High Insulin-like Growth Factor-1 Receptor Expression Research Articles

Abstract 1918: LX-101, a novel, clinical stage, payload-bearing targeted therapy directed to the insulin-like growth factor receptor (IGF-1R), demonstrates potent preclinical anti-tumor activity against multiple cancer types with well-established ties to the IGF-1/IGF-1R pathway

Abstract Objective: LX-101 is a next-generation, targeted therapy directed to the insulin-like growth factor 1 receptor (IGF-1R). LX-101 consists of a proprietary IGF-1 variant coupled to a cytotoxic methotrexate payload. LX-101 was previously evaluated in Phase 1 trials of adult patients with advanced, pretreated cancers, where it was well-tolerated and demonstrated single agent activity. Neither a dose limiting toxicity, nor a maximum tolerated dose was reached, leaving potential room for additional dose escalation and schedule optimization. Multiple aggressive cancers of unmet need have genetic alterations affecting the IGF-1R pathway and/or high IGF-1R expression that correlates with poor outcomes, including certain cancers of the breast, head and neck, Ewing’s sarcoma, osteosarcoma, and others. Prior attempts at inhibiting IGF-1R with non-payload bearing naked monoclonal antibodies or small molecules produced a range of clinical outcomes including some partial and complete responses. None of these agents, however, were ultimately approved, potentially due to suboptimal potency that allowed for escape mechanisms, including redundant signaling pathways, and the lack of enrichment for select tumor types with strong ties to the IGF-1/IGF-1R pathway. Herein, we investigated the anti-tumor activity of the payload-bearing agent LX-101 against IGF-1R-involved cancer cell lines. Methods: Cell lines were incubated with LX-101 (~1.6 - 2500nM). Cell viability was assessed by CellTiter-Glo after 4 days. IC50s were calculated using GraphPad PRISM software. Results: LX-101 displayed potency against head and neck cancer (FaDu, IC50 = 9 nM), triple negative breast cancer (BT-20, IC50 = 17 nM), Ewing’s sarcoma, including EWSR1-FLI1 gene fusion-positive cell lines RD-ES (IC50 = 10 nM), A-673 (IC50 = 14 nM), and SK-ES-1 (IC50 = 29 nM) and EWSR1-ERG gene fusion-positive cell line CADO-ES1 (IC50 = 14 nM). LX-101 was also potent against PAX3-FOXO1 gene fusion positive alveolar rhabdomyosarcoma (SJCRH30, IC50 = 23 nM), osteosarcoma (143B, IC50 = 6 nM; HOS, IC50 = 7 nM; U2OS, IC50 = 32 nM), and neuroblastoma (SK-N-AS, IC50 = 16 nM; IMR-32, IC50 = 20 nM; SH-SY5Y, IC50 = 30 nM). Conclusion: These results demonstrate that LX-101 has potent preclinical anti-tumor activity against multiple cancer cell lines with well-established ties to the IGF-1/IGF-1R pathway, including with different genetic and epigenetic alterations. These data support further clinical development of LX-101 in IGF-1R-involved cancers. New clinical trials are planned. Citation Format: Matt Hoberman, Arkadiusz Z. Dudek. LX-101, a novel, clinical stage, payload-bearing targeted therapy directed to the insulin-like growth factor receptor (IGF-1R), demonstrates potent preclinical anti-tumor activity against multiple cancer types with well-established ties to the IGF-1/IGF-1R pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1918.

The clinicopathological and prognostic significances of IGF-1R and Livin expression in patients with colorectal cancer

BackgroundColorectal cancer (CRC) is the third most common cancer worldwide. However, limited effective biomarkers are associated with the tumorigenesis and prognosis of CRC.MethodsThe present study identified potential signatures from The Cancer Genome Atlas (TCGA) database and further validated the identified biomarkers in CRC tissues by immunohistochemistry (IHC).ResultsThe expression of insulin-like growth factor 1 receptor (IGF-1R) and Livin gene was significantly upregulated in CRC samples compared to the adjacent normal samples in the TCGA dataset. IHC indicated that IGF-1R and Livin protein levels are increased in CRC and adenoma tissues compared to normal tissues. Notably, the IGF-1R protein levels differed significantly between adenoma and CRC. The elevated IGF-1R and Livin expression was associated with CRC clinicopathological features, including age, gender, histological subtype, individual cancer stages, nodal metastasis, and TP53-mutant in TCGA. Additionally, the IGF-1R promoter methylation level was closely related to CRC. Consistent with the TCGA study, IHC indicated that overexpressed IGF-1R and Livin proteins were independent risk factors for stage and metastasis. A marked correlation was established between IGF-1R and Livin expression in CRC, while the survival map showed no significant correlation with CRC. Kaplan–Meier survival curves showed that CRC patients with high IGF-1R or Livin expression had a prolonged overall disease-free survival than those with low expression in TCGA.ConclusionIGF-1R and Livin are associated with CRC tumorigenesis and might be valuable for novel biomarker identification and targeted therapeutic strategy development.

