal of Cancer | 2014

Structurally diverse MDM2–p53 antagonists act as modulators of MDR-1 function in neuroblastoma

Lindi Chen; Yan Zhao; Gail Halliday; Philip Berry; R F Rousseau; Steven Middleton; Gwen Nichols; F Del Bello; Alessandro Piergentili; David R. Newell; John Lunec; Deborah A. Tweddle

Background:A frequent mechanism of acquired multidrug resistance in human cancers is overexpression of ATP-binding cassette transporters such as the Multi-Drug Resistance Protein 1 (MDR-1). Nutlin-3, an MDM2–p53 antagonist, has previously been reported to be a competitive MDR-1 inhibitor.Methods:This study assessed whether the structurally diverse MDM2–p53 antagonists, MI-63, NDD0005, and RG7388 are also able to modulate MDR-1 function, particularly in p53 mutant neuroblastoma cells, using XTT-based cell viability assays, western blotting, and liquid chromatography–mass spectrometry analysis.Results:Verapamil and the MDM2–p53 antagonists potentiated vincristine-mediated growth inhibition in a concentration-dependent manner when used in combination with high MDR-1-expressing p53 mutant neuroblastoma cell lines at concentrations that did not affect the viability of cells when given alone. Liquid chromatography–mass spectrometry analyses showed that verapamil, Nutlin-3, MI-63 and NDD0005, but not RG7388, led to increased intracellular levels of vincristine in high MDR-1-expressing cell lines.Conclusions:These results show that in addition to Nutlin-3, other structurally unrelated MDM2–p53 antagonists can also act as MDR-1 inhibitors and reverse MDR-1-mediated multidrug resistance in neuroblastoma cell lines in a p53-independent manner. These findings are important for future clinical trial design with MDM2–p53 antagonists when used in combination with agents that are MDR-1 substrates.


Pediatric Blood & Cancer | 2015

Inhibition of MDM2 by RG7388 confers hypersensitivity to X-radiation in xenograft models of childhood sarcoma.

Doris A. Phelps; Kathryn Bondra; Star Seum; Christopher Chronowski; Justin Leasure; Raushan T. Kurmasheva; Steven Middleton; Dian Wang; Xiaokui Mo; Peter J. Houghton

Curative therapy for childhood sarcoma presents challenges when complete resection is not possible. Ionizing radiation (XRT) is used as a standard modality at diagnosis or recurrence for childhood sarcoma; however, local recurrence is still problematic. Most childhood sarcomas are TP53 wild type at diagnosis, although approximately 5–10% have MDM2 amplification or overexpression.


British Journal of Haematology | 2015

MDM2 antagonist clinical response association with a gene expression signature in acute myeloid leukaemia.

Hua Zhong; Gong Chen; Lori Jukofsky; David Geho; Sung Won Han; Fabian Birzele; Sabine Bader; Lucia Himmelein; James Cai; Zayed Albertyn; Mark Rothe; Laurent Essioux; Helmut Burtscher; Steven Middleton; Ruediger Rueger; Lin-Chi Chen; Markus Dangl; Gwen Nichols; William E. Pierceall

Acute myeloid leukaemia (AML) is uniquely sensitive to p53 activation 1, 2 as ≈90% of patients carry wild-type TP53 and frequent MDM2 overexpression.3 MDM2 blocks p53 transactivation and targets p53 for ubiquitin-dependent degradation.4, 5 Nutlins have been characterized as potent and selective small-molecule MDM2 antagonists.1, 6–8 RG7112 was the first such MDM2 antagonist to undergo clinical assessment in solid tumors and leukaemia trials.1, 2, 9 As not all patients with functional p53 will respond to MDM2 antagonists, diagnostic tools may identify patients likely to respond.


Medicinal Chemistry | 2005

8-(Heteroaryl)phenalkyl-1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-ones as Opioid Receptor Modulators

A. D. Jordan; M. J. Orsini; Steven Middleton; Peter J. Connolly; D. E. Brenneman; K. Pan; Allen B. Reitz

A series of N-biarylalkyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-ones were prepared and evaluated for biological activity at opioid (mu, delta, kappa) and opioid receptor like-1 (ORL-1) G-protein coupled receptors. Substitution on the biaryl moiety produced enhanced affinity for the mu-opioid receptor.


Expert Opinion on Therapeutic Patents | 2008

α1a/1d-selective adrenergic receptor antagonists for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms

George Chiu; Peter J. Connolly; Steven Middleton; Shengjian Li; Virginia L. Pulito; Jingchun Liu; Ellen W. Baxter; Allen B. Reitz

Background: Although α1 adrenergic receptor blockers can be very effective for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS), their usage is limited by cardiovascular-related side effects that are caused by the subtype nonselective nature of many current drugs. To overcome this problem, it was hypothesized that an α1a/1d subtype selective antagonist would be efficacious yet produce less side effects, and hence would bring greater benefit for the therapy of BPH/LUTS. Unfortunately, such highly selective α1a/1d antagonists were not available, making the validation of the new hypothesis impossible. Objective/method: This review disclosed several series of α1a/1d subtype selective antagonists that have been discovered and developed by Johnson & Johnson recently. These compounds show equal and potent affinity for both α1a and α1d subtypes with good selectivity versus the α1b subtype. Some analogues also possess favorable pharmacokinetic properties. Conclusion: Although discovery of α1a/1d subtype selective antagonists paves the way for future research, the effectiveness of α1a/1d subtype selective antagonist in BPH/LUTS patients still needs to be proven in clinical trials. This patent review will focus on the latest progress in this field from 2006 to present.


Bioorganic & Medicinal Chemistry Letters | 2015

A selective small molecule NOP (ORL-1 receptor) partial agonist for the treatment of anxiety

Tina Morgan Ross; Kathleen Battista; Gilles C. Bignan; Doug E. Brenneman; Peter J. Connolly; Jingchun Liu; Steven Middleton; Michael Orsini; Allen B. Reitz; Daniel I. Rosenthal; Malcolm K. Scott; Anil H. Vaidya

Small molecule (1) has been identified as a selective partial agonist of Opioid Receptor Like-1 (ORL-1) with potential utility for the treatment of anxiety and other disorders. Nociceptin (orphanin FQ) is an endogenous peptide ligand that binds to ORL-1, however it does not bind the classical δ, μ and κ opioid receptors with high affinity. The synthesis of 1 involved using a molecular diversity approach, to rapidly advance a library of compounds for biological testing. A lead selective potent partial agonist (35-fold ORL-1/Mu) progressed to ORL-1 (NOP or OP4) proof of concept testing in advanced studies. The synthetic approach and biological data for the related chemical series will be presented.

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Kevin R. Kelly

University of Southern California

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