Neurotensin receptor 1 is a new therapeutic target for human undifferentiated pleomorphic sarcoma growth

Undifferentiated pleomorphic sarcoma (UPS) is the second most common soft tissue sarcoma. For patients with unresectable or metastatic disease, chemotherapies are considered, but in many cases they are not curative. There is a need to identify specific molecular dysregulations that can be therapeutic targets. We focused on neurotensin receptor 1 (NTSR1), which belongs to the G‐protein‐coupled receptor. NTSR1 expression was upregulated in specimens from patients with UPS. Real‐time polymerase chain reaction showed that expression of NTSR1 messenger RNA was 5‐ to 7‐fold increased in UPS cells compared with myoblasts. Western blot showed a high expression of NTSR1 protein in UPS cell lines. Knockdown of NTSR1 prevented UPS cell proliferation and invasion. We confirmed that SR48692, an inhibitor of NTSR1, exhibited antitumor activities in UPS cells. The combination index showed that SR48692 and standard chemotherapeutic drugs prevented UPS cell proliferation synergistically. Mouse xenograft models showed that SR48692 inhibited extracellular signal‐regulated kinase phosphorylation and enhanced the response to standard chemotherapeutic drugs. Inhibition of NTSR1 improved the effect of standard chemotherapeutic drugs for UPS. SR48692 may be a new drug for targeted UPS therapy.     

Synergistic induction of apoptosis by a polo‐like kinase 1 inhibitor and microtubule‐interfering drugs in Ewing sarcoma cells

Since polo‐like kinase 1 (PLK1) is highly expressed in Ewing sarcoma (ES), we evaluated the therapeutic potential of the PLK1 inhibitor BI 6727. Here, we identify a synergistic induction of apoptosis by BI 6727 and several microtubule‐interfering drugs in ES cells, including vincristine (VCR), vinblastine (VBL), vinorelbine (VNR) and eribulin. Synergistic drug interaction is confirmed by calculation of combination index (CI). Also, BI 6727 and VCR act in concert to reduce long‐term clonogenic survival. Mechanistically, BI 6727/VCR co‐treatment cooperates to trigger mitotic arrest, phosphorylation of BCL‐2 and BCL‐X_L and downregulation of MCL‐1. This inactivation of anti‐apoptotic BCL‐2 family proteins in turn promotes activation of BAX and BAK, activation of caspase‐9 and ‐3 and caspase‐dependent apoptosis. Overexpression of BCL‐2 or simultaneous knockdown of BAX and BAK significantly rescue BI 6727/VCR‐induced apoptosis, indicating that engagement of the mitochondrial pathway is critical for BI 6727/VCR‐mediated apoptosis. The clinical relevance of PLK1 inhibitor‐based combination therapies is underscored by the fact that BI 6727 is currently evaluated in phase I clinical trials in childhood cancer. In conclusion, PLK1 inhibitors such as BI 6727 may provide a new strategy to chemosensitize ES.     

Serum insulin‐like,growth factor binding protein‐related protein 1 (IGFBP‐rP1) and endometrial cancer risk in Chinese women

Hyperinsulinemia and the metabolic syndrome confer increased risks of endometrial carcinoma. The roles of insulin, and, insulin‐like growth factor‐binding proteins (IGFBPs) in the etiology of endometrial carcinoma, remain unclear. We recruited 206 patients with endometrial carcinoma and 350 healthy women to a case–control study of fasting insulin and IGFBP‐related protein 1 (IGFBP‐rP1) in a Chinese tertiary centre. Patients with endometrial carcinoma had higher insulin concentrations (14.8 ± 16.7 vs. 8.1 ± 9.4 μU/mL; p < 0.001) and lower IGFBP‐rP1 levels (17.5 ± 17.2 vs. 22.4 ± 22.8 μg/L; p = 0.018) than controls. High insulin and IGFBP‐rP1 levels were both positively and negatively associated with endometrial cancer (odds ratio for the highest tertile versus the lowest tertile: insulin: 4.11; 95% CI = 2.61–6.47; IGFBP‐rP1: 0.38; 95% CI = 0.24–0.60). Logistic regression analysis confirmed the associations between endometrial carcinoma and fasting insulin or IGFBP‐rP1 after adjustments for age, BMI, serum glucose, cholesterol, triglycerides and high‐density lipoprotein cholesterol (odds ratio for the highest tertile versus the lowest tertile: insulin: 2.13; 95% CI = 1.30–3.49; IGFBP‐rP1: 0.57; 95% CI = 0.34–0.94). Hyperinsulinemia and high IGFBP‐rP1 levels confer altered risks for endometrial carcinoma.     