Abstract 1985: Activation of EGFR/IGF1R - beta catenin - CD44 pathway in periampullary cancer

Abstract Background: Periampullary cancer (PC) is a global medical burden, although infrequent but less than 5% of patients experience an overall survival of five years or more. The study aims to analyze the importance of Epidermal Growth Factor Receptor (EGFR)/Insulin-Like Growth Factor 1 Receptor (IGF1R) - Beta-catenin (β-catenin)- CD44 pathway in the development of periampullary cancer of Indian patients. Materials and Methods: Expression profile of EGFR, IGF1R, β-catenin, and CD44 was verified by immunohistochemical analysis in primary tumor samples (N=14) and respective adjacent normal tissues. Results: In periampullary carcinoma patients, a high level of EGFR expression was seen in 64% of the samples along with co-expression of IGF1-R in 77.8% samples. Furthermore, the high expression of EGFR and IGF1R significantly correlated with the increased expression of β-catenin along with CD44 expression of the tumors. Conclusion: The EGFR/IGF1R - β-catenin- CD44 pathway seems to be important in the development of PC with clinical importance. Key-words: Periampullary cancer; EGFR; IGF1R; β-catenin; CD44 Key Messages: Interplay of EGFR, IGF1R, β-Catenin and CD44 expressions is important phenomena in the development of PC. Citation Format: Suvendu Maji, Biswabandhu Bankura, Chinmay Kumar Panda, Neyaz Alam. Activation of EGFR/IGF1R - beta catenin - CD44 pathway in periampullary cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1985.

Insulin-Like Growth Factor-1 Receptor Expression and Disease Recurrence and Survival in Patients with Resected Pancreatic Ductal Adenocarcinoma.

Insulin-like growth factor-1 receptor (IGF1R) signaling is important in pancreatic ductal adenocarcinoma (PDAC) biology, but little is known regarding IGF1R expression and patient characteristics and outcomes. In 365 patients with resected PDAC, we evaluated IGF1R protein expression using IHC on whole-slide sections and IGF1R genomic status using next-generation sequencing. Associations of IGF1R expression, measured by H-scores incorporating staining intensity and proportion of positive tumor cells, with disease-free survival (DFS) and overall survival (OS) were evaluated in 317 and 321 patients, respectively, using Cox regression adjusting for known prognostic factors. Higher IGF1R expression in tumor cells was associated with worse DFS comparing highest versus lowest expression tertiles [median DFS, 10.8 vs. 16.1 months; adjusted hazard ratio (HR), 1.73; 95% confidence interval (CI), 1.24-2.44; P trend = 0.002] and worse OS (median OS, 17.4 vs. 25.8 months; HR, 1.39; 95% CI, 1.00-1.92; P trend = 0.046). The association between high IGF1R expression and reduced DFS was identified primarily among patients with a preoperative body mass index ≥25 kg/m2 (HR, 4.27; 95% CI, 2.03-8.96, comparing extreme tertiles; P interaction = 0.032). KRAS-mutant tumors had greater IGF1R expression, and IGF1R expression in tumor epithelium was inversely correlated with that in stromal cells. Mutations in IGF1R were infrequent, and no overt loss-of-function alterations were identified. Higher IGF1R expression was modestly associated with higher gene copy number (Pearson correlation coefficient = 0.26, P < 0.001). Higher IGF1R protein expression was associated with worse patient outcomes in resected PDAC. IGF1R expression in PDAC represents a potential biomarker to guide patient selection for more aggressive, multidrug regimens in the adjuvant setting.

Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade.

