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This article discusses findings of a study, which examined clusterin staining in tumors resected from patients with non-small lung cancer. Clusterin is a glycoprotein that has been associated with apoptosis, cell cycle regulation and DNA repair. The study used data from Vanderbilt's Lung Specialized Programs of Research Excellence database and has revealed that cytoplasmic clusterin staining was associated with better 3-year overall survival and recurrence-free survival.

Aberrant forms of the anaplastic lymphoma kinase (ALK) have been implicated in the pathogenesis of multiple human cancers, where ALK represents a rational therapeutic target in these settings. In this study, we report the identification and biological characterization of X-376 and X-396, two potent and highly specific ALK small molecule tyrosine kinase inhibitors (TKIs). In Ambit kinome screens, cell growth inhibition studies, and surrogate kinase assays, X-376 and X-396 were more potent inhibitors of ALK but less potent inhibitors of MET compared to PF-02341066 (PF-1066), an ALK/MET dual TKI currently in clinical trials. Both X-376 and X-396 displayed potent antitumor activity with favorable pharmacokinetic and toxicity profiles. Similar levels of in vivo drug sensitivity were displayed by the three most common ALK fusion proteins in lung cancer (EML4-ALK variants E13;A20, E20;A20, and E6b;A20) as well as a KIF5B-ALK fusion protein. Moreover, X-396 could potently inhibit ALK kinases engineered with two point mutations associated with acquired resistance to PF-1066, L1196M, and C1156Y, when engineered into an E13;A20 fusion variant. Finally, X-396 displayed synergistic growth inhibitory activity when combined with the mTOR inhibitor rapamycin. Our findings offer preclinical proof-of-concept for use of these novel agents to improve therapeutic outcomes of patients with mutant ALK-driven malignancies. Cancer Res; 71(14); 4920-31. ©2011 AACR. [ABSTRACT FROM AUTHOR]

Background: Indeterminate pulmonary nodules (IPN) are a diagnostic challenge in regions where pulmonary fungal disease and smoking prevalence are high. We aimed to determine the impact of a combined fungal and imaging biomarker approach compared with a validated prediction model (Mayo) to rule out benign disease and diagnose lung cancer., Methods: Adults ages 40 to 90 years with 6-30 mm IPNs were included from four sites. Serum samples were tested for histoplasmosis IgG and IgM antibodies by enzyme immunoassay and a CT-based risk score was estimated from a validated radiomic model. Multivariable logistic regression models including Mayo score, radiomics score, and IgG and IgM histoplasmosis antibody levels were estimated. The areas under the ROC curves (AUC) of the models were compared among themselves and to Mayo. Bias-corrected clinical net reclassification index (cNRI) was estimated to assess clinical reclassification using a combined biomarker model., Results: We included 327 patients; 157 from histoplasmosis-endemic regions. The combined biomarker model including radiomics, histoplasmosis serology, and Mayo score demonstrated improved diagnostic accuracy when endemic histoplasmosis was accounted for [AUC, 0.84; 95% confidence interval (CI), 0.79-0.88; P < 0.0001 compared with 0.73; 95% CI, 0.67-0.78 for Mayo]. The combined model demonstrated improved reclassification with cNRI of 0.18 among malignant nodules., Conclusions: Fungal and imaging biomarkers may improve diagnostic accuracy and meaningfully reclassify IPNs. The endemic prevalence of histoplasmosis and cancer impact model performance when using disease related biomarkers., Impact: Integrating a combined biomarker approach into the diagnostic algorithm of IPNs could decrease time to diagnosis., (©2022 American Association for Cancer Research.)

Background: Granulomas caused by infectious lung diseases present as indeterminate pulmonary nodules (IPNs) on radiography. Newly available serum enzyme immunoassay (EIA) for histoplasmosis has not been studied for the evaluation of IPNs. We investigated serum biomarkers of histoplasmosis antibodies as an indication of benign disease in IPNs from a highly endemic region., Methods: A total of 152 serum samples from patients presenting with pulmonary nodules ≤30 mm in maximum diameter were analyzed for histoplasmosis antibodies by immunodiffusion and EIA IgG and IgM tests. Serology and FDG-PET/CT scan diagnostic test characteristics were estimated and compared., Results: Cancer prevalence was 55% ( n = 83). Thirty-nine (26%) individuals were positive for IgG histoplasmosis antibodies. Twelve samples were IgM antibody positive. Immunodiffusion serology was similar to IgM antibody results with 13 positive tests. Diagnostic likelihood ratios for benign disease were 0.62, 0.33, and 0.28 for FDG-PET/CT, IgG, and IgM antibodies, respectively. When both IgG and IgM were positive ( n = 8), no nodules were cancerous and six were FDG-PET/CT avid., Conclusions: A positive EIA test for both IgM and IgG strongly suggested histoplasmosis etiology and benign granuloma for 12% of benign nodules arising from a highly endemic region. Presence of either IgG or IgM histoplasma antibodies was associated with benign disease. The EIA test was more sensitive in assessing histoplasma exposure than immunodiffusion serology., Impact: A new CLIA-certified histoplasmosis antibody EIA test measures histoplasmosis exposure, offers a possible alternative clinical diagnosis for benign IPNs, and may improve IPN evaluation while avoiding harmful invasive biopsies., (©2018 American Association for Cancer Research.)

