Browsing by Subject "Pancreatic Neoplasms"

Now showing 1 - 10 of 10
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    A Collimator Setting Optimization Algorithm for Dual-Arc Volumetric Modulated Arc Therapy in Pancreas Stereotactic Body Radiation Therapy.
    (Technology in cancer research & treatment, 2019-01) Li, Xinyi; Wu, Jackie; Palta, Manisha; Zhang, You; Sheng, Yang; Zhang, Jiahan; Wang, Chunhao
    PURPOSE:To optimize collimator setting to improve dosimetric quality of pancreas volumetric modulated arc therapy plan for stereotactic body radiation therapy. MATERIALS AND METHODS:Fifty-five volumetric modulated arc therapy cases in stereotactic body radiation therapy of pancreas were retrospectively included in this study with internal review board approval. Different from the routine practice of initializing collimator settings with a template, the proposed algorithm simultaneously optimizes the collimator angles and jaw positions that are customized to the patient geometry. Specifically, this algorithm includes 2 key steps: (1) an iterative optimization algorithm via simulated annealing that generates a set of potential collimator settings from 39 cases with pancreas stereotactic body radiation therapy, and (2) a multi-leaf collimator modulation scoring system that makes the final decision of the optimal collimator settings (collimator angles and jaw positions) based on organs at risk sparing criteria. For validation, the other 16 cases with pancreas stereotactic body radiation therapy were analyzed. Two plans were generated for each validation case, with one plan optimized using the proposed algorithm (Planopt) and the other plan with the template setting (Planconv). Each plan was optimized with 2 full arcs and the same set of constraints for the same case. Dosimetric results were analyzed and compared, including target dose coverage, conformity, organs at risk maximum dose, and modulation complexity score. All results were tested by Wilcoxon signed rank tests, and the statistical significance level was set to .05. RESULTS:Both plan groups had comparable target dose coverage and mean doses of all organs at risk. However, organs at risk (stomach, duodenum, large/small bowel) maximum dose sparing (D0.1 cc and D0.03 cc) was improved in Planopt compared to Planconv. Planopt also showed lower modulation complexity score, which suggests better capability of handling complex shape and sparing organs at risk . CONCLUSIONS:The proposed collimator settings optimization algorithm successfully improved dosimetric performance for dual-arc pancreas volumetric modulated arc therapy plans in stereotactic body radiation therapy of pancreas. This algorithm has the capability of immediate clinical application.
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    A PK2/Bv8/PROK2 antagonist suppresses tumorigenic processes by inhibiting angiogenesis in glioma and blocking myeloid cell infiltration in pancreatic cancer.
    (2011) Curtis, Valerie Forbes
    In many cancer types, infiltration of bone marrow-derived myeloid cells in the tumor microenvironment is often associated with enhanced angiogenesis and tumor progression, resulting in poor prognosis. The polypeptide chemokine PK2 (Bv8) regulates myeloid cell mobilization from the bone marrow, leading to activation of angiogenesis as well as accumulation of macrophages and neutrophils in the tumor site. Neutralizing antibodies against PK2 display potent anti-tumor efficacy, illustrating the potential of PK2-antagonists as therapeutic agents for the treatment of cancer. However, antibody-based therapies can be too large to treat certain diseases and too expensive to manufacture while small molecule therapeutics are not prohibitive in these ways. In this study, we demonstrate the anti-tumor activity of a small molecule PK2 antagonist, PKRA7, in the contexts of glioblastoma and pancreatic cancer xenograft tumor models. In the highly vascularized glioblastoma, PKRA7 decreased blood vessel density while increasing necrotic areas in the tumor mass. Consistent with the anti-angiogenic activity of PKRA7 in vivo, this compound effectively reduced PK2-induced microvascular endothelial cell branching in vitro. For the poorly vascularized pancreatic cancer, the primary anti-tumor effect of PKRA7 is mediated by the blockage of myeloid cell migration and infiltration. At the molecular level, PKRA7 inhibits PK2-induced expression of several pro-migratory chemokines and chemokine receptors in macrophages. Combining PKRA7 treatment with standard chemotherapeutic agents resulted in enhanced effects in xenograft models for both glioblastoma and pancreatic tumors. Taken together, our results indicate that the anti-tumor activity of PKRA7 can be mediated by distinct mechanisms that are relevant to the pathological features of the specific type of cancer. This small molecule PK2 antagonist holds the promise to be further developed as an effective agent for combinational cancer therapy.
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    Adjuvant radiotherapy in the treatment of invasive intraductal papillary mucinous neoplasm of the pancreas: an analysis of the surveillance, epidemiology, and end results registry.
