KRAS mutations are present in over 90% of pancreatic ductal adenocarcinomas (PDAC), and drive their poor outcomes and failure to respond to targeted therapies. Here we show that Leukemia Inhibitory Factor (LIF) expression is induced specifically by oncogenic KRAS in PDAC and that LIF depletion by genetic means or by neutralizing antibodies prevents engraftment in pancreatic xenograft models. Moreover, LIF-neutralizing antibodies synergize with gemcitabine to eradicate established pancreatic tumors in a syngeneic, Kras G12D -driven, PDAC mouse model. The related cytokine IL-6 cannot substitute for LIF, suggesting that LIF mediates KRAS-driven malignancies through a non-STAT-signaling pathway. Unlike IL-6, LIF inhibits the activity of the Hippo-signaling pathway in PDACs. Depletion of YAP inhibits the function of LIF in human PDAC cells. Our data suggest a crucial role of LIF in KRAS-driven pancreatic cancer and that blockade of LIF by neutralizing antibodies represents an attractive approach to improving therapeutic outcomes.

Purpose: The recent emergence of radioligand therapies for cancer treatment has increased enthusiasm for developing new theranostic strategies coupling both imaging and cytotoxicity in the same entity. In this study, we evaluated whether CUB domain containing protein 1 (CDCP1), a single-pass transmembrane protein highly overexpressed in diverse human cancers, might be a target for cancer theranostics.Experimental Design: The ectodomain of CDCP1 was targeted using radiolabeled forms of 4A06, a potent and specific recombinant human antibody that we developed. Imaging and antitumor assessment studies were performed in animal models of pancreatic cancer, including two patient-derived xenograft models we developed for this study. For antitumor assessment studies, the endpoints were death due to tumor volume >3,000 mm 3 or ≥20% loss in body weight. Specific tracer binding or antitumor effects were assessed with an unpaired, two-tailed Student t test and survival advantages were assessed with a log rank (Mantel-Cox) test. Differences at the 95% confidence level were interpreted to be significant.Results: 89 Zr-4A06 detected a broad dynamic range of full length or cleaved CDCP1 expression on seven human pancreatic cancer tumors (n ¼ 4/tumor). Treating mice with single or fractionated doses of 177 Lu-4A06 significantly reduced pancreatic cancer tumor volume compared with mice receiving vehicle or unlabeled 4A06 (n ¼ 8; P < 0.01). A single dose of 225 Ac-4A06 also inhibited tumor growth, although the effect was less profound compared with 177 Lu-4A06 (n ¼ 8; P < 0.01). A significant survival advantage was imparted by 225 Ac-4A06 (HR ¼ 2.56; P < 0.05).Conclusions: These data establish that CDCP1 can be exploited for theranostics, a finding with widespread implications given its breadth of overexpression in cancer.

Purpose Pancreatic cysts are estimated to be present 2–3% of the adult population. Unfortunately, current diagnostics do not accurately distinguish benign cysts from those that can progress into invasive cancer. Missregulated pericellular proteolysis is a hallmark of malignancy, and therefore, we used a global approach to discover protease activities that differentiate benign nonmucinous cysts from premalignant mucinous cysts. Experimental Design We employed an unbiased and global protease profiling approach to discover protease activities in 23 cyst fluid samples. The distinguishing activities of select proteases was confirmed in 110 samples using specific fluorogenic substrates and required less than 5 µL of cyst fluid. Results We determined that the activities of the aspartyl proteases gastricsin and cathepsin E are highly increased in fluid from mucinous cysts. Immunohistochemical analysis revealed that gastricsin expression was associated with regions of low-grade dysplasia, whereas cathepsin E expression was independent of dysplasia grade. Gastricsin activity differentiated mucinous from nonmucinous cysts with a specificity of 100% and a sensitivity of 93%, whereas cathepsin E activity was 92% specific and 70% sensitive. Gastricsin significantly outperformed the most widely used molecular biomarker, carcinoembryonic antigen (CEA), which demonstrated 94% specificity and 65% sensitivity. Combined analysis of gastricsin and CEA resulted in a near perfect classifier with 100% specificity and 98% sensitivity. Conclusions Quantitation of gastricsin and cathepsin E activities accurately distinguished mucinous from nonmucinous pancreatic cysts and has the potential to replace current diagnostics for analysis of these highly prevalent lesions.

