Maurizio Rocchetti
Pfizer
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Publication
Featured researches published by Maurizio Rocchetti.
Molecular Cancer Therapeutics | 2007
Patrizia Carpinelli; Roberta Ceruti; Maria Laura Giorgini; Paolo Cappella; Laura Gianellini; Valter Croci; Anna Degrassi; Gemma Texido; Maurizio Rocchetti; Paola Vianello; Luisa Rusconi; Paola Storici; Paola Zugnoni; Claudio Arrigoni; Chiara Soncini; Cristina Alli; Veronica Patton; Aurelio Marsiglio; Dario Ballinari; Enrico Pesenti; Daniele Fancelli; Jürgen Moll
PHA-739358 is a small-molecule 3-aminopyrazole derivative with strong activity against Aurora kinases and cross-reactivities with some receptor tyrosine kinases relevant for cancer. PHA-739358 inhibits all Aurora kinase family members and shows a dominant Aurora B kinase inhibition–related cellular phenotype and mechanism of action in cells in vitro and in vivo. p53 status–dependent endoreduplication is observed upon treatment of cells with PHA-739358, and phosphorylation of histone H3 in Ser10 is inhibited. The compound has significant antitumor activity in different xenografts and spontaneous and transgenic animal tumor models and shows a favorable pharmacokinetic and safety profile. In vivo target modulation is observed as assessed by the inhibition of the phosphorylation of histone H3, which has been validated preclinically as a candidate biomarker for the clinical phase. Pharmacokinetics/pharmacodynamics modeling was used to define drug potency and to support the prediction of active clinical doses and schedules. We conclude that PHA-739358, which is currently tested in clinical trials, has great therapeutic potential in anticancer therapy in a wide range of cancers. [Mol Cancer Ther 2007;6(12):3158–68]
Clinical Cancer Research | 2009
Roger B. Cohen; Suzanne F. Jones; Charu Aggarwal; Margaret von Mehren; Jonathan D. Cheng; David R. Spigel; F. Anthony Greco; Mariangela Mariani; Maurizio Rocchetti; Roberta Ceruti; Silvia Comis; Bernard Laffranchi; Jürgen Moll; Howard A. Burris
Purpose: This study was conducted to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the i.v. pan-aurora kinase inhibitor PHA-739358, danusertib, in patients with advanced solid tumors. Experimental Design: In part 1, patients received escalating doses of danusertib (24-hour infusion every 14 days) without filgrastim (granulocyte colony-stimulating factor, G-CSF). Febrile neutropenia was the dose-limiting toxicity without G-CSF. Further dose escalation was done in part 2 with G-CSF. Blood samples were collected for danusertib pharmacokinetics and pharmacodynamics. Skin biopsies were collected to assess histone H3 phosphorylation (pH3). Results: Fifty-six patients were treated, 40 in part 1 and 16 in part 2. Febrile neutropenia was the dose-limiting toxicity in part 1 without G-CSF. Most other adverse events were grade 1 to 2, occurring at doses ≥360 mg/m2 with similar incidence in parts 1 and 2. The maximum tolerated dose without G-CSF is 500 mg/m2. The recommended phase 2 dose in part 2 with G-CSF is 750 mg/m2. Danusertib showed dose-proportional pharmacokinetics in parts 1 and 2 with a median half-life of 18 to 26 hours. pH3 modulation in skin biopsies was observed at ≥500 mg/m2. One patient with refractory small cell lung cancer (1,000 mg/m2 with G-CSF) had an objective response lasting 23 weeks. One patient with refractory ovarian cancer had 27% tumor regression and 30% CA125 decline. Conclusions: Danusertib was well tolerated with target inhibition in skin at ≥500 mg/m2. Preliminary evidence of antitumor activity, including a partial response and several occurrences of prolonged stable disease, was seen across a variety of advanced refractory cancers. Phase II studies are ongoing. (Clin Cancer Res 2009;15(21):6694–701)
Journal of Medicinal Chemistry | 2010
Italo Beria; Dario Ballinari; Jay Aaron Bertrand; Daniela Borghi; Roberto Bossi; Maria Gabriella Brasca; Paolo Cappella; Michele Caruso; Walter Ceccarelli; Antonella Ciavolella; Cinzia Cristiani; Valter Croci; Anna De Ponti; Gabriele Fachin; Ron Ferguson; Jacqueline Lansen; Jurgen Moll; Enrico Pesenti; Helena Posteri; Rita Perego; Maurizio Rocchetti; Paola Storici; Daniele Volpi; Barbara Valsasina
Polo-like kinase 1 (Plk1) is a fundamental regulator of mitotic progression whose overexpression is often associated with oncogenesis and therefore is recognized as an attractive therapeutic target in the treatment of proliferative diseases. Here we discuss the structure-activity relationship of the 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline class of compounds that emerged from a high throughput screening (HTS) campaign as potent inhibitors of Plk1 kinase. Furthermore, we describe the discovery of 49, 8-{[2-methoxy-5-(4-methylpiperazin-1-yl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, as a highly potent and specific ATP mimetic inhibitor of Plk1 (IC(50) = 0.007 microM) as well as its crystal structure in complex with the methylated Plk1(36-345) construct. Compound 49 was active in cell proliferation against different tumor cell lines with IC(50) values in the submicromolar range and active in vivo in the HCT116 xenograft model where it showed 82% tumor growth inhibition after repeated oral administration.