Harnessing the immune system by blocking the programmed cell death protein 1 (PD-1) pathway has been a major breakthrough in non-small-cell lung cancer treatment. Nonetheless, many patients fail to respond to PD-1 inhibition. Using three syngeneic models, we demonstrate that short-term starvation synergizes with PD-1 blockade to inhibit lung cancer progression and metastasis. This antitumor activity was linked to a reduction in circulating insulin-like growth factor 1 (IGF-1) and a downregulation of IGF-1 receptor (IGF-1R) signaling in tumor cells. A combined inhibition of IGF-1R and PD-1 synergistically reduced tumor growth in mice. This effect required CD8 cells, boosted the intratumoral CD8/Treg ratio and led to the development of tumor-specific immunity. In patients with non-small-cell lung cancer, high plasma levels of IGF-1 or high IGF-1R expression in tumors was associated with resistance to anti-PD-1-programmed death-ligand 1 immunotherapy. In conclusion, our data strongly support the clinical evaluation of IGF-1 modulators in combination with PD-1 blockade.

Activation of epidermal growth factor receptor/insulin-like growth factor 1 receptor-β-Catenin-CD44 pathway in periampullary cancer

Background: Periampullary cancer (PC) is a global medical burden. Less than 5% of patients experience an overall survival of 5 years or more. The study aims to analyze the importance of epidermal growth factor receptor (EGFR)/insulin-like growth factor 1 receptor (IGF1R)–beta-catenin (β-catenin)–CD44 pathway in the development of periampullary cancer of Indian patients. Subjects and Methods: Expression profile of EGFR, IGF1R, β-catenin, and CD44 was verified by immunohistochemical analysis in primary tumor samples (N = 14) and respective adjacent normal tissues. Results: In periampullary carcinoma patients, a high level of EGFR expression was seen in 64% of the samples along with co-expression of IGF1R in 77.8% of samples. Furthermore, the high expression of EGFR and IGF1R significantly correlated with the increased expression of β-catenin along with CD44 expression of the tumors. Conclusion: The EGFR/IGF1R–β-catenin–CD44 pathway seems to be important in the development of PC with clinical importance.

Increased expression of insulin-like growth factor-1 receptor predicts poor prognosis in patients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a lethal disease worldwide. In this study, we sought to explore the expression of insulin-like growth factor-1 receptor (IGF-1R) and its prognostic value in HCC.The expressions of IGF-1R mRNA and protein were estimated using quantitative real-time polymerase chain reaction and immunohistochemistry assays, respectively. The association between IGF-1R expression and clinicopathologic characteristic of patients with HCC was analyzed through Chi-squared test. Kaplan–Meier analysis and multivariate Cox analysis were performed to analyze prognostic value of IGF-1R in HCC.The IGF-1R was significantly upregulated in HCC tissues at both mRNA and protein levels compared with adjacent normal ones (P < .01). Its expression was associated with tumor node metastasis stage (P = .037) and lymph node metastasis (P = .027) of patients with HCC. Patients with HCC with high expression of IGF-1R had worse overall survival than those with low expression. IGF-1R might be a potential prognostic biomarker for HCC (hazard ratio [HR] = 1.912, 95% confidence interval [CI]: 1.023–3.572, P = .042).The IGF-1R expression level is upregulated in HCC tissues and may act as a prognostic biomarker for the disease.

Antitumor effect of insulin-like growth factor-1 receptor inhibition in head and neck squamous cell carcinoma.

