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Publication Record


In vivo evaluation of IGF1R/IR PET ligand [F]BMS-754807 in rodents.
Prabhakaran J, Dewey SL, McClure R, Simpson NR, Tantawy MN, Mann JJ, Pham W, Kumar JSD
(2017) Bioorg Med Chem Lett 27: 941-943
MeSH Terms: Animals, Fluorine Radioisotopes, Heterografts, Humans, Mice, Positron-Emission Tomography, Pyrazoles, Radioligand Assay, Rats, Receptor, IGF Type 1, Receptor, Insulin, Triazines
Show Abstract · Added March 21, 2018
In vivo evaluation of [F]BMS-754807 binding in mice and rats using microPET and biodistribution methods is described herein. The radioligand shows consistent binding characteristics, in vivo, in both species. Early time frames of the microPET images and time activity curves of brain indicate poor penetration of the tracer across the blood brain barrier (BBB) in both species. However, microPET experiments in mice and rats show high binding of the radioligand outside the brain to heart, pancreas and muscle, the organs known for higher expression of IGF1R/1R. Biodistribution analysis 2h after injection of [F]BMS-754807 in rats show negligible [F]defluorination as reflected by the low bone uptake and clearance from blood. Overall, the data indicate that [F]BMS-754807 can potentially be a radiotracer for the quantification of IGF1R/IR outside the brain using PET.
Copyright © 2017 Elsevier Ltd. All rights reserved.
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12 MeSH Terms
InsR/IGF1R Pathway Mediates Resistance to EGFR Inhibitors in Glioblastoma.
Ma Y, Tang N, Thompson RC, Mobley BC, Clark SW, Sarkaria JN, Wang J
(2016) Clin Cancer Res 22: 1767-76
MeSH Terms: Animals, Antineoplastic Agents, Cell Line, Tumor, Disease Models, Animal, Drug Resistance, Neoplasm, ErbB Receptors, Gefitinib, Glioblastoma, Humans, Insulin, Insulin-Like Growth Factor I, Mice, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Quinazolines, Receptor, IGF Type 1, Receptor, Insulin, Signal Transduction, Tumor Burden, Xenograft Model Antitumor Assays
Show Abstract · Added April 18, 2017
PURPOSE - Aberrant activation of EGFR is a hallmark of glioblastoma. However, EGFR inhibitors exhibit at best modest efficacy in glioblastoma. This is in sharp contrast with the observations in EGFR-mutant lung cancer. We examined whether activation of functionally redundant receptor tyrosine kinases (RTKs) conferred resistance to EGFR inhibitors in glioblastoma.
EXPERIMENTAL DESIGN - We collected a panel of patient-derived glioblastoma xenograft (PDX) lines that maintained expression of wild-type or mutant EGFR in serial xenotransplantation and tissue cultures. Using this physiologically relevant platform, we tested the abilities of several RTK ligands to protect glioblastoma cells against an EGFR inhibitor, gefitinib. Based on the screening results, we further developed a combination therapy cotargeting EGFR and insulin receptor (InsR)/insulin-like growth factor 1 receptor (IGF1R).
RESULTS - Insulin and IGF1 induced significant protection against gefitinib in the majority of EGFR-dependent PDX lines with one exception that did not express InsR or IGF1R. Blockade of the InsR/IGF1R pathway synergistically improved sensitivity to gefitinib or dacomitinib. Gefitinib alone effectively attenuated EGFR activities and the downstream MEK/ERK pathway. However, repression of AKT and induction of apoptosis required concurrent inhibition of both EGFR and InsR/IGF1R. A combination of gefitinib and OSI-906, a dual InsR/IGF1R inhibitor, was more effective than either agent alone to treat subcutaneous glioblastoma xenograft tumors.
CONCLUSIONS - Our results suggest that activation of the InsR/IGF1R pathway confers resistance to EGFR inhibitors in EGFR-dependent glioblastoma through AKT regulation. Concurrent blockade of these two pathways holds promise to treat EGFR-dependent glioblastoma.
©2015 American Association for Cancer Research.
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20 MeSH Terms
Molecular Pathways: Clinical Applications and Future Direction of Insulin-like Growth Factor-1 Receptor Pathway Blockade.