Molecular Cancer Therapeutics | 2012
Barbara Valsasina; Italo Beria; Cristina Alli; Rachele Alzani; Nilla Avanzi; Dario Ballinari; Paolo Cappella; Michele Caruso; Alessia Casolaro; Antonella Ciavolella; Ulisse Cucchi; Anna De Ponti; Eduard R. Felder; Francesco Fiorentini; Arturo Galvani; Laura Gianellini; Maria Laura Giorgini; Antonella Isacchi; Jacqueline Lansen; Enrico Pesenti; Simona Rizzi; Maurizio Rocchetti; Francesco Sola; Jurgen Moll
Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase considered to be the master player of cell-cycle regulation during mitosis. It is indeed involved in centrosome maturation, bipolar spindle formation, chromosome separation, and cytokinesis. PLK1 is overexpressed in a variety of human tumors and its overexpression often correlates with poor prognosis. Although five different PLKs are described in humans, depletion or inhibition of kinase activity of PLK1 is sufficient to induce cell-cycle arrest and apoptosis in cancer cell lines and in xenograft tumor models. NMS-P937 is a novel, orally available PLK1-specific inhibitor. The compound shows high potency in proliferation assays having low nanomolar activity on a large number of cell lines, both from solid and hematologic tumors. NMS-P937 potently causes a mitotic cell-cycle arrest followed by apoptosis in cancer cell lines and inhibits xenograft tumor growth with clear PLK1-related mechanism of action at well-tolerated doses in mice after oral administration. In addition, NMS-P937 shows potential for combination in clinical settings with approved cytotoxic drugs, causing tumor regression in HT29 human colon adenocarcinoma xenografts upon combination with irinotecan and prolonged survival of animals in a disseminated model of acute myelogenous leukemia in combination with cytarabine. NMS-P937, with its favorable pharmacologic parameters, good oral bioavailability in rodent and nonrodent species, and proven antitumor activity in different preclinical models using a variety of dosing regimens, potentially provides a high degree of flexibility in dosing schedules and warrants investigation in clinical settings. Mol Cancer Ther; 11(4); 1006–16. ©2012 AACR.
Drug Discovery Today: Technologies | 2013
Monica Simeoni; Giuseppe De Nicolao; Paolo Magni; Maurizio Rocchetti; Italo Poggesi
Xenograft models are commonly used in oncology drug development. Although there are discussions about their ability to generate meaningful data for the translation from animal to humans, it appears that better data quality and better design of the preclinical experiments, together with appropriate data analysis approaches could make these data more informative for clinical development. An approach based on mathematical modeling is necessary to derive experiment-independent parameters which can be linked with clinically relevant endpoints. Moreover, the inclusion of biomarkers as predictors of efficacy is a key step towards a more general mechanism-based strategy.
Cancer Chemotherapy and Pharmacology | 2013
Maurizio Rocchetti; Massimiliano Germani; Francesca Del Bene; Italo Poggesi; Paolo Magni; Enrico Pesenti; Giuseppe De Nicolao
PurposePharmacokinetic–pharmacodynamic (PK–PD) models able to predict the action of anticancer compounds in tumor xenografts have an important impact on drug development. In case of anti-angiogenic compounds, many of the available models show difficulties in their applications, as they are based on a cell kill hypothesis, while these drugs act on the tumor vascularization, without a direct tumor cell kill effect. For this reason, a PK–PD model able to describe the tumor growth modulation following treatment with a cytostatic therapy, as opposed to a cytotoxic treatment, is proposed here.MethodsUntreated tumor growth was described using an exponential growth phase followed by a linear one. The effect of anti-angiogenic compounds was implemented using an inhibitory effect on the growth function. The model was tested on a number of experiments in tumor-bearing mice given the anti-angiogenic drug bevacizumab either alone or in combination with another investigational compound. Nonlinear regression techniques were used for estimating the model parameters.ResultsThe model successfully captured the tumor growth data following different bevacizumab dosing regimens, allowing to estimate experiment-independent parameters. A combination model was also developed under a ‘no-interaction’ assumption to assess the effect of the combination of bevacizumab with a target-oriented agent. The observation of a significant difference between model-predicted and observed tumor growth curves was suggestive of the presence of a pharmacological interaction that was further accommodated into the model.ConclusionsThis approach can be used for optimizing the design of preclinical experiments. With all the inherent limitations, the estimated experiment-independent model parameters can be used to provide useful indications for the single-agent and combination regimens to be explored in the subsequent development phases.
