NVP-BEZ235 as a new therapeutic option for sarcomas

Maria C. Manara, Giordano Nicoletti, Diana Zambelli, Selena Ventura, Clara Guerzoni, Lorena Landuzzi, Pier Luigi Lollini, Saveur Michel Maira, Carlos García-Echeverría, Mario Mercuri, Piero Picci, Katia Scotlandi

Research output: Contribution to journalArticle

Abstract

Purpose: To evaluate the in vitro and in vivo effects of NVP-BEZ235, a dual pan-phosphoinositide 3-kinase-mammalian target of rapamycin inhibitor in the three most common musculoskeletal tumors (osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma). Experimental Design: Antiproliferative activity as well as the effects on migration and metastasis were evaluated in a panel of osteosarcoma, Ewing's sarcoma, as well as rhabdomyosarcoma cell lines. Moreover, simultaneous and sequential treatments were done in association with two of the most important conventional drugs in the treatment of sarcoma, doxorubicin and vincristine. Results: NVPBEZ235 effectively blocked the pathway in in vitro and in vivo settings. Under the experimental conditions tested, the compound induced disease stasis, by arresting cells in G1 phase of cell cycle, without remarkable effects on apoptosis. As a consequence, to obtain the maximum exploitation of its therapeutic potential, NVP-BEZ235 has been evaluated in combination with conventional cytotoxic agents, thus showing promising efficacy with either doxorubicin and vincristine. Inhibition of the phosphoinositide 3-kinase/mammalian target of rapamycin pathway increased activation of extracellular signal-regulated kinase 1/2, likely due to the presence of autocrine circuits shifting growth factor signaling toward the mitogen-activated protein kinase pathway. This supports the combined use of NVP-BEZ235 with other small signaling inhibitors. Here, we showed synergistic effects when the compound was associated with a anti-insulin-like growth factor-I receptor tyrosine kinase inhibitor. NVP-BEZ235 also inhibited cell migration and metastasis. Combination with vincristine further potentiated the antimetastatic effects. Conclusions: NVP-BEZ235 displays the features to be considered for sarcoma therapy to potentiate the activity of other anticancer agents. The drug is currently undergoing phase I/II clinical trials in advanced cancer patients.

Original languageEnglish
Pages (from-to)530-540
Number of pages11
JournalClinical Cancer Research
Volume16
Issue number2
DOIs
Publication statusPublished - Jan 15 2010

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Sarcoma
Vincristine
Ewing's Sarcoma
1-Phosphatidylinositol 4-Kinase
Rhabdomyosarcoma
Osteosarcoma
Sirolimus
Doxorubicin
Therapeutics
Neoplasm Metastasis
IGF Type 1 Receptor
Phase II Clinical Trials
Clinical Trials, Phase I
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Cytotoxins
G1 Phase
Mitogen-Activated Protein Kinases
Pharmaceutical Preparations
Antineoplastic Agents

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

NVP-BEZ235 as a new therapeutic option for sarcomas. / Manara, Maria C.; Nicoletti, Giordano; Zambelli, Diana; Ventura, Selena; Guerzoni, Clara; Landuzzi, Lorena; Lollini, Pier Luigi; Maira, Saveur Michel; García-Echeverría, Carlos; Mercuri, Mario; Picci, Piero; Scotlandi, Katia.

In: Clinical Cancer Research, Vol. 16, No. 2, 15.01.2010, p. 530-540.

Research output: Contribution to journalArticle

Manara, MC, Nicoletti, G, Zambelli, D, Ventura, S, Guerzoni, C, Landuzzi, L, Lollini, PL, Maira, SM, García-Echeverría, C, Mercuri, M, Picci, P & Scotlandi, K 2010, 'NVP-BEZ235 as a new therapeutic option for sarcomas', Clinical Cancer Research, vol. 16, no. 2, pp. 530-540. https://doi.org/10.1158/1078-0432.CCR-09-0816
Manara, Maria C. ; Nicoletti, Giordano ; Zambelli, Diana ; Ventura, Selena ; Guerzoni, Clara ; Landuzzi, Lorena ; Lollini, Pier Luigi ; Maira, Saveur Michel ; García-Echeverría, Carlos ; Mercuri, Mario ; Picci, Piero ; Scotlandi, Katia. / NVP-BEZ235 as a new therapeutic option for sarcomas. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 2. pp. 530-540.
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AU - Guerzoni, Clara

AU - Landuzzi, Lorena

AU - Lollini, Pier Luigi

AU - Maira, Saveur Michel

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