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Item A risk prediction tool for individuals with a family history of breast, ovarian, or pancreatic cancer: BRCAPANCPRO(Springer Nature, 2021) Blackford, Amanda L.; Childs, Erica J.; Porter, Nancy; Petersen, Gloria M.; Rabe, Kari G.; Gallinger, Steven; Borgida, Ayelet; Syngal, Sapna; Cote, Michele L.; Schwartz, Ann G.; Goggins, Michael G.; Hruban, Ralph H.; Parmigiani, Giovanni; Klein, Alison P.; Epidemiology, Richard M. Fairbanks School of Public HealthIntroduction: Identifying families with an underlying inherited cancer predisposition is a major goal of cancer prevention efforts. Mendelian risk models have been developed to better predict the risk associated with a pathogenic variant of developing breast/ovarian cancer (with BRCAPRO) and the risk of developing pancreatic cancer (PANCPRO). Given that pathogenic variants involving BRCA2 and BRCA1 predispose to all three of these cancers, we developed a joint risk model to capture shared susceptibility. Methods: We expanded the existing framework for PANCPRO and BRCAPRO to jointly model risk of pancreatic, breast, and ovarian cancer and validated this new model, BRCAPANCPRO on three data sets each reflecting the common target populations. Results: BRCAPANCPRO outperformed the prior BRCAPRO and PANCPRO models and yielded good discrimination for differentiating BRCA1 and BRCA2 carriers from non-carriers (AUCs 0.79, 95% CI: 0.73-0.84 and 0.70, 95% CI: 0.60-0.80) in families seen in high-risk clinics and pancreatic cancer family registries, respectively. In addition, BRCAPANCPRO was reasonably well calibrated for predicting future risk of pancreatic cancer (observed-to-expected (O/E) ratio = 0.81 [0.69, 0.94]). Discussion: The BRCAPANCPRO model provides improved risk assessment over our previous risk models, particularly for pedigrees with a co-occurrence of pancreatic cancer and breast and/or ovarian cancer.Item Advanced endoscopic ultrasound management techniques for preneoplastic pancreatic cystic lesions(BMJ, 2017-01) Arshad, Hafiz Muhammad Sharjeel; Bharmal, Sheila; Duman, Deniz Guney; Liangpunsakul, Suthat; Turner, Brian G.; Department of Medicine, IU School of MedicinePancreatic cystic lesions can be benign, premalignant or malignant. The recent increase in detection and tremendous clinical variability of pancreatic cysts has presented a significant therapeutic challenge to physicians. Mucinous cystic neoplasms are of particular interest given their known malignant potential. This review article provides a brief but comprehensive review of premalignant pancreatic cystic lesions with advanced endoscopic ultrasound (EUS) management approaches. A comprehensive literature search was performed using PubMed, Cochrane, OVID and EMBASE databases. Preneoplastic pancreatic cystic lesions include mucinous cystadenoma and intraductal papillary mucinous neoplasm. The 2012 International Sendai Guidelines guide physicians in their management of pancreatic cystic lesions. Some of the advanced EUS management techniques include ethanol ablation, chemotherapeutic (paclitaxel) ablation, radiofrequency ablation and cryotherapy. In future, EUS-guided injections of drug-eluting beads and neodymium:yttrium aluminum agent laser ablation is predicted to be an integral part of EUS-guided management techniques. In summary, International Sendai Consensus Guidelines should be used to make a decision regarding management of pancreatic cystic lesions. Advanced EUS techniques are proving extremely beneficial in management, especially in those patients who are at high surgical risk.Item Augmenting Experimental Gastric Cancer Activity of Irinotecan through Liposomal Formulation and Antiangiogenic Combination Therapy(American Association for Cancer Research, 2022) Awasthi, Niranjan; Schwarz, Margaret A.; Zhang, Changhua; Klinz, Stephan G.; Meyer-Losic, Florence; Beaufils, Benjamin; Thiagalingam, Arunthathi; Schwarz, Roderich E.; Surgery, School of MedicineGastric adenocarcinoma (GAC) is the third most common cause of cancer-related deaths worldwide. Combination chemotherapy remains the standard treatment for advanced GAC. Liposomal irinotecan (nal-IRI) has improved pharmacokinetics (PK) and drug biodistribution compared with irinotecan (IRI, CPT-11). Angiogenesis plays a crucial role in the progression and metastasis of GAC. We evaluated the antitumor efficacy of nal-IRI in combination with novel antiangiogenic agents in GAC mouse models. Animal survival studies were performed in peritoneal dissemination xenografts. Tumor