Iams WT, Lovly CM
(2015) Clin Cancer Res 21: 4270-7
MeSH Terms: Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Clinical Trials as Topic, Drug Resistance, Neoplasm, Female, Humans, Male, Molecular Targeted Therapy, Neoplasms, Protein Kinase Inhibitors, Receptor, IGF Type 1, Signal Transduction, Translational Medical Research, Treatment Outcome
Show Abstract · Added January 26, 2016
The IGF1R signaling pathway is a complex and tightly regulated network that is critical for cell proliferation, growth, and survival. IGF1R is a potential therapeutic target for patients with many different malignancies. This brief review summarizes the results of clinical trials targeting the IGF1R pathway in patients with breast cancer, sarcoma, and non-small cell lung cancer (NSCLC). Therapeutic agents discussed include both monoclonal antibodies to IGF1R (dalotuzumab, figitumumab, cixutumumab, ganitumab, R1507, AVE1642) and newer IGF1R pathway targeting strategies, including monoclonal antibodies to IGF1 and IGF2 (MEDI-573 and BI 836845) and a small-molecule tyrosine kinase inhibitor of IGF1R (linsitinib). The pullback of trials in patients with breast cancer and NSCLC based on several large negative trials is noted and contrasted with the sustained success of IGF1R inhibitor monotherapy in a subset of patients with sarcoma. Several different biomarkers have been examined in these trials with varying levels of success, including tumor expression of IGF1R and its pathway components, serum IGF ligand levels, alternate pathway activation, and specific molecular signatures of IGF1R pathway dependence. However, there remains a critical need to define predictive biomarkers in order to identify patients who may benefit from IGF1R-directed therapies. Ongoing research focuses on uncovering such biomarkers and elucidating mechanisms of resistance, as this therapeutic target is currently being analyzed from the bedside to bench.
©2015 American Association for Cancer Research.
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14 MeSH Terms
Protective role of insulin-like growth factor-1 receptor in endothelial cells against unilateral ureteral obstruction-induced renal fibrosis.
Liang M, Woodard LE, Liang A, Luo J, Wilson MH, Mitch WE, Cheng J
(2015) Am J Pathol 185: 1234-50
MeSH Terms: Animals, Blotting, Western, Cells, Cultured, Disease Models, Animal, Endothelial Cells, Fibrosis, Humans, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Electron, Transmission, Polymerase Chain Reaction, Receptor, IGF Type 1, Renal Insufficiency, Chronic, Transfection, Umbilical Veins, Ureteral Obstruction
Show Abstract · Added April 8, 2015
Insulin-like growth factor-1 receptor (IGF-1R) can regulate vascular homeostasis and endothelial function. We studied the role of IGF-1R in oxidative stress-induced endothelial dysfunction. Unilateral ureteral obstruction (UUO) was performed in wild-type (WT) mice and mice with endothelial cell (EC)-specific IGF-1R knockout (KO). After UUO in endothelial IGF-1R KO mice, endothelial barrier dysfunction was more severe than in WT mice, as seen by increased inflammatory cell infiltration and vascular endothelial (VE)-cadherin phosphorylation. UUO in endothelial IGF-1R KO mice increased interstitial fibroblast accumulation and enhanced extracellular protein deposition as compared with the WT mice. Endothelial barrier function measured by transendothelial migration in response to hydrogen peroxide (H2O2) was impaired in ECs. Silencing IGF-1R enhanced the influence of H2O2 in disrupting the VE-protein tyrosine phosphatase/VE-cadherin interaction. Overexpression of IGF-1R suppressed H2O2-induced endothelial barrier dysfunction. Furthermore, by using the piggyBac transposon system, we expressed IGF-1R in VE cells in mice. The expression of IGF-1R in ECs also suppressed the inflammatory cell infiltration and renal fibrosis induced by UUO. IGF-1R KO in the VE-cadherin lineage of bone marrow cells had no significant effect on the UUO-induced fibrosis, as compared with control mice. Our results indicate that IGF-1R in the endothelium maintains the endothelial barrier function by stabilization of the VE-protein tyrosine phosphatase/VE-cadherin complex. Decreased expression of IGF-1R impairs endothelial function and increases the fibrosis of kidney disease.
Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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19 MeSH Terms
Skeletal muscle insulin resistance in zebrafish induces alterations in β-cell number and glucose tolerance in an age- and diet-dependent manner.