The insulin-like growth factor-1 receptor (IGF1R) has been implicated in therapeutic resistance in head and neck squamous cell carcinoma (HNSCC), and small molecule tyrosine kinase inhibitors (TKIs) of IGF1R activity may have anticancer activity. Therefore, the relationship between survival and IGF1R expression was assessed for oral cavity (OC) cancer, and the antitumor effects of two IGF1R-TKIs, OSI-906 and BMS-754807, were evaluated in HNSCC cell lines in vitro. Clinical outcome data and tissue microarray immunohistochemistry were used to generate IGF1R expression-specific survival curves. Immunoblot, alamarBlue proliferation assay, trypan blue exclusion viability test, clonogenic assay, flow cytometry, and reverse phase protein array (RPPA) were used to evaluate in vitro responses to IGF1R-TKIs. For patients with stage III/IV OCSCC, higher IGF1R expression was associated with poorer overall 5-year survival (P = 0.029). Both BMS-754807 and OSI-906 caused dose-dependent inhibition of IGF1R and Akt phosphorylation and inhibited proliferation; BMS-754807 was more potent than OSI-906. Both drugs reduced HNSCC cell viability; only OSI-906 was able to eliminate all viable cells at 10 μM. The two drugs similarly inhibited clonogenic cell survival. At 1 μM, only BMS-754807 caused a fourfold increase in the basal apoptotic rate. RPPA demonstrated broad effects of both drugs on canonical IGF1R signaling pathways and also inhibition of human epidermal growth factor receptor-3 (HER3), Src, paxillin, and ezrin phosphorylation. OSI-906 and BMS-754807 inhibit IGF1R activity in HNSCC cell lines with reduction in prosurvival and proliferative signaling and with concomitant antiproliferative and proapoptotic effects. Such antagonists may have utility as adjuvants to existing therapies for HNSCC. NA Laryngoscope, 130:1470-1478, 2020.

IGF1R as druggable target mediating PI3K-δ inhibitor resistance in a murine model of chronic lymphocytic leukemia

AbstractTargeted therapy is revolutionizing the treatment of cancers, but resistance evolves against these therapies and derogates their success. The phosphatidylinositol 3-kinase delta (PI3K-δ) inhibitor idelalisib has been approved for treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma, but the mechanisms conferring resistance in a subset of patients are unknown. Here, we modeled resistance to PI3K-δ inhibitor in vivo using a serial tumor transfer and treatment scheme in mice. Whole-exome sequencing did not identify any recurrent mutation explaining resistance to PI3K-δ inhibitor. In the murine model, resistance to PI3K-δ inhibitor occurred as a result of a signaling switch mediated by consistent and functionally relevant activation of insulin-like growth factor 1 receptor (IGF1R), resulting in enhanced MAPK signaling in the resistant tumors. Overexpression of IGF1R in vitro demonstrated its prominent role in PI3K-δ inhibitor resistance. IGF1R upregulation in PI3K-δ inhibitor–resistant tumors was mediated by functional activation and enhanced nuclear localization of forkhead box protein O1 transcription factors and glycogen synthase kinase 3β. In human CLL, high IGF1R expression was associated with trisomy 12. CLL cells from an idelalisib-treated patient showed decreased sensitivity to idelalisib in vitro concomitant with enhanced MAPK signaling and strong upregulation of IGF1R upon idelalisib exposure. Thus, our results highlight that alternative signaling cascades play a predominant role in the resistance and survival of cancer cells under PI3K-δ inhibition. We also demonstrate that these pathway alterations can serve as therapeutic targets, because inhibition of IGF1R offered efficacious salvage treatment of PI3K-δ inhibitor–resistant tumors in vitro and in vivo.

Abstract 78: IGF-1R inhibition activates p70S6K1 to promote survival via MEK1/2 activation in colon cancer cells

