R1507, a fully human monoclonal antibody targeting IGF‐1R, is effective alone and in combination with rapamycin in inhibiting growth of osteosarcoma xenografts

Kolb, E. Anders; Kamara, Davida; Zhang, Wendong; Lin, Juan; Hingorani, Pooja; Baker, Laurence H.; Houghton, Peter J.; Görlick, Richard

doi:10.1002/pbc.22479

Cited by 70 publications

(58 citation statements)

References 15 publications

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“…Several anti-IGFIR mAbs with in vitro and in vivo antitumor activities in sarcoma models have been developed (21)(22)(23)(24)(25). These mAbs inhibit IGFI and IGFII signaling through IGFIR and heterodimeric IGFIR/IR-A, but do not inhibit IGFII signaling through IR-A.…”

Section: Introductionmentioning

confidence: 99%

MEDI-573, Alone or in Combination with Mammalian Target of Rapamycin Inhibitors, Targets the Insulin-like Growth Factor Pathway in Sarcomas

Zhong¹,

Fazenbaker²,

Breen³

et al. 2014

Molecular Cancer Therapeutics

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MEDI-573 is a human antibody that neutralizes insulin-like growth factor (IGF) I and IGFII. IGFs are overexpressed in multiple types of cancer; their overexpression is a potential mechanism for resistance to IGFI receptor (IGFIR)-targeting therapy. Effects of IGF on cell proliferation, differentiation, and survival are mediated through its binding to and activation of IGFIR or insulin receptor A (IR-A). In this study, we measured the mRNA levels of IGFI, IGFII, and IGFIR in human pediatric sarcoma xenografts, and protein levels in sarcoma cell lines. MEDI-573 potently inhibited in vitro proliferation of sarcoma cell lines, with Ewing sarcoma cell lines being the most sensitive. In addition, MEDI-573 inhibited IGFI-and IGFII-induced sarcoma cell proliferation in vitro. The effect of MEDI-573 on IGF signaling was also examined. Treatment with MEDI-573 markedly reduced levels of pIGFIR, pIR-A, and pAKT and significantly blocked IGFI-and IGFII-induced activation of the IGFIR and AKT pathways. MEDI-573 inhibited the growth of sarcoma xenografts in vivo and inhibition correlated with neutralization of IGFI and IGFII. Combination of MEDI-573 with either rapamycin or AZD2014, another mTOR inhibitor (mTORi), significantly enhanced the antitumor activity of MEDI-573, and this response correlated with modulation of AKT and mTOR signaling. In summary, sarcoma cells respond to autocrine or paracrine growth stimulation by IGFI and IGFII, and inhibition of IGFI and IGFII by MEDI-573 results in significant slowing of tumor growth rate in sarcoma models, particularly in Ewing sarcoma. These data provide evidence for the potential benefits of MEDI-573 and mTORi combinations in patients with Ewing sarcoma. Mol Cancer Ther; 13(11); 2662-73. Ó2014 AACR.

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Section: Introductionmentioning

confidence: 99%

MEDI-573, Alone or in Combination with Mammalian Target of Rapamycin Inhibitors, Targets the Insulin-like Growth Factor Pathway in Sarcomas

Zhong¹,

Fazenbaker²,

Breen³

et al. 2014

Molecular Cancer Therapeutics

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“…Consistent expression of IGF-1R, IGF-1, and IGF-2 in osteosarcoma cell lines and patient samples has been reported (24,25). Blocking IGF-mediated growth in osteosarcoma can inhibit tumor growth and metastasis in murine osteosarcoma (5,26,27). In vivo study also demonstrated that tumor growth in xenografts can be inhibited with anti-IGF-1R antibody (5).…”

Section: Discussionmentioning

confidence: 91%

“…Blocking IGF-mediated growth in osteosarcoma can inhibit tumor growth and metastasis in murine osteosarcoma (5,26,27). In vivo study also demonstrated that tumor growth in xenografts can be inhibited with anti-IGF-1R antibody (5). In this study, we first used molecular modeling (Fig.5), and Western blot analysis (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous studies have reported that the levels of IGF-1R, IGF-1 and IGF-2 were higher in human osteosarcoma cells than that in normal cells (5,6). Many studies in therapeutic agents for osteosarcoma have focused on novel target therapies through induction of IGF-1R signaling, reduction of cell growth and anti-metastatic effects in osteogenic sarcoma (5,7).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, novel agents are used for optimizing chemotherapy and it is reported that quinazoline derivatives have multiple biological activities, as receptor tyrosine kinase inhibitors (9). We designed the novel fluorinated compounds with a quinazoline core structure as anti-tumor candidates in order to increase their metabolic stability and be SHENG-CHU KUO 4 , CHI-CHENG LU 5 , YU-JEN CHIU 1 , YI-HSUAN CHUANG 1 and JAI-SING YANG recognized by macromolecular recognition sites after entering human circulation (10). In this study, we synthesized a series of 6-fluoro-2-(3-fluorophenyl)-4-substituted anilinoquinazoline derivatives and assayed for cytotoxicity in vitro against seven types of cancer cell lines (10).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The novel synthesized 6-fluoro-(3-fluorophenyl)-4-(3-methoxyanilino)quinazoline (LJJ-10) compound exhibits anti-metastatic effects in human osteosarcoma U-2 OS cells through targeting insulin-like growth factor-I receptor

