Antitumor Activity of the Insulin-Like Growth Factor-I Receptor Kinase Inhibitor NVP-AEW541 in Musculoskeletal Tumors

Scotlandi, Katia; Manara, Maria Cristina; Nicoletti, Giordano; Lollini, Pier‐Luigi; Lukas, Stella; Benini, Stefania; Croci, Stefania; Perdichizzi, Stefania; Zambelli, Diana; Serra, Massimo; García‐Echeverría, Carlos; Hofmann, Francesco; Picci, Piero

doi:10.1158/0008-5472.can-04-3192

Cited by 269 publications

(211 citation statements)

References 35 publications

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“…Furthermore, IGF-1R activation induces motility [64] and protects tumor cells from apoptosis-inducing agents such as cytotoxic drugs, osmotic stress, and hypoxia [13,54,56]. Therefore, IGF-1R inhibition may provide tumor chemosensitization and enhance the effect of traditional chemotherapeutic agents when used in combination [56,59]. Our results support the development and investigation of novel IGF-1R inhibitors.…”

Section: Discussionsupporting

confidence: 59%

Specific Tyrosine Kinase Inhibitors Regulate Human Osteosarcoma Cells In vitro

Messerschmitt

Rettew

Brookover

et al. 2008

Clin Orthop Relat Res

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Inhibitors of specific tyrosine kinases are attractive lead compounds for development of targeted chemotherapies for many tumors, including osteosarcoma. We asked whether inhibition of specific tyrosine kinases would decrease the motility, colony formation, and/or invasiveness by human osteosarcoma cell lines (TE85, MNNG, 143B, SAOS-2, LM-7). An EGF-R inhibitor reduced motility of all five cell lines by 50% to 80%. In contrast, an IGF-1R inhibitor preferentially reduced motility by 42% in LM-7 cells and a met inhibitor preferentially reduced motility by 80% in MNNG cells. The inhibitors of EGF-R, IGF-1R, and met reduced colony formation by more than 80% in all tested cell lines (TE85, MNNG, 143B). The EGF-R inhibitor reduced invasiveness by 62% in 143B cells. The JAK inhibitor increased motility of SAOS-2 and LM7 cells without affecting colony formation or invasiveness. Inhibitors of HER-2, NGF-R, and PDGF-Rs did not affect motility, invasiveness, or colony formation. These results support the hypothesis that specific tyrosine kinases regulate tumorigenesis and/or metastasis in osteosarcoma.

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Section: Discussionsupporting

confidence: 59%

Specific Tyrosine Kinase Inhibitors Regulate Human Osteosarcoma Cells In vitro

Messerschmitt

Rettew

Brookover

et al. 2008

Clin Orthop Relat Res

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“…In the case of IGF-mediated signal transduction, highly specific RTK inhibitors are necessary to discriminate between IGF-1R and INSR (Pautsch et al, 2001) to prevent diabetogenic effects. Several highly selective inhibitors such as tyrphostins (Ohmichi et al, 1993;Parrizas et al, 1997;Blum et al, 2000Blum et al, , 2003, NVP-AEW541 (GarciaEcheverria et al, 2004;Scotlandi et al, 2005), NVP-ADW742 (Mitsiades et al, 2004;Warshamana-Greene et al, 2004 and cyclolignans Vasilcanu et al, 2004;Menu et al, 2005) reduce the activation of IGF-1R and downstream effectors such as AKT/PKB. In vitro as well as in vivo, these substances efficiently reduce tumor cell growth, often in combination with chemotherapeutic agents (Mitsiades et al, 2004;Scotlandi et al, 2005).…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Dysregulation of growth factor signaling in human hepatocellular carcinoma

2006

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“…Many pediatric tumors including neuroblastoma, Wilms' tumor, osteosarcoma, and rhabdomyosarcoma are embryonal tumors of the childhood and exhibit increased expression of IGF-II and IGF-IR establishing autocrine loops to perpetuate growth and survival (10)(11)(12)(13)(14)(15). The role of IGF-I in the development of Ewing's sarcoma has also been well documented in addition to the induction of IGF-IR expression by the Ewing's sarcoma fusion protein (16)(17)(18)(19). Increased expression of IGF-IR in rhabdomyosarcomas has also been linked to chimeric transcription factor PAX3-FKHR (20).…”

Section: Introductionmentioning

confidence: 99%

A Fully Human Insulin-Like Growth Factor-I Receptor Antibody SCH 717454 (Robatumumab) Has Antitumor Activity as a Single Agent and in Combination with Cytotoxics in Pediatric Tumor Xenografts

Wang¹,

Lipari²,

Wang³

et al. 2010

Molecular Cancer Therapeutics

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The insulin-like growth factor-I receptor (IGF-IR) and its ligands (IGF-I and IGF-II) have been implicated in the growth, survival, and metastasis of a broad range of malignancies including pediatric tumors. Blocking the IGF-IR action is a potential cancer treatment. A fully human neutralizing monoclonal antibody, SCH 717454 (19D12, robatumumab), specific to IGF-IR, has shown potent antitumor effects in ovarian cancer in vitro and in vivo. In this study, SCH 717454 was evaluated in several pediatric solid tumors including neuroblastoma, osteosarcoma, and rhabdomyosarcoma. SCH 717454 is shown here to downregulate IGF-IR as well as inhibit IGF-IR and insulin receptor substrate-1 phosphorylation in pediatric tumor cells. IGF-IR and insulin receptor substrate-1 phosphorylation in the tumor cells. In vivo, SCH 717454 exhibits activity as a single agent and significantly inhibited growth of neuroblastoma, osteosarcoma, and rhabdomyosarcoma tumor xenografts. Combination of SCH 717454 with cisplatin or cyclophosphamide enhanced both the degree and the duration of the in vivo antitumor activity compared with single-agent treatments. Furthermore, SCH 717454 treatment markedly reduced Ki-67 expression and blood vessel formation in tumor xenografts, showing that the in vivo activity is derived from its inhibition of tumor cell proliferation and angiogenesis activity. Mol Cancer Ther; 9(2); 410-8. ©2010 AACR.

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Antitumor Activity of the Insulin-Like Growth Factor-I Receptor Kinase Inhibitor NVP-AEW541 in Musculoskeletal Tumors

Abstract: Identification of new drugs is strongly needed for sarcomas.

Cited by 269 publications

References 35 publications

Specific Tyrosine Kinase Inhibitors Regulate Human Osteosarcoma Cells In vitro

Specific Tyrosine Kinase Inhibitors Regulate Human Osteosarcoma Cells In vitro

Dysregulation of growth factor signaling in human hepatocellular carcinoma

A Fully Human Insulin-Like Growth Factor-I Receptor Antibody SCH 717454 (Robatumumab) Has Antitumor Activity as a Single Agent and in Combination with Cytotoxics in Pediatric Tumor Xenografts

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