    (Ann Surg Oncol, 2012-04) Worni, M; Akushevich, I; Gloor, B; Scarborough, J; Chino, JP; Jacobs, DO; Hahn, SM; Clary, BM; Pietrobon, R; Shah, A
    BACKGROUND: Management and outcomes of patients with invasive intraductal papillary mucinous neoplasm (IPMN) of the pancreas are not well established. We investigated whether adjuvant radiotherapy (RT) improved cancer-specific survival (CSS) and overall survival (OS) among patients undergoing surgical resection for invasive IPMN. METHODS: The Surveillance, Epidemiology, and End Results (SEER) registry was used in this retrospective cohort study. All adult patients with resection of invasive IPMN from 1988 to 2007 were included. CSS and OS were analyzed using Kaplan-Meier curves. Unadjusted and propensity-score-adjusted Cox proportional-hazards modeling were used for subgroup analyses. RESULTS: 972 patients were included. Adjuvant RT was administered to 31.8% (n=309) of patients. There was no difference in overall median CSS or OS in patients who received adjuvant RT (5-year CSS: 26.5 months; 5-year OS: 23.5 months) versus those who did not (CSS: 28.5 months, P=0.17; OS: 23.5 months, P=0.23). Univariate predictors of survival were lymph node (LN) involvement, T4-classified tumors, and poorly differentiated tumor grade (all P<0.05). In the propensity-score-adjusted analysis, adjuvant RT was associated with improved 5-year CSS [hazard ratio (HR): 0.67, P=0.004] and 5-year OS (HR: 0.73, P=0.014) among all patients with LN involvement, though further analysis by T-classification demonstrated no survival differences among patients with T1/T2 disease; patients with T3/T4-classified tumors had improved CSS (HR: 0.71, P=0.022) but no difference in OS (HR: 0.76, P=0.06). CONCLUSION: On propensity-score-adjusted analysis, adjuvant RT was associated with improved survival in selected subsets of patients with invasive IPMN, particularly those with T3/T4 tumors and LN involvement.
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    Brachytherapy via a depot of biopolymer-bound 131I synergizes with nanoparticle paclitaxel in therapy-resistant pancreatic tumours.
    (Nature biomedical engineering, 2022-10) Schaal, Jeffrey L; Bhattacharyya, Jayanta; Brownstein, Jeremy; Strickland, Kyle C; Kelly, Garrett; Saha, Soumen; Milligan, Joshua; Banskota, Samagya; Li, Xinghai; Liu, Wenge; Kirsch, David G; Zalutsky, Michael R; Chilkoti, Ashutosh
    Locally advanced pancreatic tumours are highly resistant to conventional radiochemotherapy. Here we show that such resistance can be surmounted by an injectable depot of thermally responsive elastin-like polypeptide (ELP) conjugated with iodine-131 radionuclides (131I-ELP) when combined with systemically delivered nanoparticle albumin-bound paclitaxel. This combination therapy induced complete tumour regressions in diverse subcutaneous and orthotopic mouse models of locoregional pancreatic tumours. 131I-ELP brachytherapy was effective independently of the paclitaxel formulation and dose, but external beam radiotherapy (EBRT) only achieved tumour-growth inhibition when co-administered with nanoparticle paclitaxel. Histological analyses revealed that 131I-ELP brachytherapy led to changes in the expression of intercellular collagen and junctional proteins within the tumour microenvironment. These changes, which differed from those of EBRT-treated tumours, correlated with the improved delivery and accumulation of paclitaxel nanoparticles within the tumour. Our findings support the further translational development of 131I-ELP depots for the synergistic treatment of localized pancreatic cancer.
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    Clinical Insights Into the Biology and Treatment of Pancreatic Cancer.
    (J Oncol Pract, 2016-01) Mettu, Niharika B; Abbruzzese, James L
    Pancreatic cancer is a devastating disease with a universally poor prognosis. In 2015, it is estimated that there will be 48,960 new cases of pancreatic cancer and that 40,560 people will die of the disease. The 5-year survival rate is 7.2% for all patients with pancreatic cancer; however, survival depends greatly on the stage at diagnosis. Unfortunately, 53% of patients already have metastatic disease at diagnosis, which corresponds to a 5-year survival rate of 2.4%. Even for the 9% of patients with localized disease confined to the pancreas, the 5-year survival is still modest at only 27.1%. These grim statistics highlight the need for ways to identify cohorts of individuals at highest risk, methods to screen those at highest risk to identify preinvasive pathologic precursors, and development of effective systemic therapies. Recent clinical and translational progress has emphasized the relationship with diabetes, the role of the stroma, and the interplay of each of these with inflammation in the pathobiology of pancreatic cancer. In this article, we will discuss these relationships and how they might translate into novel management strategies for the treatment of this disease.
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    Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance.