Abstract The insulin-like growth factor 1 receptor (IGF-1R) is a heterotetramer with tyrosine kinase activity, composed of two α subunits containing the ligand-binding site and two β subunits harboring the tyrosine kinase activity. Upon binding with ligands (IGF-1, IGF-2, and insulin), IGF-1R leads to activation of downstream pathways including PI3-K/AKT and Ras/MAPK, two frequently activated pathways for promoting cell survival and proliferation in various cancers including colorectal cancer. Immunohistochemical studies revealed that IGF-1R is over-expressed in colorectal cancer tissues compared to the adjacent normal tissues. Most importantly, a higher expression of IGF-1R is associated with a higher grade and stage in colorectal cancer patients. Since the IGF-1R signaling pathway plays an essential role in development, maintenance, and survival of tumors, many small molecule compounds and antibodies targeting IGF-1R have been developed. Unfortunately, these anti-IGF-1R agents demonstrate very limited efficacy in clinical trials, suggesting the existence of a mechanism to overcome the inhibitory effect of IGF-1R in cancer cells. In this study, we aim to understand the resistance mechanism of IGF-1R inhibition in colon cancer cells. Prolonged treatment of IGF-1R resistant colon cancer cells with IGF-1R inhibitors (OSI-906, BMS-754807, and GSK1838705A) stimulates p70S6K1 activation, a well-known kinase signaling for cell survival. We also found that p70S6K1 activation is independent of mutation of K-RAS and PIK3CA, frequently occurring in colorectal cancer. Genetic knockdown or pharmacologic inhibition of p70S6K1 efficiently suppresses cell viability in response to IGF-1R inhibition, indicating that p70S6K1 activation contributes to the survival of IGF-1R inhibitor-treated cells. In addition to the increased phosphorylation of p70S6K1, phosphorylation of MEK1/2 is also elevated in colon cancer cells with prolonged inhibition of IGF-1R. Knockdown of MEK1/2 results in reduction of p70S6K1 activation in response to IGF-1R inhibition and subsequently increases apoptosis, suggesting that MEK1/2 is involved in p70S6K1 activation for survival. Furthermore, the combination of BMS754807 and U0126, a MEK1/2 inhibitor, effectively decreases the cell viability and increases apoptosis. Our data suggest that inhibition of MEK1/2 enhances the anti-proliferation effects of IGF-1R inhibitors, pointing out a new direction for overcoming the resistance of IGF-1R inhibition in colorectal cancer. Citation Format: Qing Wang, Hsin-Sheng Yang. IGF-1R inhibition activates p70S6K1 to promote survival via MEK1/2 activation in colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 78.

Systemic analysis of different colorectal cancer cell lines and TCGA datasets identified IGF-1R/EGFR-PPAR-CASPASE axis as important indicator for radiotherapy sensitivity

Insulin-like growth factor 1 receptor (IGF-1R) is proved to contribute the development of many types of cancers. But, little is known about its roles in radio-resistance of colorectal cancer (CRC). Here, we demonstrated that low IGF-1R expression value was associated with the better radiotherapy sensitivity of CRC. Besides, through Quantitative Real-time PCR (qRT-PCR), the elevated expression value of epidermal growth factor receptor (EGFR) was observed in CRC cell lines (HT29, RKO) with high radio-sensitivity compared with those with low sensitivity (SW480, LOVO). The irradiation induced apoptosis rates of wild type and EGFR agonist (EGF) or IGF-1R inhibitor (NVP-ADW742) treated HT29 and SW480 cells were quantified by flow cytometry. As a result, the apoptosis rate of EGF and NVP-ADW742 treated HT29 cells was significantly higher than that of those wild type ones, which indicated that high EGFR and low IGF-1R expression level in CRC was associated with the high sensitivity to radiotherapy. We next conducted systemic bioinformatics analysis of genome-wide expression profiles of CRC samples from the Cancer Genome Atlas (TCGA). Differential expression analysis between IGF-1R and EGFR abnormal CRC samples, i.e. CRC samples with higher IGF-1R and lower EGFR expression levels based on their median expression values, and the rest of CRC samples identified potential genes contribute to radiotherapy sensitivity. Functional enrichment of analysis of those differential expression genes (DEGs) in the Database for Annotation, Visualization and Integrated Discovery (DAVID) indicated PPAR signaling pathway as an important pathway for the radio-resistance of CRC. Our study identified the potential biomarkers for the rational selection of radiotherapy for CRC patients.

IGF-1R signalling contributes to IL-6 production and T cell dependent inflammation in rheumatoid arthritis

BackgroundSignalling through insulin-like growth factor 1 receptor (IGF-1R) is essential for cell survival, but may turn pathogenic in uncontrolled tissue growth in tumours. In rheumatoid arthritis (RA), the IGF-1R signalling is activated and supports expansion of the inflamed synovia. AimIn the present study, we assess if disruption of IGF-1R signalling resolves arthritis. Material and methodsClinical associations of IGF-1R expression in leukocytes of the peripheral blood were studied in 84 RA patients. Consequences of the IGF-1R signalling inhibition for arthritis were studied in mBSA immunised Balb/c mice treated with NT157 compound promoting degradation of insulin receptor substrates. ResultsIn RA patients, high expression of IGF-1R in leukocytes was associated with systemic inflammation as verified by higher expression of NF-kB, serum levels of IL6 and erythrocyte sedimentation rate, and higher pain perception. Additionally, phosphorylated IGF-1R and STAT3 enriched T cells infiltrate in RA synovia. Treatment with NT157 inhibited the phosphorylation of IGF-1R and STAT3 in synovia, and alleviated arthritis and joint damage in mice. It also reduced expression of IGF-1R and despaired ERK and Akt signalling in spleen T cells. This limited IL-6 production, changed RoRgt/FoxP3 balance and IL17 levels. ConclusionIGF-1R signalling contributes to T cell dependent inflammation in arthritis. Inhibition of IGF-1R on the level of insulin receptor substrates alleviates arthritis by restricting IL6-dependent formation of Th17 cells and may open for new treatment strategies in RA.

