Majority Of Pancreatic Cancer Patients Research Articles

NLRP4 renders pancreatic cancer resistant to olaparib through promotion of the DNA damage response and ROS-induced autophagy

Olaparib has been approved as a therapeutic option for metastatic pancreatic ductal adenocarcinoma patients with BRCA1/2 mutations. However, a significant majority of pancreatic cancer patients have inherent resistance or develop tolerance to olaparib. It is crucial to comprehend the molecular mechanism underlying olaparib resistance to facilitate the development of targeted therapies for pancreatic cancer. In this study, we conducted an analysis of the DepMap database to investigate gene expression variations associated with olaparib sensitivity. Our findings revealed that NLRP4 upregulation contributes to increased resistance to olaparib in pancreatic cancer cells, both in vitro and in vivo. RNA sequencing and Co-IP MS analysis revealed that NLRP4 is involved in the DNA damage response and autophagy pathway. Our findings confirmed that NLRP4 enhances the capacity for DNA repair and induces the production of significant levels of reactive oxygen species (ROS) and autophagy in response to treatment with olaparib. Specifically, NLRP4-generated mitochondrial ROS promote autophagy in pancreatic cancer cells upon exposure to olaparib. However, NLRP4-induced ROS do not affect DNA damage. The inhibition of mitochondrial ROS using MitoQ and autophagy using chloroquine (CQ) may render cells more susceptible to the effects of olaparib. Taken together, our findings highlight the significant roles played by NLRP4 in the processes of autophagy and DNA repair when pancreatic cancer cells are treated with olaparib, thereby suggesting the potential therapeutic utility of olaparib in pancreatic cancer patients with low NLRP4 expression.

Exploring the application and future outlook of Artificial intelligence in pancreatic cancer.

Pancreatic cancer, an exceptionally malignant tumor of the digestive system, presents a challenge due to its lack of typical early symptoms and highly invasive nature. The majority of pancreatic cancer patients are diagnosed when curative surgical resection is no longer possible, resulting in a poor overall prognosis. In recent years, the rapid progress of Artificial intelligence (AI) in the medical field has led to the extensive utilization of machine learning and deep learning as the prevailing approaches. Various models based on AI technology have been employed in the early screening, diagnosis, treatment, and prognostic prediction of pancreatic cancer patients. Furthermore, the development and application of three-dimensional visualization and augmented reality navigation techniques have also found their way into pancreatic cancer surgery. This article provides a concise summary of the current state of AI technology in pancreatic cancer and offers a promising outlook for its future applications.

Abstract C011: Detection of circulating tumor cells for the early detection of pancreatic cancer

Abstract Introduction The majority of pancreatic cancer patients are diagnosed with advanced, metastatic disease. Biomarkers to detect pancreatic cancer at earlier stages could drastically improve the poor survival rates. Circulating tumor cells (CTCs) are tumor cells that disseminate or are shed into the vascular system and have been detected in patients at pre-malignant stages. However, detecting these rare cells accurately and reliably remains a challenge. The AccuCyte-CyteFinder system uses density-based enrichment of blood nucleated cells followed by detection of CTCs using fluorescence staining, whole slide scanning and automated image analysis. This study aimed to examine whether CTCs could be used to identify patients with pancreatic lesions likely to malignant. Methods 50 patients undergoing an endoscopic ultrasound procedure for a pancreatic mass were recruited at the Royal Prince Alfred Hospital, Sydney, Australia or Chris O’Brien Lifehouse, Sydney, Australia. Peripheral blood was collected prior to the procedure and processed for CTCs on the AccuCyte-CyteFinder platform using a CK+ EpCAM+ CD45- staining panel. Results 28% (14/50) were found to have an intraductal papillary mucinous neoplasm (IPMN), 10% (5/50) pancreatic ductal adenocarcinoma (PDAC), 6% (3/50) pancreatic neuroendocrine tumor (PNET), 42% (21/50) non-neoplastic pancreatic cyst, and 14% (7/50) normal (no mass found). CTCs were highest in the PDAC group with an average of 5 cells/ml, followed by the IPMN (3 cells/ml), pancreatic cyst (2.5 cells/ml), and PNET (0 cells/ml). 86% (12/14) of IPMN patients had detectable CTCs. 2 IPMN patients with CTC counts of more than 5 cells/ml resulted in a resected sample having high-grade dysplasia while 3 IPMN patients with no/low CTC counts resulted in a resected sample having low-grade dysplasia. There was no correlation with the size of the pancreatic mass and CTC number. Conclusions CTCs could be detected in patients with pre-malignant pancreatic cancer and could determine malignancy. CTCs could potentially be used to detect pancreatic cancer early however, larger patient numbers and longer follow-up are required to validate these findings. Citation Format: Dannel Yeo, Vera Klemm, Payal Saxena, Althea Bastian, Heidi Strauss, Charbel Sandroussi, Sara Wahlroos, Peter Grimison, John E.J. Rasko. Detection of circulating tumor cells for the early detection of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C011.