    (Nature medicine, 2017-05) Daley, Donnele; Mani, Vishnu R; Mohan, Navyatha; Akkad, Neha; Ochi, Atsuo; Heindel, Daniel W; Lee, Ki Buom; Zambirinis, Constantinos P; Pandian, Gautam Sd Balasubramania; Savadkar, Shivraj; Torres-Hernandez, Alejandro; Nayak, Shruti; Wang, Ding; Hundeyin, Mautin; Diskin, Brian; Aykut, Berk; Werba, Gregor; Barilla, Rocky M; Rodriguez, Robert; Chang, Steven; Gardner, Lawrence; Mahal, Lara K; Ueberheide, Beatrix; Miller, George
    The progression of pancreatic oncogenesis requires immune-suppressive inflammation in cooperation with oncogenic mutations. However, the drivers of intratumoral immune tolerance are uncertain. Dectin 1 is an innate immune receptor crucial for anti-fungal immunity, but its role in sterile inflammation and oncogenesis has not been well defined. Furthermore, non-pathogen-derived ligands for dectin 1 have not been characterized. We found that dectin 1 is highly expressed on macrophages in pancreatic ductal adenocarcinoma (PDA). Dectin 1 ligation accelerated the progression of PDA in mice, whereas deletion of Clec7a-the gene encoding dectin 1-or blockade of dectin 1 downstream signaling was protective. We found that dectin 1 can ligate the lectin galectin 9 in mouse and human PDA, which results in tolerogenic macrophage programming and adaptive immune suppression. Upon disruption of the dectin 1-galectin 9 axis, CD4+ and CD8+ T cells, which are dispensable for PDA progression in hosts with an intact signaling axis, become reprogrammed into indispensable mediators of anti-tumor immunity. These data suggest that targeting dectin 1 signaling is an attractive strategy for developing an immunotherapy for PDA.
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    Genetic variants in the platelet-derived growth factor subunit B gene associated with pancreatic cancer risk.
    (International journal of cancer, 2018-04) Duan, Bensong; Hu, Jiangfeng; Liu, Hongliang; Wang, Yanru; Li, Hongyu; Liu, Shun; Xie, Jichun; Owzar, Kouros; Abbruzzese, James; Hurwitz, Herbert; Gao, Hengjun; Wei, Qingyi
    The platelet-derived growth factor (PDGF) signaling pathway plays important roles in development and progression of human cancers. In our study, we aimed to identify genetic variants of the PDGF pathway genes associated with pancreatic cancer (PC) risk in European populations using three published genome-wide association study datasets, which consisted of 9,381 cases and 7,719 controls. The expression quantitative trait loci (eQTL) analysis was also performed using data from the 1000 Genomes, TCGA and GTEx projects. As a result, we identified two potential susceptibility loci (rs5757573 and rs6001516) of PDGFB associated with PC risk [odds ratio (OR) = 1.10, 95% confidence interval (CI) = 1.05-1.16, and p = 4.70 × 10-5 for the rs5757573 C allele and 1.21, 1.11-1.32, and 2.01 × 10-5 for the rs6001516 T allele]. Haplotype analysis revealed that the C-T haplotype carriers had a significantly increased risk of PC than those carrying the T-C haplotype (OR = 1.23, 95% CI = 1.12-1.34, p =5.00 × 10-6 ). The multivariate regression model incorporating the number of unfavorable genotypes (NUGs) with age and sex showed that carriers with 1-2 NUGs, particularly among 60-70 age group or males, had an increased risk of PC, compared to those without NUG. Furthermore, the eQTL analysis revealed that both loci were correlated with a decreased mRNA expression level of PDGFB in lymphoblastoid cell lines and pancreatic tumor tissues (p = 0.015 and 0.071, respectively). Our results suggest that genetic variants in PDGFB may play a role in susceptibility to PC. Further population and functional validations of our findings are warranted.
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    NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma.
    (The Journal of experimental medicine, 2017-06) Daley, Donnele; Mani, Vishnu R; Mohan, Navyatha; Akkad, Neha; Pandian, Gautam SD Balasubramania; Savadkar, Shivraj; Lee, Ki Buom; Torres-Hernandez, Alejandro; Aykut, Berk; Diskin, Brian; Wang, Wei; Farooq, Mohammad S; Mahmud, Arif I; Werba, Gregor; Morales, Eduardo J; Lall, Sarah; Wadowski, Benjamin J; Rubin, Amanda G; Berman, Matthew E; Narayanan, Rajkishen; Hundeyin, Mautin; Miller, George
    The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance, which enables disease to progress unabated by adaptive immunity. However, the drivers of this tolerogenic program are incompletely defined. In this study, we found that NLRP3 promotes expansion of immune-suppressive macrophages in PDA. NLRP3 signaling in macrophages drives the differentiation of CD4+ T cells into tumor-promoting T helper type 2 cell (Th2 cell), Th17 cell, and regulatory T cell populations while suppressing Th1 cell polarization and cytotoxic CD8+ T cell activation. The suppressive effects of NLRP3 signaling were IL-10 dependent. Pharmacological inhibition or deletion of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD complex), or caspase-1 protected against PDA and was associated with immunogenic reprogramming of innate and adaptive immunity within the TME. Similarly, transfer of PDA-entrained macrophages or T cells from NLRP3-/- hosts was protective. These data suggest that targeting NLRP3 holds the promise for the immunotherapy of PDA.