Maddison LA, Joest KE, Kammeyer RM, Chen W
(2015) Am J Physiol Endocrinol Metab 308: E662-9
MeSH Terms: Aging, Animals, Animals, Genetically Modified, Biological Transport, Cell Count, Disease Progression, Glucose, Glucose Intolerance, Green Fluorescent Proteins, Hyperglycemia, Insulin, Insulin Resistance, Insulin-Like Growth Factor I, Insulin-Secreting Cells, Luminescent Proteins, Muscle, Skeletal, Overnutrition, Receptor, IGF Type 1, Recombinant Fusion Proteins, Zebrafish, Zebrafish Proteins
Show Abstract · Added February 12, 2015
Insulin resistance creates an environment that promotes β-cell failure and development of diabetes. Understanding the events that lead from insulin resistance to diabetes is necessary for development of effective preventional and interventional strategies, and model systems that reflect the pathophysiology of disease progression are an important component toward this end. We have confirmed that insulin enhances glucose uptake in zebrafish skeletal muscle and have developed a zebrafish model of skeletal muscle insulin resistance using a dominant-negative IGF-IR. These zebrafish exhibit blunted insulin signaling and glucose uptake in the skeletal muscle, confirming insulin resistance. In young animals, we observed an increase in the number of β-cells and normal glucose tolerance that was indicative of compensation for insulin resistance. In older animals, the β-cell mass was reduced to that of control with the appearance of impaired glucose clearance but no elevation in fasting blood glucose. Combined with overnutrition, the insulin-resistant animals have an increased fasting blood glucose compared with the control animals, demonstrating that the β-cells in the insulin-resistant fish are in a vulnerable state. The relatively slow progression from insulin resistance to glucose intolerance in this model system has the potential in the future to test cooperating genes or metabolic conditions that may accelerate the development of diabetes and provide new therapeutic targets.
Copyright © 2015 the American Physiological Society.
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21 MeSH Terms
Genome-wide association meta-analysis identifies novel variants associated with fasting plasma glucose in East Asians.
Hwang JY, Sim X, Wu Y, Liang J, Tabara Y, Hu C, Hara K, Tam CH, Cai Q, Zhao Q, Jee S, Takeuchi F, Go MJ, Ong RT, Ohkubo T, Kim YJ, Zhang R, Yamauchi T, So WY, Long J, Gu D, Lee NR, Kim S, Katsuya T, Oh JH, Liu J, Umemura S, Kim YJ, Jiang F, Maeda S, Chan JC, Lu W, Hixson JE, Adair LS, Jung KJ, Nabika T, Bae JB, Lee MH, Seielstad M, Young TL, Teo YY, Kita Y, Takashima N, Osawa H, Lee SH, Shin MH, Shin DH, Choi BY, Shi J, Gao YT, Xiang YB, Zheng W, Kato N, Yoon M, He J, Shu XO, Ma RC, Kadowaki T, Jia W, Miki T, Qi L, Tai ES, Mohlke KL, Han BG, Cho YS, Kim BJ
(2015) Diabetes 64: 291-8
MeSH Terms: Adult, Aged, Asian Continental Ancestry Group, Blood Glucose, Far East, Fasting, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Guanine Nucleotide Exchange Factors, Humans, Male, Middle Aged, Phenotype, Protein-Serine-Threonine Kinases, Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase, Receptor, IGF Type 1, Tumor Suppressor Proteins
Show Abstract · Added February 22, 2016
Fasting plasma glucose (FPG) has been recognized as an important indicator for the overall glycemic state preceding the onset of metabolic diseases. So far, most indentified genome-wide association loci for FPG were derived from populations with European ancestry, with a few exceptions. To extend a thorough catalog for FPG loci, we conducted meta-analyses of 13 genome-wide association studies in up to 24,740 nondiabetic subjects with East Asian ancestry. Follow-up replication analyses in up to an additional 21,345 participants identified three new FPG loci reaching genome-wide significance in or near PDK1-RAPGEF4, KANK1, and IGF1R. Our results could provide additional insight into the genetic variation implicated in fasting glucose regulation.
© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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19 MeSH Terms
Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer.
