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1.
Mol Cancer Res ; 13(12): 1615-26, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26263910

ABSTRACT

UNLABELLED: Despite a recent shift away from anti-insulin-like growth factor I receptor (IGF-IR) therapy, this target has been identified as a key player in the resistance mechanisms to various conventional and targeted agents, emphasizing its value as a therapy, provided that it is used in the right patient population. Molecular markers predictive of antitumor activity of IGF-IR inhibitors remain largely unidentified. The aim of this study is to evaluate the impact of insulin receptor (IR) isoforms on the antitumor efficacy of cixutumumab, a humanized mAb against IGF-IR, and to correlate their expression with therapeutic outcome. The data demonstrate that expression of total IR rather than individual IR isoforms inversely correlates with single-agent cixutumumab efficacy in pediatric solid tumor models in vivo. Total IR, IR-A, and IR-B expression adversely affects the outcome of cixutumumab in combination with chemotherapy in patient-derived xenograft models of lung adenocarcinoma. IR-A overexpression in tumor cells confers complete resistance to cixutumumab in vitro and in vivo, whereas IR-B results in a partial resistance. Resistance in IR-B-overexpressing cells is fully reversed by anti-IGF-II antibodies, suggesting that IGF-II is a driver of cixutumumab resistance in this setting. The present study links IR isoforms, IGF-II, and cixutumumab efficacy mechanistically and identifies total IR as a biomarker predictive of intrinsic resistance to anti-IGF-IR antibody. IMPLICATIONS: This study identifies total IR as a biomarker predictive of primary resistance to IGF-IR antibodies and provides a rationale for new clinical trials enriched for patients whose tumors display low IR expression.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antigens, CD/metabolism , Drug Resistance, Neoplasm , Lung Neoplasms/genetics , Receptor, Insulin/metabolism , Antibodies, Monoclonal, Humanized , Antigens, CD/genetics , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , MCF-7 Cells , Protein Isoforms/genetics , Protein Isoforms/metabolism , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, Insulin/genetics , Up-Regulation , Xenograft Model Antitumor Assays
2.
Cancer Biol Ther ; 15(9): 1208-18, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24921944

ABSTRACT

Stem cell factor receptor (c-Kit) exerts multiple biological effects on target cells upon binding its ligand stem cell factor (SCF). Aberrant activation of c-Kit results in dysregulated signaling and is implicated in the pathogenesis of numerous cancers. The development of more specific and effective c-Kit therapies is warranted given its essential role in tumorigenesis. In this study, we describe the biological properties of CK6, a fully human IgG1 monoclonal antibody against the extracellular region of human c-Kit. CK6 specifically binds c-Kit receptor with high affinity (EC 50 = 0.06 nM) and strongly blocks its interaction with SCF (IC 50 = 0.41 nM) in solid phase assays. Flow cytometry shows CK6 binding to c-Kit on the cell surface of human small cell lung carcinoma (SCLC), melanoma, and leukemia tumor cell lines. Furthermore, exposure to CK6 inhibits SCF stimulation of c-Kit tyrosine kinase activity and downstream signaling pathways such as mitogen-activated protein kinase (MAPK) and protein kinase B (AKT), in addition to reducing tumor cell line growth in vitro. CK6 treatment significantly decreases human xenograft tumor growth in NCI-H526 SCLC (T/C% = 57) and Malme-3M melanoma (T/C% = 58) models in vivo. The combination of CK6 with standard of care chemotherapy agents, cisplatin and etoposide for SCLC or dacarbazine for melanoma, more potently reduces tumor growth (SCLC T/C% = 24, melanoma T/C% = 38) compared with CK6 or chemotherapy alone. In summary, our results demonstrate that CK6 is a c-Kit antagonist antibody with tumor growth neutralizing properties and are highly suggestive of potential therapeutic application in treating human malignancies harboring c-Kit receptor.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Immunoglobulin G/therapeutic use , Lung Neoplasms/drug therapy , Melanoma, Experimental/drug therapy , Proto-Oncogene Proteins c-kit/metabolism , Small Cell Lung Carcinoma/drug therapy , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Cisplatin/administration & dosage , Dacarbazine/administration & dosage , Etoposide/administration & dosage , Female , Heterografts , Humans , Immunoglobulin G/administration & dosage , Immunoglobulin G/pharmacology , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Melanoma, Experimental/metabolism , Melanoma, Experimental/pathology , Mice, Nude , Mitogen-Activated Protein Kinase Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-kit/genetics , Proto-Oncogene Proteins c-kit/immunology , Signal Transduction , Small Cell Lung Carcinoma/metabolism , Small Cell Lung Carcinoma/pathology
3.
Anticancer Res ; 31(6): 2149-60, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21737635