Formation of the IGF1R/CAV1/SRC tri-complex antagonizes TRAIL-induced apoptosis in gastric cancer cells.

Lipid rafts provide a biological platform for apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We previously reported that insulin-like growth factor 1 receptor (IGF1R) translocation into lipid rafts helped to explain TRAIL resistance. However, it was not clear whether TRAIL resistance was caused by the interaction of IGF1R with caveolin-1 (CAV1) and the non-receptor tyrosine kinase SRC in lipid rafts of gastric cancer cells. Here, we observed high IGF1R expression in TRAIL-resistant gastric cancer cells, and showed that IGF1R combined with both CAV1 and SRC in a native complex. TRAIL was shown to promote the formation of the IGF1R/CAV1/SRC tri-complex and the activation of these three molecules. Knockdown of IGF1R or CAV1 or inhibition of SRC activity reduced the formation of this tri-complex and enhanced TRAIL-induced apoptosis. Furthermore, the overexpression of microRNA-194 reversed TRAIL resistance by reducing IGF1R expression. In summary, TRAIL increased formation of the IGF1R/CAV1/SRC tri-complex and the activation of downstream survival pathways, leading to TRAIL resistance in gastric cancer cells.

Expression of GRK2 and IGF1R in hepatocellular carcinoma: clinicopathological and prognostic significance

AimIt has been shown that G-protein-coupled receptor kinase 2 (GRK2) negatively regulates the insulin-like growth factor 1 receptor (IGF1R) signalling pathway in hepatocellular carcinoma (HCC). The aim of this study...

The Prognostic and Clinicopathological Significance of IGF-1R in NSCLC: a Meta-Analysis

Background/Aims: Accumulating studies have reported that IGF-1R (Insulin-like growth factor-1 receptor) is aberrantly expressed in NSCLC (non-small cell lung cancer), but the role of IGF-1R in NSCLC remains controversial. The present paper assessed the precise role of IGF-1R in NSCLC. Methods: We comprehensively searched PubMed, EMBASE, and Web of Science in March 2017. Combined HRs and ORs were used to evaluate the prognostic and clinicopathological significance of IGF-1R in NSCLC respectively. Results: A total of 10 eligible studies including 8 on overall survival, and 10 on clinicopathological features were identified from the databases. The results showed that high expression of IGF-1R was associated with shorter OS (overall survival) of NSCLC patients (pooled HR 1.17,95 % CI 1.00–1.36). In addition, we found that IGF-1R was related to smoking status (OR=1.82, 95 % CI=1.35-2.44) and IGF-1R tended to be highly expressed in SCC (squamous cell carcinoma) (OR=3.40 95 % CI: 1.95-5.95). Conclusions: In summary, this meta-analysis revealed that high expression of IGF-1R was associated with poor prognosis in NSCLC.

Endometrial Cancer Insulin-Like Growth Factor 1 Receptor (IGF1R) Expression Increases with Body Mass Index and Is Associated with Pathologic Extent and Prognosis.