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    PPDPF Promotes the Development of Mutant KRAS-Driven Pancreatic Ductal Adenocarcinoma by Regulating the GEF Activity of SOS1.
    (Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2023-01) Ni, Qian-Zhi; Zhu, Bing; Ji, Yan; Zheng, Qian-Wen; Liang, Xin; Ma, Ning; Jiang, Hao; Zhang, Feng-Kun; Shang, Yu-Rong; Wang, Yi-Kang; Xu, Sheng; Zhang, Er-Bin; Yuan, Yan-Mei; Chen, Tian-Wei; Yin, Fen-Fen; Cao, Hui-Jun; Huang, Jing-Yi; Xia, Ji; Ding, Xu-Fen; Qiu, Xiao-Song; Ding, Kai; Song, Chao; Zhou, Wen-Tao; Wu, Meng; Wang, Kang; Lui, Rui; Lin, Qiu; Chen, Wei; Li, Zhi-Gang; Cheng, Shu-Qun; Wang, Xiao-Fan; Xie, Dong; Li, Jing-Jing
    The guanine nucleotide exchange factor (GEF) SOS1 catalyzes the exchange of GDP for GTP on RAS. However, regulation of the GEF activity remains elusive. Here, the authors report that PPDPF functions as an important regulator of SOS1. The expression of PPDPF is significantly increased in pancreatic ductal adenocarcinoma (PDAC), associated with poor prognosis and recurrence of PDAC patients. Overexpression of PPDPF promotes PDAC cell growth in vitro and in vivo, while PPDPF knockout exerts opposite effects. Pancreatic-specific deletion of PPDPF profoundly inhibits tumor development in KRASG12D -driven genetic mouse models of PDAC. PPDPF can bind GTP and transfer GTP to SOS1. Mutations of the GTP-binding sites severely impair the tumor-promoting effect of PPDPF. Consistently, mutations of the critical amino acids mediating SOS1-PPDPF interaction significantly impair the GEF activity of SOS1. Therefore, this study demonstrates a novel model of KRAS activation via PPDPF-SOS1 axis, and provides a promising therapeutic target for PDAC.
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    Three novel genetic variants in NRF2 signaling pathway genes are associated with pancreatic cancer risk.
    (Cancer science, 2019-06) Yang, Wenjun; Liu, Hongliang; Duan, Bensong; Xu, Xinyuan; Carmody, Dennis; Luo, Sheng; Walsh, Kyle M; Abbruzzese, James L; Zhang, Xuefeng; Chen, Xiaoxin; Wei, Qingyi
    Pancreatic cancer (PanC) is one of the most lethal solid malignancies, and metastatic PanC is often present at the time of diagnosis. Although several high- and low-penetrance genes have been implicated in PanC, their roles in carcinogenesis remain only partially elucidated. Because the nuclear factor erythroid2-related factor2 (NRF2) signaling pathway is involved in human cancers, we hypothesize that genetic variants in NRF2 pathway genes are associated with PanC risk. To test this hypothesis, we assessed associations between 31 583 common single nucleotide polymorphisms (SNP) in 164 NRF2-related genes and PanC risk using three published genome-wide association study (GWAS) datasets, which included 8474 cases and 6944 controls of European descent. We also carried out expression quantitative trait loci (eQTL) analysis to assess the genotype-phenotype correlation of the identified significant SNP using publicly available data in the 1000 Genomes Project. We found that three novel SNP (ie, rs3124761, rs17458086 and rs1630747) were significantly associated with PanC risk (P = 5.17 × 10-7 , 5.61 × 10-4 and 5.52 × 10-4 , respectively). Combined analysis using the number of unfavorable genotypes (NUG) of these three SNP suggested that carriers of two to three NUG had an increased risk of PanC (P < 0.0001), compared with those carrying zero to one NUG. Furthermore, eQTL analysis showed that both rs3124761 T and rs17458086 C alleles were associated with increased mRNA expression levels of SLC2A6 and SLC2A13, respectively (P < 0.05). In conclusion, genetic variants in NRF2 pathway genes could play a role in susceptibility to PanC, and further functional exploration of the underlying molecular mechanisms is warranted.