ABSTRACT

BACKGROUND: Clinically relevant targets for developmental drug efficacy in animal models of cancer are critical yet understudied parameters. MATERIALS AND METHODS: Cetuximab, a chimeric antibody to epidermal growth factor receptor (EGFR), was administered to athymic mice bearing subcutaneous tumors established with 13 human colorectal cancer cell lines of varying biomarker status, defined by DNA sequencing and RT-PCR. RESULTS: If tumor growth inhibition is taken as a target, as is commonly done, then in contrast to the clinical situation where KRAS mutation strongly predicts for a lack of clinically meaningful benefit in colorectal cancer patients, cetuximab alone and in combination with irinotecan-based chemotherapy were efficacious in a similar proportion of KRAS wild-type and mutant models. It was only when tumor regression was utilized to define relevant efficacy that cetuximab monotherapy was efficacious in KRAS wild-type, but not mutant models. Adding cytotoxic therapy to cetuximab treatment increased tumor regression frequency in both genotypes to the point that once again the response was similar for KRAS wild-type and mutant models. CONCLUSION: Our data support shifting the threshold for claiming clinically relevant targeted therapy efficacy in subcutaneous xenograft models towards tumor regression, rather than tumor growth inhibition, focusing on the evaluation of tumor cells that are addicted to the pathways being targeted.


Subject(s)
Antibodies, Monoclonal/pharmacology , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Genes, ras , Mutation , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Biomarkers, Tumor/metabolism , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Cetuximab , Colorectal Neoplasms/metabolism , Gene Dosage , Genes, erbB-1 , Humans , Irinotecan , Mice , Mice, Nude , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Proto-Oncogene Proteins B-raf/genetics , Xenograft Model Antitumor Assays
4.
Neoplasia ; 13(1): 49-59, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21245940

ABSTRACT

The benefits of inhibiting vascular endothelial growth factor (VEGF) signaling in cancer patients are predominantly attributed to effects on tumor endothelial cells. Targeting non-endothelial stromal cells to further impact tumor cell growth and survival is being pursued through the inhibition of additional growth factor pathways important for the survival and/or proliferation of these cells. However, recent data suggest that VEGF receptor (VEGFR)-specific inhibitors may target lymphatic vessels and pericytes in addition to blood vessels. Here, in fact, we demonstrate that DC101 (40 mg/kg, thrice a week), an antibody specific to murine VEGFR2, significantly reduces all three of these stromal components in subcutaneous (SKRC-29) and orthotopic (786-O-LP) models of renal cell carcinoma (RCC) established in nu/nu athymic mice. Sunitinib (40 mg/kg, once daily), a receptor tyrosine kinase inhibitor of VEGFR2 and other growth factor receptors, also caused significant loss of tumor blood vessels in RCC models but had weaker effects than DC101 on pericytes and lymphatic vessels. In combination, sunitinib did not significantly add to the effects of DC101 on tumor blood vessels, lymphatic vessels, or pericytes. Nevertheless, sunitinib increased the effect of DC101 on tumor burden in the SKRC-29 model, perhaps related to its broader specificity. Our data have important implications for combination therapy design, supporting the conclusion that targeting VEGFR2 alone in RCC has the potential to have pleiotropic effects on tumor stroma.


Subject(s)
Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , Carcinoma, Renal Cell/drug therapy , Indoles/pharmacology , Kidney Neoplasms/drug therapy , Pyrroles/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/blood supply , Carcinoma, Renal Cell/pathology , Disease Models, Animal , Drug Interactions , Female , Humans , Hypoxia-Inducible Factor 1/biosynthesis , Indoles/therapeutic use , Kidney Neoplasms/blood supply , Kidney Neoplasms/pathology , Lymphatic Vessels/drug effects , Lymphatic Vessels/pathology , Mice , Mice, Nude , Mutation , Neoplasm Transplantation , Neovascularization, Pathologic , Pericytes/drug effects , Pericytes/pathology , Pyrroles/therapeutic use , Stromal Cells/drug effects , Stromal Cells/pathology , Sunitinib , Tumor Burden , Tumor Cells, Cultured , Vascular Endothelial Growth Factor Receptor-2/immunology , Von Hippel-Lindau Tumor Suppressor Protein/genetics
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