NVP-BEZ235 as a New Therapeutic Option for Sarcomas

Manara, Maria Cristina; 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

doi:10.1158/1078-0432.ccr-09-0816

Cited by 143 publications

(153 citation statements)

References 31 publications

Supporting

Mentioning

141

Contrasting

Order By: Relevance

“…NVP-BEZ235 is a pan-PI3K inhibitor that acts against all of the isoforms of PI3K and PI3K mutants. Previous studies have demonstrated the efficacy of NVP-BEZ235 as an antitumor agent in vitro and in vivo in glioblastoma, multiple myeloma, melanoma, lymphoma, www.nature.com/aps Pal I et al Acta Pharmacologica Sinica npg sarcoma, breast, lung, and ovarian cancer models [84][85][86][87][88][89][90][91][92][93] . In the case of colon cancer, NVP-BEZ23 decreases cellular proliferation and causes sustained inhibition of mTORC1 and mTORC2 with a transient PI3K blockade with no subsequent effect on apoptosis either in vitro or in vivo in a GEM model.…”

Section: Current Progress In Clinical Trialsmentioning

confidence: 99%

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

2012

View full text Add to dashboard Cite

The PI3K-Akt pathway is a vital regulator of cell proliferation and survival. Alterations in the PIK3CA gene that lead to enhanced PI3K kinase activity have been reported in many human cancer types, including cancers of the colon, breast, brain, liver, stomach and lung. Deregulation of PI3K causes aberrant Akt activity. Therefore targeting this pathway could have implications for cancer treatment. The first generation PI3K-Akt inhibitors were proven to be highly effective with a low IC 50 , but later, they were shown to have toxic side effects and poor pharmacological properties and selectivity. Thus, these inhibitors were only effective in preclinical models. However, derivatives of these first generation inhibitors are much more selective and are quite effective in targeting the PI3K-Akt pathway, either alone or in combination. These second-generation inhibitors are essentially a specific chemical moiety that helps to form a strong hydrogen bond interaction with the PI3K/Akt molecule. The goal of this review is to delineate the current efforts that have been undertaken to inhibit the various components of the PI3K and Akt pathway in different types of cancer both in vitro and in vivo. Our focus here is on these novel therapies and their inhibitory effects that depend upon their chemical nature, as well as their development towards clinical trials.

show abstract

Section: Current Progress In Clinical Trialsmentioning

confidence: 99%

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

2012

View full text Add to dashboard Cite

show abstract

“…The cell lines have been obtained as previously specified (Manara et al, 2010). Most of them have been authenticated recently (Ottaviano et al, 2010).…”

Section: Drugsmentioning

confidence: 99%

“…The ethical committee of the Rizzoli Institute approved the studies and informed consent was obtained from all subjects involved. To assess IGF-1R and IR expression, avidin-biotin-peroxidase procedure was used for immunostaining, as previously described (Manara et al, 2010). Sections were pretreated with a citrate buffer solution (0.01 mol/l citric acid and 0.01 mol/l sodium citrate (pH 6.0)) in a microwave oven at 750 W for three cycles of 5 min each to ensure antigen retrieval.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Efficacy of and resistance to anti-IGF-1R therapies in Ewing's sarcoma is dependent on insulin receptor signaling

et al. 2011

View full text Add to dashboard Cite

“…Previous data suggest that tyrosine kinase receptor signaling may play a role in the biology of more common pediatric solid tumors, such as medulloblastomas, ependymomas, and choroid plexus tumors, and in Ewing sarcomas and neuroblastomas. [9][10][11][12][13][14][15][16] Imatinib, a tyrosine kinase inhibitor directed against c-Abl, c-Kit and platelet-derived growth factor (PDGF) receptor subtypes a and b, 17 reportedly is tolerated relatively well in children. 18,19 Because it has been demonstrated that imatinib inhibits proliferation of the rhabdoid tumor cell line BT12, 20 our objective was to investigate the expression and functional role of tyrosine kinases targeted by imatinib in rhabdoid tumors.…”

mentioning

confidence: 99%

The tyrosine kinase c‐Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors

Koos

Jeibmann

Lünenbürger

et al. 2010

Cancer

View full text Add to dashboard Cite

BACKGROUND: Atypical teratoid/rhaboid tumors (AT/RTs) and extracranial malignant rhabdoid tumors are highly malignant neoplasms with a dismal prognosis. These tumors predominantly affect infants and targeted, adjuvant treatment approaches would be highly desirable. METHODS: In the current study, the authors investigated the expression and functional role of tyrosine kinases in 2 malignant rhabdoid tumor cell lines (A204 and G401) and in a series of 5 AT/RTs and 18 malignant rhabdoid tumors (13 rhabdoid tumors of the kidney and 5 extrarenal rhabdoid tumors). RESULTS: Both cell lines consistently expressed the tyrosine kinase c-Abl, which promoted proliferation as assessed by small interfering RNA knockdown. Blockage of c-Abl using the tyrosine kinase inhibitor imatinib resulted in reduced cellular growth in both cell lines. Furthermore, c-Abl was expressed in all rhabdoid tumors, whereas expression of platelet-derived growth factor receptor subtypes alpha and beta was infrequent and c-Kit expression was absent. CONCLUSIONS: The current data pointed toward a role for c-Abl in the biology of malignant rhabdoid tumors and provided a rationale for the investigation of tyrosine kinase inhibitors that target c-Abl for the treatment of these aggressive tumors. Cancer 2010;116:5075-81.

show abstract

NVP-BEZ235 as a New Therapeutic Option for Sarcomas

Abstract: 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.

Cited by 143 publications

References 31 publications

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

Efficacy of and resistance to anti-IGF-1R therapies in Ewing's sarcoma is dependent on insulin receptor signaling

The tyrosine kinase c‐Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors

Contact Info

Product

Resources

About