growth and PK studies were performed in subcutaneous xenografts. Compared with controls, extension in animal survival by nal-IRI and IRI was >156% and >94%, respectively. The addition of nintedanib or DC101 extended nal-IRI response by 13% and 15%, and IRI response by 37% and 31% (MKN-45 xenografts); nal-IRI response by 11% and 3%, and IRI response by 16% and 40% (KATO-III xenografts). Retardation of tumor growth was greater with nal-IRI (92%) than IRI (71%). Nintedanib and DC101 addition tend to augment nal-IRI or IRI response in this model. The addition of antiangiogenic agents enhanced tumor cell proliferation inhibition effects of nal-IRI or IRI. The tumor vasculature was decreased by nintedanib (65%) and DC101 (58%), while nal-IRI and IRI alone showed no effect. PK characterization in GAC xenografts demonstrated that compared with IRI, nal-IRI treatment groups had higher retention, circulation time, and tumor levels of CPT-11 and its active metabolite SN-38. These findings indicate that nal-IRI, alone and in combination with antiangiogenic agents, has the potential for improving clinical GAC therapy.Item Blocking muscle wasting via deletion of the muscle-specific E3 ligase MuRF1 impedes pancreatic tumor growth(Springer Nature, 2023-05-13) Neyroud, Daria; Laitano, Orlando; Dasgupta, Aneesha; Lopez, Christopher; Schmitt, Rebecca E.; Schneider, Jessica Z.; Hammers, David W.; Sweeney, H. Lee; Walter, Glenn A.; Doles, Jason; Judge, Sarah M.; Judge, Andrew R.; Anatomy, Cell Biology and Physiology, School of MedicineCancer-induced muscle wasting reduces quality of life, complicates or precludes cancer treatments, and predicts early mortality. Herein, we investigate the requirement of the muscle-specific E3 ubiquitin ligase, MuRF1, for muscle wasting induced by pancreatic cancer. Murine pancreatic cancer (KPC) cells, or saline, were injected into the pancreas of WT and MuRF1-/- mice, and tissues analyzed throughout tumor progression. KPC tumors induces progressive wasting of skeletal muscle and systemic metabolic reprogramming in WT mice, but not MuRF1-/- mice. KPC tumors from MuRF1-/- mice also grow slower, and show an accumulation of metabolites normally depleted by rapidly growing tumors. Mechanistically, MuRF1 is necessary for the KPC-induced increases in cytoskeletal and muscle contractile protein ubiquitination, and the depression of proteins that support protein synthesis. Together, these data demonstrate that MuRF1 is required for KPC-induced skeletal muscle wasting, whose deletion reprograms the systemic and tumor metabolome and delays tumor growth.Item Cyclooxygenase-2 Expression in Hamster and Human Pancreatic Neoplasia(Elsevier, 2006-06) Crowell, Pamela L.; Schmidt, C. Max; Yip-Schneider, Michele T.; Savage, Jesse J.; Hertzler II, Dean A.; Cummings, William O.; Biochemistry and Molecular Biology, School of MedicineCyclooxygenase-2 (COX-2) has been implicated in the development of gastrointestinal malignancies. The aim of the present study was to determine COX-2 expression/activity throughout stages of experimental and human pancreatic neoplasia. COX-2 immunohistochemistry was performed in pancreata of hamsters subjected to the carcinogen N-nitrosobis-(2-oxopropyl)amine (BOP) and in human pancreatic tumors. COX-2 activity was determined by prostaglandin E2 assay in tumor versus matched normal pancreatic tissues. The activity of the COX inhibitor sulindac was tested in the PC-1 hamster pancreatic cancer model. COX-2 expression was elevated in all pancreatic intraepithelial neoplasias (PanINs) and adenocarcinomas. In BOP-treated hamsters, there were significant progressive elevations in COX-2 expression throughout pancreatic tumorigenesis. In human samples, peak COX-2 expression occurred in PanIN2 lesions and remained moderately elevated in PanIN3 and adenocarcinoma tissues. COX-2 activity was significantly elevated in hamster and human pancreatic cancers compared to pair-matched normal pancreas. Furthermore, hamster pancreatic tumor engraftment/formation in the PC-1 hamster pancreatic cancer model was reduced 4.9-fold by oral administration of sulindac. Increased COX-2 expression is an early event in pancreatic carcinogeneses. The BOP-induced hamster carcinogenesis model is a representative model used to study the role of COX-2 in well-differentiated pancreatic tumorigenesis. COX inhibitors may have a role in preventing tumor engraftment/formation.Item Early-Onset Pancreas Cancer: Clinical Descriptors, Genomics, and Outcomes(Oxford University Press, 2021) Varghese, Anna