et al. 2011

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Abstract. Our previous study demonstrated that 6-fluoro-(3-fluorophenyl)-4-(3-methoxyanilino)quinazoline (LJJ-10) possesses potential anticancer activity and exhibits greater antitumor effect than the other quinazoline compounds in human osteogenic sarcoma U-2 OS cells via in vitro screening. In this study, we focused on investigating the anti-metastatic activity and the signaling pathways involved in LJJ-10 action in U-2 OS cells. The results from wound healing and Boyden chamber transwell assays indicated that LJJ-10 exhibited an inhibitory effect on the migration and invasion of U-2 OS cells. LJJ-10 also inhibited matrix metalloproteinase-2 (MMP-2) and MMP-9 enzyme activities and caused a concentration-dependent decrease in protein levels by gelatin zymography assay and Western blot analysis, respectively. Meanwhile, LJJ-10 suppressed MMP-2 and MMP-9 mRNA levels in a concentration-dependent fashion after 12-h exposure in U-2 OS cells. Computational modeling showed that LJJ-10 is bound into the IGF-1R via hydrophobic interactions with Leu 975

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High‐throughput genotyping in osteosarcoma identifies multiple mutations in phosphoinositide‐3‐kinase and other oncogenes

Choy

Hornicek

MacConaill

et al. 2011

Cancer

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Background Identification of new genes that are mutated in osteosarcomas is critical to developing a better understanding of the molecular pathogenesis of this disease and discovering new targets for therapeutic development. Methods We identified somatic non-synonymous coding mutations in oncogenes associated with human cancers and hotspot mutations from tumor suppressor genes that were either well-described in literature or seen multiple times in human cancer sequencing efforts. We then systematically characterized 961 mutations in 89 genes across 98 osteosarcoma tumor samples and cell lines. All identified mutations were replicated on an independent platform using homogeneous mass extend MALDI-TOF (Sequenom hME Genotyping). Results We identified 14 mutations in at least one osteosarcoma tumor sample or cell line. Some of the genetic changes identified were in tumor suppressor genes previously known to be altered in osteosarcoma: p53 (R273H, R273C, and Y163C) and RB1 (E137*). Notably, we identified multiple mutations in PIK3CA (H1047R, E545K, and H701P) which have never previously been observed in osteosarcoma. Additionally, we observed mutations in KRAS (G12S), CUBN (I3189V, seen in two separate tumor samples), CDH1 (A617T, seen in two separate tumor samples), CTNNB1 (N287S), and FSCB (S775L). Conclusion We performed the largest mutational profiling of osteosarcoma to date and identified for the first time several mutations involving the PI3 kinase pathway – adding osteosarcoma on to the growing list of malignancies with PI3 kinase mutations. Additionally, we initiated a mutational map detailing DNA sequence changes across a variety of osteosarcoma subtypes and offered new candidates for therapeutic targeting.

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R1507, a fully human monoclonal antibody targeting IGF‐1R, is effective alone and in combination with rapamycin in inhibiting growth of osteosarcoma xenografts

Cited by 70 publications

References 15 publications

MEDI-573, Alone or in Combination with Mammalian Target of Rapamycin Inhibitors, Targets the Insulin-like Growth Factor Pathway in Sarcomas

MEDI-573, Alone or in Combination with Mammalian Target of Rapamycin Inhibitors, Targets the Insulin-like Growth Factor Pathway in Sarcomas

The novel synthesized 6-fluoro-(3-fluorophenyl)-4-(3-methoxyanilino)quinazoline (LJJ-10) compound exhibits anti-metastatic effects in human osteosarcoma U-2 OS cells through targeting insulin-like growth factor-I receptor

High‐throughput genotyping in osteosarcoma identifies multiple mutations in phosphoinositide‐3‐kinase and other oncogenes

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