Clinical observations of patients with metastatic castration-resistant prostate cancer living in the Tambov region

Treatment of patients with metastatic castration-resistant prostate cancer in clinical practice is a vital necessity and a challenging task since the causes of castration resistance are not fully understood. Adherence to treatment regimens in accordance with the National Clinical Guidelines allows to achieve an increase in both overall survival and progression-free survival, as well as to reduce the mortality rate in this category of patients. Administration of 1st-line treatment regimens stabilizes the disease in the majority of pancreatic cancer patients; in some cases, the disease becomes aggressive, distant metastases appear, most oſten in bones, lymph nodes, and internal organs, as demonstrated by three clinical observations presented in this article. The administration of enzalutamide (in 2 cases) and abiraterone acetate (in 1 case) at the stage of resistance to castration therapy allowed to obtain a complete “response” from visceral lesions, stabilise bone metastatic foci and increase the life expectancy of patients.

Abstract IA-002: Dendritic cell corner stone of tumor immunity in PDAC

Abstract T cell-directed immunotherapies have not been effective for the majority of pancreatic cancer patients, in part, due to our limited understanding of how T cell immunity is subverted in this disease. We sought to identify mechanisms for this failure using spontaneous mouse models. We report that endogenous antigen-specific responses in PDAC are aberrant due to a scarcity of dendritic cells, which favors the expansion of tumor-promoting TH17 immunity. Restoring cDCs in pancreatic cancer can enhance CD8+ T cell and TH1 activity to ultimately help control disease. These findings expand our understanding of T cell ineffectiveness in pancreatic cancer, and propose combinatorial strategies to modulate cDCs in conjunction with existing therapies for pancreatic cancer and similar solid malignancies. Citation Format: David G. DeNardo. Dendritic cell corner stone of tumor immunity in PDAC [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr IA-002.

Abstract PO-098: Longitudinal profiling of pancreatic cancer patients identifies interleukin-8 as a mediator of myeloid-epithelial crosstalk

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related death in the US. A key hallmark of this disease is that, while tumors initially show susceptibility to standard chemotherapeutic agents, most patients eventually develop resistance, leading to poor survival. While the mechanisms of chemoresistance are unclear, murine studies have implicated the myeloid compartment of the tumor immune microenvironment. Correlative data in human tumors supports this notion, however, mechanistic studies are lacking, thus impairing translation to the clinic. The study of human pancreatic cancer has historically been challenging due to difficulty of fresh biospecimen acquisition, patient heterogeneity, and a diverse tumor microenvironment. Moreover, the vast majority of pancreatic cancer patients do not qualify for surgical resection, further limiting tissue availability. We have overcome these difficulties by developing a pipeline to analyze human tumor samples and matched blood using high-fidelity techniques including single-cell RNA sequencing (scRNAseq) and mass cytometry (CyTOF), together with establishment of organoids from the same tumors. Notably, in this pipeline we can use small amounts of tissue from endoscopic fine needle biopsies, thus allowing us to sample tumors from patients at any disease stage. Results: We performed CyTOF on longitudinally-matched peripheral blood mononuclear cells (PBMCs) from 30 patients and single-cell RNA sequencing on 6 patients in the treatment naïve and on-treatment (FOLFIRINOX) state. CyTOF revealed distinct alterations in the myeloid population, with a shift toward CXCR2hiPD-L1hi granulocytes with FOLFIRINOX treatment over time. Analysis of PBMCs from scRNAseq showed a distinct myeloid gene signature with FOLFIRINOX and in particular highlighted interleukin-8 (IL8), a chemokine involved in myeloid cell chemotaxis that is associated with poor prognosis in pancreatic cancer. Further mapping of IL8 in tumor tissue by scRNAseq showed that it is highly expressed in subpopulations of tumor epithelial cells and tumor-infiltrating granulocytes. IL8-high tumor-infiltrating granulocytes also highly expressed VEGF and CXCR4, suggesting immunosuppressive and angiogenic roles. IL8-high tumor epithelial cells were found to have a basal-like phenotype and also expressed a network of other chemokines including CXCL1, CXCL3, CXCL5, which are known to recruit immunosuppressive myeloid cells. Conclusions: Through longitudinal and multimodal mapping using PDAC patient blood and tumor biospecimens, we have identified IL8 as a potential mediator of epithelial-myeloid crosstalk in PDAC chemoresistance and tumor aggression. Validation studies using an all-human co-culture system of PDAC patient-derived organoids and myeloid cells are currently underway. Citation Format: Eileen S. Carpenter, Samantha Kemp, Padma Kadiyala, Nina Steele, Ahmed Elhossiny, Stephanie The, Valerie Gunchick, Rémy Nicolle, Michelle Anderson, Wenting Du, Carlos Espinoza, Richard Kwon, Erik-Jan Wamsteker, Anoop Prabhu, Allison Schulman, Vaibhav Sahai, Timothy Frankel, Filip Bednar, Marina Pasca di Magliano. Longitudinal profiling of pancreatic cancer patients identifies interleukin-8 as a mediator of myeloid-epithelial crosstalk [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-098.