Lovly CM, McDonald NT, Chen H, Ortiz-Cuaran S, Heukamp LC, Yan Y, Florin A, Ozretić L, Lim D, Wang L, Chen Z, Chen X, Lu P, Paik PK, Shen R, Jin H, Buettner R, Ansén S, Perner S, Brockmann M, Bos M, Wolf J, Gardizi M, Wright GM, Solomon B, Russell PA, Rogers TM, Suehara Y, Red-Brewer M, Tieu R, de Stanchina E, Wang Q, Zhao Z, Johnson DH, Horn L, Wong KK, Thomas RK, Ladanyi M, Pao W
(2014) Nat Med 20: 1027-34
MeSH Terms: Anaplastic Lymphoma Kinase, Crizotinib, Female, Gene Knockdown Techniques, Humans, Insulin Receptor Substrate Proteins, Lung Neoplasms, Middle Aged, Pyrazoles, Pyridines, Receptor Protein-Tyrosine Kinases, Receptor, IGF Type 1, Up-Regulation
Show Abstract · Added February 13, 2015
Crizotinib, a selective tyrosine kinase inhibitor (TKI), shows marked activity in patients whose lung cancers harbor fusions in the gene encoding anaplastic lymphoma receptor tyrosine kinase (ALK), but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the clinical observation of a patient with ALK fusion-positive lung cancer who had an exceptional response to an insulin-like growth factor 1 receptor (IGF-1R)-specific antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor insulin receptor substrate 1 (IRS-1), and IRS-1 knockdown enhances the antitumor effects of ALK inhibitors. In models of ALK TKI resistance, the IGF-1R pathway is activated, and combined ALK and IGF-1R inhibition improves therapeutic efficacy. Consistent with this finding, the levels of IGF-1R and IRS-1 are increased in biopsy samples from patients progressing on crizotinib monotherapy. Collectively these data support a role for the IGF-1R-IRS-1 pathway in both ALK TKI-sensitive and ALK TKI-resistant states and provide a biological rationale for further clinical development of dual ALK and IGF-1R inhibitors.
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13 MeSH Terms
Insulin growth factor signaling is regulated by microRNA-486, an underexpressed microRNA in lung cancer.
Peng Y, Dai Y, Hitchcock C, Yang X, Kassis ES, Liu L, Luo Z, Sun HL, Cui R, Wei H, Kim T, Lee TJ, Jeon YJ, Nuovo GJ, Volinia S, He Q, Yu J, Nana-Sinkam P, Croce CM
(2013) Proc Natl Acad Sci U S A 110: 15043-8
MeSH Terms: 3' Untranslated Regions, Animals, Apoptosis, Carcinoma, Non-Small-Cell Lung, Cell Cycle Checkpoints, Cell Line, Tumor, Cell Movement, Cell Proliferation, Class Ia Phosphatidylinositol 3-Kinase, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Genes, p53, Humans, Insulin-Like Growth Factor I, Lung Neoplasms, Mice, Mice, Nude, MicroRNAs, Phosphoinositide-3 Kinase Inhibitors, RNA, Small Interfering, Receptor, IGF Type 1, Signal Transduction
Show Abstract · Added December 22, 2013
MicroRNAs (miRNAs) are small 19- to 24-nt noncoding RNAs that have the capacity to regulate fundamental biological processes essential for cancer initiation and progression. In cancer, miRNAs may function as oncogenes or tumor suppressors. Here, we conducted global profiling for miRNAs in a cohort of stage 1 nonsmall cell lung cancers (n = 81) and determined that miR-486 was the most down-regulated miRNA in tumors compared with adjacent uninvolved lung tissues, suggesting that miR-486 loss may be important in lung cancer development. We report that miR-486 directly targets components of insulin growth factor (IGF) signaling including insulin-like growth factor 1 (IGF1), IGF1 receptor (IGF1R), and phosphoinositide-3-kinase, regulatory subunit 1 (alpha) (PIK3R1, or p85a) and functions as a potent tumor suppressor of lung cancer both in vitro and in vivo. Our findings support the role for miR-486 loss in lung cancer and suggest a potential biological link to p53.
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22 MeSH Terms
Autocrine IGF-I/insulin receptor axis compensates for inhibition of AKT in ER-positive breast cancer cells with resistance to estrogen deprivation.
Fox EM, Kuba MG, Miller TW, Davies BR, Arteaga CL
(2013) Breast Cancer Res 15: R55
MeSH Terms: Animals, Breast Neoplasms, Cell Line, Tumor, Cell Membrane, Cell Proliferation, Disease Models, Animal, Drug Resistance, Neoplasm, Estrogen Receptor Modulators, Female, Humans, Insulin-Like Growth Factor I, Ligands, MCF-7 Cells, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Kinase Inhibitors, Protein Transport, Proto-Oncogene Proteins c-akt, Pyrimidines, Pyrroles, Receptor Protein-Tyrosine Kinases, Receptor, IGF Type 1, Receptor, Insulin, Receptors, Estrogen, Tumor Burden, Up-Regulation, Xenograft Model Antitumor Assays
Show Abstract · Added September 3, 2013
INTRODUCTION - Estrogen receptor α-positive (ER+) breast cancers adapt to hormone deprivation and acquire resistance to antiestrogen therapies. Upon acquisition of hormone independence, ER+ breast cancer cells increase their dependence on the phosphatidylinositol-3 kinase (PI3K)/AKT pathway. We examined the effects of AKT inhibition and its compensatory upregulation of insulin-like growth factor (IGF)-I/InsR signaling in ER+ breast cancer cells with acquired resistance to estrogen deprivation.