Basal expression of insulin‐like growth factor 1 receptor determines intrinsic resistance of cancer cells to a phosphatidylinositol 3‐kinase inhibitor ZSTK474

Drug resistance often critically limits the efficacy of molecular targeted drugs. Although pharmacological inhibition of phosphatidylinositol 3‐kinase (PI3K) is an attractive therapeutic strategy for cancer therapy, molecular determinants for efficacy of PI3K inhibitors (PI3Kis) remain unclear. We previously identified that overexpression of insulin‐like growth factor 1 receptor (IGF1R) contributed to the development of drug resistance after long‐term exposure to PI3Kis. In this study, we examined the involvement of basal IGF1R expression in intrinsic resistance of drug‐naïve cancer cells to PI3Kis and whether inhibition of IGF1R overcomes the resistance. We found that cancer cells highly expressing IGF1R showed resistance to dephosphorylation of Akt and subsequent antitumor effect by ZSTK474 treatment. Knockdown of IGF1R by siRNAs facilitated the dephosphorylation and enhanced the drug efficacy. These cells expressed tyrosine‐phosphorylated insulin receptor substrate 1 at high levels, which was dependent on basal IGF1R expression. In these cells, the efficacy of ZSTK474 in vitro and in vivo was improved by its combination with the IGF1R inhibitor OSI‐906. Finally, we found a significant correlation between the basal expression level of IGF1R and the inefficacy of ZSTK474 in an in vivo human cancer panel, as well as in vitro. These results suggest that basal IGF1R expression affects intrinsic resistance of cancer cells to ZSTK474, and IGF1R is a promising target to improve the therapeutic efficacy. The current results provide evidence of combination therapy of PI3Kis with IGF1R inhibitors for treating IGF1R‐positive human cancers.     

Insulin‐like growth factor 1 expression correlates with clinical outcome in K‐RAS wild type colorectal cancer patients treated with cetuximab and irinotecan

Seventy to 40% of K‐RAS wild type colorectal tumors does not seem to benefit from treatment with antiepidermal growth factor receptor (anti‐EGFR) monoclonal antibodies. Recent data suggested that in presence of IGF‐1 system, altered activation colorectal cancer cells may escape anti‐EGFR mediated cell death. The interaction between IGF‐1 expression and K‐RAS mutational analysis was tested to verify the ability of IGF‐1 to identify a subgroup of patients more likely to benefit from EGFR‐targeted antibodies treatment. IGF‐1 expression and K‐RAS mutational status was assessed in advanced colorectal cancer patients receiving irinotecan/cetuximab. One hundred twelve patients were analyzed. IGF‐1 was negative in 30 patients (27%) and overexpressed in the remaining 82 cases (73%). In IGF‐1 negative and IGF‐1 positive tumors, we observed progressive disease in 9 (30%) and 55 (67%) patients, respectively (p = 0.001). Median progression‐free survival was 7.5 mo in patients showing IGF‐1 negative tumors and 3 mo for IGF‐1 expressing tumors (p = 0.002). Among K‐RAS wild type patients, IGF‐1 negative and positive tumors showed a partial response to cetuximab‐irinotecan in 13 (65%) and 11 (22%) cases, respectively (p = 0.002). Median progression‐free survival in IGF‐1 negative tumors was 10 mo and 3.2 mo in IGF‐1 positive colorectal cancers (p = 0.02). IGF‐1 proved to be a possible predictive factor for resistance to anti‐EGFR monoclonal antibodies in K‐RAS wild type colorectal cancer. Combined IGF‐1 and K‐RAS analysis may represent an effective strategy for a better selection of responding colorectal cancer patients.     

The clinical outcomes of undifferentiated pleomorphic sarcoma (UPS): A single-centre experience of two decades with the assessment of PD-L1 expressions

IntroductionLittle is known about undifferentiated pleomorphic sarcoma (UPS) because of the low incidence and heterogeneous diagnosis of sarcoma. We investigated the oncologic outcomes of patients with UPS in a real-practice setting in association with adjuvant treatments and assessment of PD-L1 expression.Materials and methodsWe retrospectively reviewed consecutive patients who were diagnosed with UPS in Asan Medical Center between January 1995 and December 2016. PD-L1 staining was performed using formalin-fixed paraffin-embedded tumour tissue by immunohistochemistry, and positive PD-L1 expression was defined as staining in ≥1% of tumour cells. The PD-L1 H-score, which was calculated for statistical analysis as intensity (0–3) multiplied by proportion (0–100), ranged from 0 to 300.ResultsOf 205 patients included in our analysis, 176 underwent a curative-intent operation for localised disease. The five-year disease-free survival (DFS) rate of resected UPS patients was 54.3%. Administration of adjuvant therapy did not overcome the poor prognostic factors such as primary tumour size (>5 cm) and locations, especially the abdomen and pelvis. The PD-L1 analysis was available for 114 patients, and 83 (72.8%) showed immunoreactivity for PD-L1 with weak (44/83), intermediate (29/83), and strong (10/83) staining intensities. The positive PD-L1 expression seemed to be associated with prolonged DFS, though no statistical significance was observed.ConclusionComplete surgical resection was the most important UPS treatment strategy, and adjuvant radio- or chemotherapy was insufficient to improve survival. Our results raise the possibility that immunotherapy could be a breakthrough in the treatment of UPS patients.