Specific Receptors for the Chemokines CXCR2 and CXCR4 in Pancreatic Cancer.

Background: The mortality rate of pancreatic cancer (PC) is equal to its incidence and the majority of PC patients die within a few months of diagnosis. Therefore, a search for new biomarkers useful in the diagnosis and prognosis of PC is ongoing. Objectives: The aim of our study was to compare the utility of CXCR2 and CXCR4 in the diagnosis and prediction of PC with classical tumor marker (carcinoembryonic antigen, CEA) and marker of inflammation–C-reactive protein (CRP). Patients and Methods: The study comprised 64 subjects — 32 PC patients and 32 healthy volunteers. Serum concentrations of tested proteins were analysed using immunological methods. Results: Serum CXCR2 and CXCR4 concentrations, similarly to those of CEA and CRP, were significantly elevated in PC patients compared to healthy controls. Moreover, concentrations of CXCR4 were significantly correlated with CXCR2 and CRP levels, while CRP concentrations were correlated with CXCR2 and CEA levels. The diagnostic sensitivity and the predictive value for negative (PV−ve) results for CXCR4 were similar to those of CEA and higher than those of CXCR2 and CRP, while the area under the ROC curve (AUC) for CXCR4 was the highest among all tested proteins (CXCR2, CEA, CRP). Moreover, serum CXCR2 was found to be a significant predictor of PC risk. Conclusions: CXCR4 is a better candidate for a tumor marker than CXCR2 in the diagnosis of PC, while serum CXCR2 is a significant predictor of PC risk.

Goals of care designations in advanced pancreatic cancer patients undergoing palliative chemotherapy.

683 Background: Discussion of goals of care (GoC) is a key part of quality care for patients with palliative cancer. Numerous studies have shown that documentation of GoC in this population remains low. In 2014, Alberta Health Services launched a health-system wide initiative to provide patients with physical copies of their GoC designation intended to be available at all health-system interactions. Here we describe rates of GoC documentation in the period surrounding this initiative. Methods: This is a retrospective cohort analysis of 240 patients with locally advanced or metastatic pancreatic cancer treated with palliative chemotherapy from 2012-2015 in Alberta, Canada. Data were obtained from outpatient electronic medical record documentation and the provincial cancer registry. Results: 63.8% (153/240) of patients had a documented GoC discussion, with 60.4% (145/240) receiving a specific GoC designation. 59.6% (143/240) of patients were referred to palliative care, with 32.5% (78/240) seen by palliative care physician. Of 334 individual GoC discussions documented, 38.6% (129/334) were by medical oncologists, 2.3% (10/334) were by radiation oncologists, 27.2% (91/334) were by palliative care, and 19.2% (64/334) were by other inpatient physicians during hospital admissions. At least 9.6% (32/334) referenced discussions that occurred prior to initial consultation with an oncology physician. Conclusions: The majority of pancreatic cancer patients undergoing palliative chemotherapy had a documented GoC designation during the study period. Providing patients with physical copies of their GoC designation may therefore represent a simple but effective means of increasing GoC documentation in the outpatient oncology setting.