Unlabelled: Here, we report that novel epidermal growth factor receptor (EGFR) gene fusions comprising the N-terminal of EGFR linked to various fusion partners, most commonly RAD51, are recurrent in lung cancer. We describe five patients with metastatic lung cancer whose tumors harbored EGFR fusions, four of whom were treated with EGFR tyrosine kinase inhibitors (TKI) with documented antitumor responses. In vitro, EGFR-RAD51 fusions are oncogenic and can be therapeutically targeted with available EGFR TKIs and therapeutic antibodies. These results support the dependence of EGFR-rearranged tumors on EGFR-mediated signaling and suggest several therapeutic strategies for patients whose tumors harbor this novel alteration., Significance: We report for the first time the identification and therapeutic targeting of EGFR C-terminal fusions in patients with lung cancer and document responses to the EGFR inhibitor erlotinib in 4 patients whose tumors harbored EGFR fusions. Findings from these studies will be immediately translatable to the clinic, as there are already several approved EGFR inhibitors. Cancer Discov; 6(6); 601-11. ©2016 AACR.See related commentary by Paik, p. 574This article is highlighted in the In This Issue feature, p. 561., (©2016 American Association for Cancer Research.)

We identified acyl-coenzyme A-binding protein (ACBP) as part of a proteomic signature predicting the risk of having lung cancer. Because ACBP is known to regulate β-oxidation, which in turn controls cellular proliferation, we hypothesized that ACBP contributes to regulation of cellular proliferation and survival of non-small cell lung cancer (NSCLC) by modulating β-oxidation. We used matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS) and immunohistochemistry (IHC) to confirm the tissue localization of ABCP in pre-invasive and invasive NSCLCs. We correlated ACBP gene expression levels in NSCLCs with clinical outcomes. In loss-of-function studies, we tested the effect of the downregulation of ACBP on cellular proliferation and apoptosis in normal bronchial and NSCLC cell lines. Using tritiated-palmitate ((3)H-palmitate), we measured β-oxidation levels and tested the effect of etomoxir, a β-oxidation inhibitor, on proliferation and apoptosis. MALDI-IMS and IHC analysis confirmed that ACBP is overexpressed in pre-invasive and invasive lung cancers. High ACBP gene expression levels in NSCLCs correlated with worse survival (HR = 1.73). We observed a 40% decrease in β-oxidation and concordant decreases in proliferation and increases in apoptosis in ACBP-depleted NSCLC cells as compared with bronchial airway epithelial cells. Inhibition of β-oxidation by etomoxir in ACBP-overexpressing cells produced dose-dependent decrease in proliferation and increase in apoptosis (P = 0.01 and P < 0.001, respectively). These data suggest a role for ACBP in controlling lung cancer progression by regulating β-oxidation., (©2014 American Association for Cancer Research.)

Adenomatous polyps are known precursor lesions for colorectal cancer and some hyperplastic polyps also have malignant potential. The use of aspirin and nonsteroidal anti-inflammatory drugs (NSAID) is associated with a reduced risk of adenomatous polyps; however, less evidence exists with regard to NSAID use and hyperplastic polyp risk. We conducted a colonoscopy-based case-control study including 2,028 polyp cases (1,529 adenomatous and 499 hyperplastic) and 3,431 polyp-free controls. Multivariate logistic regression models were constructed to derived adjusted ORs and 95% CIs as the measure of the association between NSAID use and polyp risk. Use of baby aspirin, regular aspirin, and nonaspirin NSAIDs, were associated with a reduced risk of adenomatous polyps (OR = 0.79, 95% CI: 0.66-0.93, OR = 0.73, 95% CI: 0.58-0.90, and OR = 0.67, 95% CI: 0.53-0.86, respectively). Baby aspirin was also associated with a reduced risk of hyperplastic polyps (OR = 0.74, 0.56-0.97). Although a dose response was seen with adenoma risk and regular use of any NSAIDs (less than 7 doses per week, 7 doses per week, and greater than 7 doses per week), a dose response was not seen with hyperplastic polyps. We found no evidence of interaction between NSAID dose and duration and polyp risk. The use of any NSAID regardless of type was associated with a reduced risk of adenomatous polyps; however, regular aspirin and COX-2 inhibitors use was not associated with hyperplastic polyp risk.

DNA-dependent protein kinase (DNA-PK)-defective severe combined immunodeficient (SCID) mice have a greater sensitivity to ionizing radiation compared with wild-type mice due to deficient repair of DNA double-strand break. SCID cells were therefore studied to determine whether radiosensitization by the specific inhibitor of DNA-PK, IC87361, is eliminated in the absence of functional DNA-PK. IC87361 enhanced radiation sensitivity in wild-type C57BL6 endothelial cells but not in SCID cells. The tumor vascular window model was used to assess IC87361-induced radiosensitization of SCID and wild-type tumor microvasculature. Vascular density was 5% in irradiated SCID host compared with 50% in C57BL6 mice (P < 0.05). IC87361 induced radiosensitization of tumor microvasculature in wild-type mice that resembled the radiosensitive phenotype of tumor vessels in SCID mice. Radiosensitization by IC87361 was eliminated in SCID tumor vasculature, which lack functional DNA-PK. Irradiated LLC and B16F0 tumors implanted into SCID mice showed greater tumor growth delay compared with tumors implanted into either wild-type C57BL6 or nude mice. Furthermore, LLC tumors treated with radiation and IC87361 showed tumor growth delay that was significantly greater than tumors treated with radiation alone (P < 0.01 for 3 Gy alone versus 3 Gy + IC87361). DNA-PK inhibitors induced no cytotoxicity and no toxicity in mouse normal tissues. Mouse models deficient in enzyme activity are useful to assess the specificity of novel kinase inhibitors. DNA-PK is an important target for the development of novel radiation-sensitizing drugs that have little intrinsic cytotoxicity.