M.; Singh, Isha; Singh, Rituraj; Kunte, Siddharth; Chou, Joanne F.; Capanu, Marinela; Wong, Winston; Lowery, Maeve A.; Stadler, Zsofia K.; Salo-Mullen, Erin; Saadat, Lily V.; Wei, Alice C.; Reyngold, Marsha; Basturk, Olca; Benayed, Ryma; Mandelker, Diana; Iacobuzio-Donahue, Christine A.; Kelsen, David P.; Park, Wungki; Yu, Kenneth H.; O’Reilly, Eileen M.; Medicine, School of MedicineBackground: Recent evidence suggests a rising incidence of cancer in younger individuals. Herein, we report the epidemiologic, pathologic, and molecular characteristics of a patient cohort with early-onset pancreas cancer (EOPC). Methods: Institutional databases were queried for demographics, treatment history, genomic results, and outcomes. Overall survival from date of diagnosis was estimated using Kaplan-Meier method. Results: Between 2008 and 2018, 450 patients with EOPC were identified at Memorial Sloan Kettering. Median overall survival was 16.3 (95% confidence interval [CI] = 14.6 to 17.7) months in the entire cohort and 11.3 (95% CI = 10.2 to 12.2) months for patients with stage IV disease at diagnosis. Of the patients, 132 (29.3% of the cohort) underwent somatic testing; 21 of 132 (15.9%) had RAS wild-type cancers with identification of several actionable alterations, including ETV6-NTRK3, TPR-NTRK1, SCLA5-NRG1, and ATP1B1-NRG1 fusions, IDH1 R132C mutation, and mismatch repair deficiency. A total of 138 patients (30.7% of the cohort) underwent germline testing; 44 of 138 (31.9%) had a pathogenic germline variant (PGV), and 27.5% harbored alterations in cancer susceptibility genes. Of patients seen between 2015 and 2018, 30 of 193 (15.5%) had a PGV. Among 138 who underwent germline testing, those with a PGV had a reduced all-cause mortality compared with patients without a PGV controlling for stage and year of diagnosis (hazard ratio = 0.42, 95% CI = 0.26 to 0.69). Conclusions: PGVs are present in a substantial minority of patients with EOPC. Actionable somatic alterations were identified frequently in EOPC, enriched in the RAS wild-type subgroup. These observations underpin the recent guidelines for universal germline testing and somatic profiling in pancreatic ductal adenocarcinoma.Item Exploring Covalent Bond Formation at Tyr-82 for Inhibition of Ral GTPase Activation(Wiley, 2023) Landgraf, Alexander D.; Yeh, I-Ju; Ghozayel, Mona K.; Bum-Erdene, Khuchtumur; Gonzalez-Gutierrez, Giovanni; Meroueh, Samy O.; Biochemistry and Molecular Biology, School of MedicineRal RAS GTPases are directly activated by KRAS through a trimeric complex with a guanine exchange factor. Ral is considered undruggable and lacks an accessible cysteine for covalent drug development. Previously we had reported an aryl sulfonyl fluoride fragment that formed a covalent bond at Tyr-82 on Ral and created a deep and well-defined pocket. Here, we explore this pocket further through design and synthesis of several fragment derivatives. The fragment core is modified by introducing tetrahydronaphthalene or benzodioxane rings to enhance affinity and stability of the sulfonyl fluoride reactive group. The deep pocket in the Switch II region is also explored by modifying the aromatic ring of the fragment that is ensconced into the pocket. Compounds 19 (SOF-658) and 26 (SOF-648) formed a single robust adduct specifically at Tyr-82, inhibited Ral GTPase exchange in buffer and in mammalian cells, and blocked invasion of pancreatic ductal adenocarcinoma cancer cells. Compound 19 (SOF-658) was stable in buffer, mouse, and human microsomes suggesting that further optimization could lead to small molecules to probe Ral activity in tumor models.Item Exposure to perfluorooctanoic acid leads to promotion of pancreatic cancer(Oxford University Press, 2022) Kamendulis, Lisa M.; Hocevar, Jessica M.; Stephens, Mikayla; Sandusky, George E.; Hocevar, Barbara A.; Pathology and Laboratory Medicine, School of MedicinePancreatic cancer is the fourth leading cause of cancer deaths in the United States. Perfluorooctanoic acid (PFOA), a persistent environmental pollutant, has been shown to induce pancreatic acinar cell tumors in rats. Human epidemiologic studies have linked PFOA exposure to adverse chronic health effects including several types of cancer. Previously, we demonstrated that PFOA induces oxidative stress and focal ductal hyperplasia in the mouse pancreas. Here, we evaluated whether PFOA promotes pancreatic cancer using the LSL-KRasG12D;Pdx-1 Cre (KC) mouse model of pancreatic cancer. KC mice were exposed to 5 ppm PFOA in drinking water starting at 8 weeks of age and