High glucose promotes pancreatic cancer cells to escape from immune surveillance via AMPK-Bmi1-GATA2-MICA/B pathway

BackgroundModulation of cell surface expression of MHC class I chain-related protein A/B (MICA/B) has been proven to be one of the mechanisms by which tumor cells escape from NK cell-mediated killing. Abnormal metabolic condition, such as high glucose, may create a cellular stress milieu to induce immune dysfunction. Hyperglycemia is frequently presented in the majority of pancreatic cancer patients and is associated with poor prognosis. In this study, we aimed to detect the effects of high glucose on NK cell-mediated killing on pancreatic cancer cells through reduction of MICA/B expression.MethodsThe lysis of NK cells on pancreatic cancer cells were compared at different glucose concentrations through lactate dehydrogenase release assay. Then, qPCR, Western Blot, Flow cytometry and Immunofluorescence were used to identify the effect of high glucose on expression of MICA/B, Bmi1, GATA2, phosphorylated AMPK to explore the underlying mechanisms in the process. Moreover, an animal model with diabetes mellitus was established to explore the role of high glucose on NK cell-mediated cytotoxicity on pancreatic cancer in vivo.ResultsIn our study, high glucose protects pancreatic cancer from NK cell-mediated killing through suppressing MICA/B expression. Bmi1, a polycomb group (PcG) protein, was found to be up-regulated by high glucose, and mediated the inhibition of MICA/B expression through promoting GATA2 in pancreatic cancer. Moreover, high glucose inhibited AMP-activated protein kinase signaling, leading to high expression of Bmi1.ConclusionOur findings identify that high glucose may promote the immune escape of pancreatic cancer cells under hyperglycemic tumor microenvironment. In this process, constitutive activation of AMPK-Bmi1-GATA2 axis could mediate MICA/B inhibition, which may serve as a therapeutic target for further intervention of pancreatic cancer immune evasion.

The current surgical treatment of pancreatic cancer in China: a national wide cross-sectional study

Abstract Objective: The aim of this study is to investigate the current status of pancreatic cancer patients undoing surgical treatment in China and to find ways to improve the survival of these patients in the future. Methods: This study is a national, multicenter, cross-sectional study in China. Information regarding pancreatic cancer patients undergoing surgical treatment from 34 high-volume tertiary IIIA level hospitals was collected and analyzed from the March 1, 2016 to the February 28, 2017. Results: In total, 2200 pancreatic cancer patients were enrolled from 34 tertiary IIIA level hospitals in 16 provinces across China. The male-to-female ratio was 1.5. More than 80% of the patients were between 50 and 70 years old. The top 4 symptoms were epigastric discomfort, abdominal pain, jaundice, and weight loss. Carbohydrate antigen 19-9 and carcinoembryonic antigen were elevated in 70.9% and 27.1% of patients, respectively. A multidisciplinary team (MDT) discussion was carried out for 35.0% of patients before surgery. The proportion of minimally invasive pancreatic surgeries was approximately 20%. A total of 83.4% of the operations achieved R0 resection, and the incidence of grade 3/4 postoperative complications was 7.7%. Only 13.4% of the patients received postoperative adjuvant chemotherapy. The percentage of pathological stage I tumors was only 24.5%. Conclusion: The majority of pancreatic cancer patients undergoing surgical resection in China are in an advanced stage. The MDT consultations for pancreatic cancer have not been widely carried out. R0 resection has been achieved in most cases, with relatively low incidence of serious complications, but minimally invasive pancreatic surgery should be further promoted. The application of postoperative chemotherapy remains low. This national, multicentre, cross-sectional study comprehensively presents the current status of pancreatic cancer patients undergoing surgical treatment and shows the road to improve survival of these patients in the future.

Use of nano engineered approaches to overcome the stromal barrier in pancreatic cancer.

While chemotherapy is the only approved non-surgical option for the majority of pancreatic cancer patients, it rarely results in a cure. The failure to respond to chemotherapy is due to the presence of an abundant dysplastic stroma that interferes in drug delivery and as a result of drug resistance. It is appropriate, therefore, to consider the stromal contribution to the resistance to chemotherapy and sidestepping this barrier with nanocarriers that improve survival outcome. In this paper, we provide a short overview of the role of the stroma in chemotherapy resistance, including the use of nanocarriers to negate this barrier. We provide a perspective and guidance towards the implementation of nanotherapeutic approaches to improve therapeutic delivery and efficacy of PDAC management.

