Insulin-like growth factor

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.

Protein kinase 6 (PTK6) is a member of the Frk family of non-receptor tyrosine kinase that is overexpressed in several types of cancers with the highest overexpression observed in breast tumors. PTK6 shows sequence homology to the src tyrosine kinase family. Its functional domains, including a SH3, a SH2 and a kinase domain, are arranged similarly with src family kinases although PTK6 lacks a myristoylation domain. We have identified a potent small molecule PTK6 kinase inhibitor from kinase cross screens that inhibits PTK6 autophosphorylation and phosphorylation of its substrate Sam68, a member of the KH domain containing RNA binding proteins. In cell culture, the compound inhibited proliferation, soft agar growth and migration of tumor cells. The compound inhibited soft agar growth of breast tumor cells more potently than dasatinib. A specific PTK6 kinase inhibitor may provide a novel approach to inhibit the growth of selected tumors, sensitize the response of the tumor cells to other chemotherapeutics and prevent/inhibit metastasis of cancer in a wide range of cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1945. doi:10.1158/1538-7445.AM2011-1945

Supplementary Figure 3 from 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

<div>Abstract<p>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 <i>in vitro</i> and <i>in vivo</i>. 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. <i>In vivo</i>, 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 <i>in vivo</i> 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 <i>in vivo</i> activity is derived from its inhibition of tumor cell proliferation and angiogenesis activity. Mol Cancer Ther; 9(2); 410–8</p></div>