METHODS - Inhibition of AKT using the catalytic inhibitor AZD5363 was examined in four ER+ breast cancer cell lines resistant to long-term estrogen deprivation (LTED) by western blotting and proliferation assays. Feedback upregulation and activation of receptor tyrosine kinases (RTKs) was examined by western blotting, real-time qPCR, ELISAs, membrane localization of AKT PH-GFP by immunofluorescence and phospho-RTK arrays. For studies in vivo, athymic mice with MCF-7 xenografts were treated with AZD5363 and fulvestrant with either the ATP-competitive IGF-IR/InsR inhibitor AZD9362 or the fibroblast growth factor receptor (FGFR) inhibitor AZD4547.
RESULTS - Treatment with AZD5363 reduced phosphorylation of the AKT/mTOR substrates PRAS40, GSK3α/β and S6K while inducing hyperphosphorylation of AKT at T308 and S473. Inhibition of AKT with AZD5363 suppressed growth of three of four ER+ LTED lines and prevented emergence of hormone-independent MCF-7, ZR75-1 and MDA-361 cells. AZD5363 suppressed growth of MCF-7 xenografts in ovariectomized mice and a patient-derived luminal B xenograft unresponsive to tamoxifen or fulvestrant. Combined treatment with AZD5363 and fulvestrant suppressed MCF-7 xenograft growth better than either drug alone. Inhibition of AKT with AZD5363 resulted in upregulation and activation of RTKs, including IGF-IR and InsR, upregulation of FoxO3a and ERα mRNAs as well as FoxO- and ER-dependent transcription of IGF-I and IGF-II ligands. Inhibition of IGF-IR/InsR or PI3K abrogated AKT PH-GFP membrane localization and T308 P-AKT following treatment with AZD5363. Treatment with IGFBP-3 blocked AZD5363-induced P-IGF-IR/InsR and T308 P-AKT, suggesting that receptor phosphorylation was dependent on increased autocrine ligands. Finally, treatment with the dual IGF-IR/InsR inhibitor AZD9362 enhanced the anti-tumor effect of AZD5363 in MCF-7/LTED cells and MCF-7 xenografts in ovariectomized mice devoid of estrogen supplementation.
CONCLUSIONS - These data suggest combinations of AKT and IGF-IR/InsR inhibitors would be an effective treatment strategy against hormone-independent ER+ breast cancer.
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27 MeSH Terms
Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial.
Schwartz GK, Tap WD, Qin LX, Livingston MB, Undevia SD, Chmielowski B, Agulnik M, Schuetze SM, Reed DR, Okuno SH, Ludwig JA, Keedy V, Rietschel P, Kraft AS, Adkins D, Van Tine BA, Brockstein B, Yim V, Bitas C, Abdullah A, Antonescu CR, Condy M, Dickson MA, Vasudeva SD, Ho AL, Doyle LA, Chen HX, Maki RG
(2013) Lancet Oncol 14: 371-82
MeSH Terms: Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Bone Neoplasms, Disease-Free Survival, Drug-Related Side Effects and Adverse Reactions, Female, Humans, Male, Middle Aged, Neoplasm Grading, Protein Kinase Inhibitors, Receptor, IGF Type 1, Sarcoma, Sirolimus, TOR Serine-Threonine Kinases
Show Abstract · Added March 11, 2014
BACKGROUND - Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry.
METHODS - We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015.
FINDINGS - Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21-43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24-47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28-51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8%) of which were grade 3-4. The most common grade 3-4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%), hypophosphataemia in 16 (9%), lymphopenia in 25 (14%), oral mucositis in 19 (11%), and thrombocytopenia in 19 (11%).
INTERPRETATION - The combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination.
FUNDING - National Cancer Institute and CycleforSurvival Fund, Memorial Sloan-Kettering Cancer Center.
Copyright © 2013 Elsevier Ltd. All rights reserved.
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19 MeSH Terms