Superoxide Dismutases in Pancreatic Cancer.

The incidence of pancreatic cancer is increasing as the population ages but treatment advancements continue to lag far behind. The majority of pancreatic cancer patients have a K-ras oncogene mutation causing a shift in the redox state of the cell, favoring malignant proliferation. This mutation is believed to lead to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and superoxide overproduction, generating tumorigenic behavior. Superoxide dismutases (SODs) have been studied for their ability to manage the oxidative state of the cell by dismuting superoxide and inhibiting signals for pancreatic cancer growth. In particular, manganese superoxide dismutase has clearly shown importance in cell cycle regulation and has been found to be abnormally low in pancreatic cancer cells as well as the surrounding stromal tissue. Likewise, extracellular superoxide dismutase expression seems to favor suppression of pancreatic cancer growth. With an increased understanding of the redox behavior of pancreatic cancer and key regulators, new treatments are being developed with specific targets in mind. This review summarizes what is known about superoxide dismutases in pancreatic cancer and the most current treatment strategies to be advanced from this knowledge.

Abstract A45: Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy

Abstract Introduction: With the current epidemic of obesity, the majority of pancreatic cancer patients are overweight or obese at diagnosis. Importantly, obesity worsens treatment outcomes in pancreatic cancer patients. Therefore, understanding the mechanisms that underlie the poorer prognosis of obese cancer patients is of paramount importance. Obesity causes inflammation and fibrosis in the normal pancreas due to the accumulation of dysfunctional hypertrophic adipocytes. Importantly, desmoplasia—a fibro-inflammatory microenvironment—is a hallmark of pancreatic ductal adenocarcinoma (PDAC), and we have shown that activation of pancreatic stellate cells (PSCs) via angiotensin-II type 1 receptor (AT1) pathway is a major contribution to tumor desmoplasia. Whether obesity affects inflammation, PSCs and desmoplasia in PDACs, and interferes with delivery and response of chemotherapeutics is currently unknown. Experimental Design: Using mouse models of PDAC—multiple syngeneic models of PDAC: PAN02, AK4.4, KPC, iKRAS in diet-induced and genetic obese mouse models—we determined the effects of obesity on desmoplasia and inflammation, tumor growth and delivery and response to chemotherapy. We further evaluated whether the obesity-induced effects were mediated by AT1 signaling as well as via immune cell recruitment, and dissected the crosstalk between PSCs, cancer-associated adipocytes (CAAs), and tumor-associated neutrophils (TANs). In addition, we determined if an anti-diabetic drug metformin could counter these effects in vivo, and further dissected the mechanism of action in vitro. Results: We found that obesity aggravates desmoplasia in PDACs in multiple mouse models. In addition, tumors in obese mice presented with elevated levels of activated PSCs and fibrosis, as well as inflammatory cytokines and TANs. These alterations in the tumor microenvironment in obesity associated with accelerated tumor growth, reduced tumor blood perfusion and increased hypoxia, and impaired delivery and efficacy of chemotherapeutics. Genetic ablation and pharmacological inhibition (losartan) of AT1 signaling reversed obesity-augmented desmoplasia and tumor growth, and improved the response to chemotherapy to the level observed in lean mice. We further discovered the underlying mechanisms: 1) obesity increases intra-tumor adipocytes and IL-1ß secretion by these cells; 2) increased IL-1ß induces TAN recruitment; 3) recruited TANs activate PSCs; and 4) activated PSCs enhance desmoplasia. Conversely, activated PSCs also secrete IL-1ß that recruits further TANs. Hence, inactivation of PSCs through AT1 blockade resulted in not only decreased fibrosis but also reduced IL-1ß level and TAN recruitment. Furthermore, reduction of either TANs, IL-1ß, or PSC activation reduced tumor growth in obese mice. These findings suggest that crosstalk between adipocytes, immune cells, and PSCs exacerbates desmoplasia and promotes tumor progression during obesity. Of clinical relevance, we found that metformin not only normalizes the abnormal systemic metabolism, but also alleviates the fibro-inflammatory microenvironment in pancreatic cancer in obesity/diabetes. This occurred via direct reprogramming of PSCs and immune cells by metformin. Importantly, the strategies described above were not effective in the normal weight setting. Conclusion: Here we successfully demonstrated that targeting desmoplasia, including immunomodulation with anti-IL-1ß, or treatment with generic drugs such as losartan and metformin are potential strategies to potentiate treatments in PDAC patients with excess weight. With a better understanding of the mechanisms by which obesity promotes tumor progression and therapy resistance, we will be able to improve the current standard of care in pancreatic cancer. Citation Format: Joao Incio, Hao Liu, Priya Suboj, Shan Min, Ivy Chen, Mei Ng, Hadi Nia, Jelena Grahovac, Shannon Kao, Suboj Babykutty, Yuhui Huang, Keehoon Jung, Nuh Rahbari, Xiaoxing Han, Vikash Chauhan, John Martin, Julia Kahn, Peigen Huang, Vikram Deshpande, James Michaelson, Cristina Ferrone, Raquel Soares, Yves Boucher, Dai Fukumura, Rakesh Jain. Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A45.