Obesity is a main risk factor for endometrial carcinoma (EC). Insulin-like growth factor 1 receptor (IGF1R) expression may influence this association. IGF1R IHC was performed on a tissue microarray with 894 EC and scored according to the percentage and intensity of staining to create immunoreactivity scores, which were dichotomized into low and high IGF1R expression groups. Logistic regression modeling assessed associations with body mass index (BMI), age, histology, pathologic extent of disease (pT), and lymph node metastasis (pN). Overall survival (OS) and disease-free survival (DFS) were compared between IGF1R expression groups using Kaplan-Meier curves and log-rank tests. The proportion of patients with high IGF1R expression increased as BMI (<30, 30-39, and 40+ kg/m(2)) increased (P = 0.002). The adjusted odds of having high IGF1R expression was 1.49 [95% confidence interval (CI), 1.05-2.10, P = 0.024] for patients with BMI 30 to 39 kg/m(2) compared with <30 kg/m(2) and 1.62 (95% CI, 1.13-2.33, P = 0.009) for patients with BMI 40+ kg/m(2) compared with <30 kg/m(2). High IGF1R expression was associated with pT and pN univariately and with pT after adjusting for BMI, pN, age, and histologic subtype. DFS and OS were better with high IGF1R expression, P = 0.020 and P = 0.002, respectively, but DFS was not significant after adjusting for pT, pN, and histologic subtype of the tumor. There is an association between BMI and EC IGF1R expression. Higher IGF1R expression is associated with lower pT and better DFS and OS. These findings suggest a link between IGF1R EC expression and obesity, as well as IGF1R expression and survival.

Highlights of This Issue

The analysis of miRNAs may aid risk prediction in individuals diagnosed with Barrett's esophagus. Towards this goal, Drahos and colleagues examined whether certain miRNAs can positively distinguish esophageal adenocarcinoma (EA) from Barrett's esophagus. In a case–control study of 150 EA cases frequency-matched to 148 Barrett's esophagus cases, the authors observed 46 miRNAs significantly increased in EA compared with Barrett's esophagus. Three miRNAs were detected in greater than 80% EA and fewer than 20% of Barrett's esophagus, and several exhibited the most extreme differences in expression with &gt;5-fold increases. These candidate miRNAs may provide a means for improved risk stratification and more cost-effective surveillance.Obesity is a risk factor for endometrial carcinoma, and insulin-like growth factor 1 receptor (IGF1R) expression may influence this association. Joehlin-Price and colleagues performed IGF1R immunohistochemistry on a tissue microarray containing 894 endometrial carcinoma samples and scored according to staining to create immunoreactivity scores. The proportion of patients with high IGF1R expression increased as body mass index increased. These findings suggest a link between IGF1R endometrial carcinoma expression and obesity, as well as IGF1R expression and survival.Numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, but few associations have been reported with overall survival. Winham and colleagues assessed the contribution of rare coding region variants using data from the exome-based genotyping projects of the Ovarian Cancer Association Consortium. The primary patient set (Set 1) included 14 EOC studies and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies and 114,620 variants. An SNP, rs8170, previously implicated to be associated with EOC risk and survival, showed the strongest evidence of association with EOC survival. Rare variants in ATG2B, an autophagy gene important for apoptosis, were also significantly associated with EOC survival.Massat and colleagues conducted a case–control study to assess the impact of mammography screening attendance on breast cancer mortality in an English population. Cancer registry cases who died from primary breast cancer (869 women) were matched to one or two general population controls with no diagnosis of breast cancer who were alive at the case's death. Attendance at breast screening resulted in a breast cancer mortality reduction of 39%, supporting that mammography screening is an important tool for reducing breast cancer mortality.

Impact Study: MK-0646 (Dalotuzumab), Insulin Growth Factor 1 Receptor Antibody Combined with Pemetrexed and Cisplatin in Stage IV Metastatic Non-squamous Lung Cancer.

Insulin-like growth factor 1 receptor (IGF-1R) regulates cell growth, proliferation, and apoptosis. Adenocarcinoma and never-smokers have a higher expression of IGF-1R, which is associated with worse overall survival. Dalotuzumab-MK0646 (D) is a humanized monoclonal antibody that targets IGF-1R. Pemetrexed (P) has higher activity in non-squamous lung cancer (NSQL). We initiated a randomized phase II trial to test the combination of P and Cisplatin (C) ± D in NSQL. Eligibility criteria were untreated NSQL stage IV, ECOG 0 or 1, measurable disease, adequate renal, hepatic and hematologic function, and no other intercurrent illness. P at 500 mg/m(2) and C at 75 mg/m(2) IV were given every 3 weeks. D was given at 10 mg/kg IV weekly on days 1, 8, and 15 of every 3-week cycle in the experimental group. The patients had a radiographic assessment after every two cycles and were treated for a maximum of six cycles if there was a response or stable disease. The primary objective of the study was to compare the clinical response rates of PC vs. PC + D. From 1/2009 to 2/2011, the study accrued 26 subjects: 16 male and 10 female, with a median age of 59; 14 were treated with PC and 12 were treated with PC + D. We observed two partial responses (PR), seven stable disease (SD), three progressive disease (PD), and two not evaluable (NE) in the PC arm. In comparison, for the PC + D arm, there were three PR, four SD, four PD, and one NE. The hematologic toxicity was similar in both groups. There was higher incidence of hyperglycemia in the experimental group; four cases with grade 3 and one case with grade 4. PC + D had a similar response rate compared to PC, with a higher rate of hyperglycemia. Identification of responders using predictive markers would be key to continuing the study of D in NSQL. NCT00799240, clinicaltrials.gov.