analyzed at 6 and 9 months of age. At the 6-month time point, PFOA exposure increased pancreatic intraepithelial neoplasia (PanIN) area by 58%, accompanied by a 2-fold increase in lesion number. Although PanIN area increased at 9 months, relative to 6 months, no treatment effect was observed. Collagen deposition was enhanced by PFOA at both the 6- and 9-month time points. PFOA also induced oxidative stress in the pancreas evidenced by elevated antioxidant activity of superoxide dismutase (Sod), catalase and thioredoxin reductase, and a ~3-fold increase in Sod1 mRNA and protein levels at 6 months. Although antioxidant activity was not enhanced by PFOA exposure at the 9-month time point, increased pancreatic oxidative damage was observed. Collectively, these results show that PFOA elicited temporal increases in PanIN lesion area and desmoplasia concomitant with the induction of oxidative stress, demonstrating that it functions to promote pancreatic cancer progression.Item Intake of methyl-related nutrients and risk of pancreatic cancer in a population-based case-control study in Minnesota(Springer Nature, 2018-08) Marley, Andrew R.; Fan, Hao; Hoyt, Margaret L.; Anderson, Kristin E.; Zhang, Jianjun; Epidemiology, School of Public HealthBACKGROUND/OBJECTIVES: Folate, vitamin B6, vitamin B12, and methionine are involved in DNA synthesis and methylation and thus may modulate pancreatic cancer risk. We investigated these associations in a population-based case-control study conducted in 1994-1998. SUBJECTS/METHODS: Cases (n = 150) were identified from all hospitals in the metropolitan areas of the Twin Cities and the Mayo Clinic, Minnesota. Controls (n = 459) were selected randomly from the general population and were frequency matched to cases by age, sex, and race. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for risk of pancreatic cancer in relation to intake of nutrients considered. RESULTS: Dietary intake of folate was associated with a reduced pancreatic cancer risk [OR (95% CI) for quartile (Q) 4 vs. Q1: 0.31 (0.12-0.78)]. A composite score (range from 2 to 8), reflecting combined dietary intake of folate and vitamin B6, was also inversely associated with pancreatic cancer risk [OR (95% CI) for Q4 vs. Q1: 0.24 (0.08-0.70)]. Null associations were found for intake of vitamin B12 and methionine. CONCLUSIONS: Dietary folate intake was associated with a reduced pancreatic cancer risk, and this association became stronger when dietary intake of folate and vitamin B6 was combined in analysis.Item Intron-Retention Neoantigen Load Predicts Favorable Prognosis in Pancreatic Cancer(American Society of Clinical Oncology, 2022) Dong, Chuanpeng; Reiter, Jill L.; Dong, Edward; Wang, Yue; Lee, Kelvin P.; Lu, Xiongbin; Liu, Yunlong; BioHealth Informatics, School of Informatics and ComputingPurpose: High tumor mutation burden (TMB) in many cancer types is associated with the production of tumor-specific neoantigens, a favorable outcome and response to immune checkpoint blockade (ICB) therapy. Besides mutation-derived neoantigens, aberrant intron retention also produces tumor neopeptides that could trigger an immune response. The relationship between intron-retention-derived tumor neoantigens (IR-neoAg) and clinical outcomes in pancreatic cancer remains uncertain. Here, we quantify IR-neoAg in pancreatic cancer and evaluate whether IR-neoAg load might serve as a biomarker for selecting patients who may benefit from ICB therapy. Methods: We developed a computational approach to estimate patient-specific IR-neoAg load from transcriptome data available in The Cancer Genome Atlas pancreatic cancer cohort. Associations between IR-neoAg load and patient overall survival were evaluated using Kaplan-Meier estimates and Cox regression. Differential expression of immune checkpoint and HLA-I genes was evaluated in tumors with high IR-neoAg load. Results: High IR-neoAg load predicted better overall survival in pancreatic cancer, although no association was found for TMB. IR-neoAg load remained a significant prognostic factor after adjusting for patient age, sex, tumor stage and grade, and TMB. Moreover, pancreatic tumors with both high IR-neoAg load and high HLA-I gene expression had similar gene expression profiles as other tumor types that showed response to anti-programmed cell death protein 1 therapy. Conclusion: IR-neoAg load is associated with favorable survival in pancreatic cancer. These findings provide strong evidence for considering IR-neoAgs when selecting patients who might benefit from ICB therapy.