Neuromuscular Disorders | 2016
Paolo Bettica; Stefania Petrini; Valentina D'Oria; Adele D'Amico; Michela Catteruccia; Marika Pane; Serena Sivo; Francesca Magri; Simona Brajkovic; Sonia Messina; Gian Luca Vita; Barbara Gatti; Maurizio Moggio; Pier Lorenzo Puri; Maurizio Rocchetti; Giuseppe De Nicolao; Giuseppe Vita; Giacomo P. Comi; Enrico Bertini; Eugenio Mercuri
Duchenne Muscular Dystrophy (DMD) is caused by mutations in the dystrophin gene leading to dystrophin deficiency, muscle fiber degeneration and progressive fibrotic replacement of muscles. Givinostat, a histone deacetylase (HDAC) inhibitor, significantly reduced fibrosis and promoted compensatory muscle regeneration in mdx mice. This study was conducted to evaluate whether the beneficial histological effects of Givinostat could be extended to DMD boys. Twenty ambulant DMD boys aged 7 to <11 years on stable corticosteroid treatment were enrolled in the study and treated for ≥12 months with Givinostat. A muscle biopsy was collected at the beginning and at the end of treatment to evaluate the amount of muscle and fibrotic tissue. Histological effects were the primary objectives of the study. Treatment with Givinostat significantly increased the fraction of muscle tissue in the biopsies and reduced the amount of fibrotic tissue. It also substantially reduced tissue necrosis and fatty replacement. Overall the drug was safe and tolerated. Improvement in functional tests was not observed in this study, but the sample size of the study was not sufficient to draw definitive conclusions. This study showed that treatment with Givinostat for more than 1 year significantly counteracted histological disease progression in ambulant DMD boys aged 7 to 10 years.
Cancer Chemotherapy and Pharmacology | 2009
Francesca Del Bene; Massimiliano Germani; Giuseppe De Nicolao; Paolo Magni; Claudia Ernestina Re; Dario Ballinari; Maurizio Rocchetti
PurposeThe use of in vitro screening tests for characterizing the activity of anticancer agents is a standard practice in oncology research and development. In these studies, human A2780 ovarian carcinoma cells cultured in plates are exposed to different concentrations of the compounds for different periods of time. Their anticancer activity is then quantified in terms of EC50 comparing the number of metabolically active cells present in the treated and the control arms at specified time points. The major concern of this methodology is the observed dependency of the EC50 on the experimental design in terms of duration of exposure. This dependency could affect the efficacy ranking of the compounds, causing possible biases especially in the screening phase, when compound selection is the primary purpose of the in vitro analysis. To overcome this problem, the applicability of a modeling approach to these in vitro studies was evaluated.MethodsThe model, consisting of a system of ordinary differential equations, represents the growth of tumor cells using a few identifiable and biologically relevant parameters related to cell proliferation dynamics and drug action. In particular, the potency of the compounds can be measured by a unique and drug-specific parameter that is essentially independent of drug concentration and exposure time. Parameter values were estimated using weighted nonlinear least squares.ResultsThe model was able to adequately describe the growth of tumor cells at different experimental conditions. The approach was validated both on commercial drugs and discovery candidate compounds. In addition, from this model the relationship between EC50 and the exposure time was derived in an analytic form.ConclusionsThe proposed approach provides a new tool for predicting and/or simulating cell responses to different treatments with useful indications for optimizing in vitro experimental designs. The estimated potency parameter values obtained from different compounds can be used for an immediate ranking of anticancer activity.
Life Sciences | 1988
Davide Verotta; Paola Petrillo; A. La Regina; Maurizio Rocchetti; Alessandra Tavani
The D-optimal design, a minimal sample design that minimizes the volume of the joint confidence region for the parameters, was used to evaluate binding parameters in a saturation curve with a view to reducing the number of experimental points without loosing accuracy in binding parameter estimates. Binding saturation experiments were performed in rat brain crude membrane preparations with the opioid mu-selective ligand [3H]-[D-Ala2,MePhe4,Gly-ol5]enkephalin (DAGO), using a sequential procedure. The first experiment consisted of a wide-range saturation curve, which confirmed that [3H]-DAGO binds only one class of specific sites and non-specific sites, and gave information on the experimental range and a first estimate of binding affinity (Ka), capacity (Bmax) and non-specific constant (k). On this basis the D-optimal design was computed and sequential experiments were performed each covering a wide-range traditional saturation curve, the D-optimal design and a splitting of the D-optimal design with the addition of 2 points (+/- 15% of the central point). No appreciable differences were obtained with these designs in parameter estimates and their accuracy. Thus sequential experiments based on D-optimal design seem a valid method for accurate determination of binding parameters, using far fewer points with no loss in parameter estimation accuracy.
IFAC Proceedings Volumes | 2000
Paolo Magni; Riccardo Bellazzi; Giuseppe De Nicolao; Maurizio Rocchetti; Italo Poggesi
Abstract AUC is an important index of exposure to a drug. Being able to estimate the population AUC without passing through the individual AUCs is of interest because the number of plasma samples that can be collected in each subject is often limited by technical, ethical and cost reasons. In the literature, ad hoc solutions have been proposed toestimate the population AUC when particular sampling schemes are adopted. However, restrictive assumptions are made in order to derive the precision of the estimated AUC. In this work, a new approach is proposed and tested on real data. AUC estimation is performed through a Markov Chain Monte Carlo algorithm.