The value of insulin-like growth factor-1 receptor for predicting early glottic carcinoma response to radiotherapy.

The optimal management of laryngeal carcinoma requires tumor treatment and preservation of laryngeal functions, such as swallowing and voice quality. Radiotherapy (RT) can fulfill both criteria, although it remains important to identify predictors of radioresistance and reduce unnecessary irradiation. Insulin-like growth factor-1 receptor (IGF-1R) is a transmembrane receptor that plays a key role in cancer development, although its prognostic value after RT remains unknown. We evaluated the predictive value of IGF-1R expression for RT response in patients with early glottic squamous cell carcinoma. We retrospectively reviewed 43 patients with T1N0 and T2N0 glottic squamous cell carcinoma who were treated with RT alone. Biopsy specimens were stained using an anti-IGF-1R antibody, and we evaluated the relationships between IGF-1R expression and T classification or tumor recurrence. We also evaluated the loco-regional control (LRC) rate and the prognostic value of various clinical factors. All cases achieved complete response after the initial RT, and 10 (23.3%) patients experienced local tumor recurrence. Twenty-five patients (58.1%) exhibited high IGF-1R expression, although the level of IGF-1R expression was not correlated with T classification. Local recurrence was observed in 36% (9/25) of patients with high IGF-1R expression and in only 5% (1/18) of patients with low IGF-1R expression (p<0.05). The 2-year LRC rate was 94.1% for the low IGF-1R expression group, compared to 49.8% for the high IGF-1R expression group (p=0.04). Anterior commissure involvement and IGF-1R expression were independent adverse factors for LRC. High IGF-1R expression was more common among patients with recurrent early glottic carcinoma, which suggests that there is a biological relationship between IGF-1R expression and RT response. Thus, IGF-1R may be a useful screening parameter for RT response in laryngeal carcinoma.

Membranous Insulin-like Growth Factor-1 Receptor (IGF1R) Expression Is Predictive of Poor Prognosis in Patients with Epidermal Growth Factor Receptor (EGFR)-Mutant Lung Adenocarcinoma.

Background:Insulin-like growth factor-1 receptor (IGF1R) is a membrane receptor-type tyrosine kinase that has attracted considerable attention as a potential therapeutic target, although its clinical significance in non-small cell lung cancer (NSCLC) is controversial. This study aimed to clarify the clinical significance of IGF1R expression in human NSCLC.Methods:IGF1R protein expression was evaluated using immunohistochemistry in 372 patients with NSCLC who underwent curative surgical resection (146 squamous cell carcinomas [SqCCs] and 226 adenocarcinomas [ADCs]). We then analyzed correlations between expression of IGF1R and clinicopathological and molecular features and prognostic significance.Results:Membranous and cytoplasmic IGF1R expression were significantly higher in SqCCs than in ADCs. In patients with SqCC, membranous IGF1R expression was associated with absence of vascular, lymphatic, and perineural invasion; lower stage; and better progression-free survival (PFS) (hazard ratio [HR], 0.586; p = .040). In patients with ADC, IGF1R expression did not have a significant prognostic value; however, in the subgroup of epidermal growth factor receptor (EGFR)-mutant ADC, membranous IGF1R expression was associated with lymphatic and perineural invasion, solid predominant histology, and higher cancer stage and was significantly associated with worse PFS (HR, 2.582; p = .009).Conclusions:Lung ADC and SqCC showed distinct IGF1R expression profiles that demonstrated prognostic significance. High membranous IGF1R expression was predictive of poor PFS in EGFR-mutant lung ADC, while it was predictive of better PFS in SqCC. These findings will help improve study design for subsequent investigations and select patients for future anti-IGF1R therapy.