Purpose:To compare the agreement of three-dimensional (3D) tumor measurements for therapeutic response assessment of Ewing sarcoma according to the Children's Oncology Group (COG) criteria, one-dimensional (1D) Response Evaluation Criteria in Solid Tumors (RECIST), and two-dimensional (2D) measurements defined by the World Health Organization (WHO) with tumor volume measurements as the standard of reference and to determine which method correlates best with clinical outcomes. Materials andMethods:This retrospective study was approved by the institutional review board of three institutions. Seventy-four patients (mean age 6 standard deviation, 14.5 years 6 6.5) with newly diagnosed Ewing sarcoma treated at three medical centers were evaluated. Primary tumor size was assessed on pre-and posttreatment magnetic resonance images according to 1D RECIST, 2D WHO, and 3D COG measurements. Tumor responses were compared with the standard of reference (tumor volume) on the basis of RECIST, COG, and WHO therapeutic response thresholds. Agreement between the percentage reduction measurements of the methods was assessed with concordance correlation, Bland-Altman analysis, and Spearman rank correlation. Agreement between therapeutic responses was assessed with Kendall tau and unweighted k statistics. Tumor responses were compared with patient survival by using the log-rank test, Kaplan-Meier plots, and Cox regression. Results:Agreement with the reference standard was significantly better for 3D measurement than for 1D and 2D measurements on the basis of RECIST and COG therapeutic response thresholds (concordance correlation of 0.41, 0.72, and 0.84 for 1D, 2D, and 3D measurements, respectively; P , .0001). Comparison of overall survival of responders and nonresponders demonstrated P values of .4133, .0112, .0032, and .0027 for 1D, 2D, 3D, and volume measurements, respectively, indicating that higher dimensional measurements were significantly better predictors of overall survival. Conclusion:The 3D tumor measurements according to COG are better predictors of therapeutic response of Ewing sarcoma than 1D RECIST or 2D WHO measurements and show a significantly higher correlation with clinical outcomes.q RSNA, 2016

Background Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue of children and young adults. Patients with ES are treated with intensive chemotherapy regimens. We describe predictors of acute chemotherapy-associated toxicity in this population. Procedure In this retrospective cohort study, records of ES patients treated at two academic medical centers between 1980 and 2010 were reviewed. Grade 3 and 4 non-hematologic chemotherapy-associated toxicities during frontline therapy were recorded for each patient, along with potential clinical and demographic predictors of toxicity. Bivariate analyses were performed using the Fisher exact test. Multivariate analysis was performed using logistic regression. Results The cohort included 142 patients with ES and toxicity data. In bivariate analyses, age <12 years at diagnosis, Latino ethnicity, low family income, and treatment on a clinical trial were associated with higher incidence of toxicity (p <0.01). Tumor size, site, stage, mode of local control, body mass index, overall chemotherapy exposure and dose-intensity were not associated with toxicity. In multivariate analysis, low income (odds ratio (OR) 4.97, 95% CI 1.9–13.1), clinical trial enrollment (OR 3.67, 95% CI 1.2–10.9), pelvic tumor site (OR 3.88, 95% CI 1.17–12.88), and age <12 years (OR 2.8, 95% CI 1.0–7.5) were independent predictors of toxicity. Conclusion ES patients who are younger, of Latino ethnicity, have pelvic tumors or low income have higher rates of toxicity that may require increased supportive care. Treatment on a clinical trial was also associated with higher rates of toxicity, though this finding may reflect better reporting in these patients.

Background Ewing sarcoma (ES) is a malignancy of bone and soft tissue in children and adults. Previous registry-based studies indicate that Latino patients with ES have inferior outcomes compared to non-Latino patients, though an etiology for this difference could not be identified. To explore possible differences that might underlie this disparity, we conducted a retrospective study to compare clinical characteristics, tumor features, healthcare access, and treatment outcomes between Latino and non-Latino patients with ES. Methods Primary data for 218 ES patients treated at two academic medical centers between 1980 and 2010 were collected. Categorical data were compared using Fisher exact tests; Wilcoxon rank-sum tests were used for continuous variables. Survival was estimated using Kaplan-Meier analysis and compared using log-rank testing. Results Latino patients were diagnosed at a younger age (p=0.014). All other clinical and histological data were similar between groups, including radiologic and histologic response to neoadjuvant chemotherapy. Latino patients had lower socioeconomic status (p=0.001), were less likely to have insurance (p=0.001), and were more likely to present to the emergency room at onset of symptoms (p= 0.031) rather than to primary care physicians. Five-year event free survival (EFS) and overall survival (OS) were similar between Latino and non-Latino patients (EFS: 60.5% vs. 50.9% p=0.37; OS: 77.6% vs. 68.6% p=0.54). Conclusion Latino patients with ES present at a younger age, and have evidence of impaired access to healthcare. Response to initial therapy appears similar between Latino and non-Latino patients.

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These results suggest that the combination of ixabepilone and mitoxantrone is feasible and active in CRPC and requires dosing with pegfilgrastim.