Current status of biomarker and targeted nanoparticle development: The precision oncology approach for pancreatic cancer therapy

Pancreatic cancer remains one of the major causes of cancer-related mortality. The majority of pancreatic cancer patients are diagnosed at the advanced stage with unresectable and drug resistant tumors. The new treatments with the combination of chemotherapy, molecular targeted therapy, and immunotherapy have shown modest effects on therapeutic efficacy and survival of the patients. Therefore, there is an urgent need to develop effective therapeutic approaches targeting highly heterogeneous pancreatic cancer cells and tumor microenvironments. Recent advances in biomarker targeted cancer therapy and image-guided drug delivery and monitoring treatment response using multifunctional nanoparticles, also referred to as theranostic nanoparticles, offer a new opportunity of effective detection and treatment of pancreatic cancer. Increasing evidence from preclinical studies has shown the potential of applications of theranostic nanoparticles for designing precision oncology approaches for pancreatic cancer therapy. In this review, we provide an update on the current understanding and strategies for the development of targeted therapy for pancreatic cancer using nanoparticle drug carriers. We address issues concerning drug delivery barriers in stroma rich pancreatic cancer and the potential approaches to improve drug delivery efficiency, therapeutic responses and tumor imaging. Research results presented in this review suggest the development of an integrated therapy protocol through image-guided and targeted drug delivery and therapeutic effect monitoring as a promising precision oncology strategy for pancreatic cancer treatment.

Pancreatic cancer cell invasion: mesenchymal switch or just hitchhiking?

For the majority of pancreatic cancer patients, metastatic spread is the most life-threatening issue, significantly shortening survival (1). Yet, the road for a cancer cell to successfully set its metastatic niche and to grow there is fortunately long and sown with pitfalls. Consistently, the estimated time for pancreatic cancer patients to develop a widely disseminated disease through subclonal metastatic evolution from a parental clone inside the primary carcinoma is 6.8-year, as recently reported (2). To the important question of whether the poor prognosis of pancreatic cancer is due to its late diagnosis, or because it metastasizes early during clonal evolution, Yachida et al . indeed answered that there is a long latency to development of an infiltrating cancer, and thus a large window of opportunity for early diagnosis and cure. Yet, until early detection of pancreatic cancer becomes routine, the reality is that most patients will likely continue to be diagnosed with advanced disease, as recently mathematically predicted through a comprehensive study that benefited from a large group of patient’s autopsy data (3).

Abstract 898: Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy

Abstract INTRODUCTION: With the current epidemic of obesity, the majority of pancreatic cancer patients are overweight or obese at diagnosis. Importantly, obesity worsens treatment outcomes in pancreatic cancer patients. Therefore, understanding the mechanisms that underlie the poorer prognosis of obese cancer patients is of paramount importance. Obesity causes inflammation and fibrosis in the normal pancreas due to the accumulation of dysfunctional hypertrophic adipocytes. Importantly, desmoplasia - a fibroinflammatory microenvironment - is a hallmark of pancreatic ductal adenocarcinoma (PDAC), and we have shown that activation of pancreatic stellate cells (PSCs) via angiotensin-II type 1 receptor (AT1) pathway is a major contribution to tumor desmoplasia. Whether obesity affects desmoplasia in PDACs, and interferes with delivery and response of chemotherapeutics is currently unknown. EXPERIMENTAL DESIGN: Using both human samples and mouse models of PDAC - multiple syngeneic models of PDAC: PAN02, AK4.4, KPC, iKRAS in diet-induced and genetic obese mouse models -, we determined the effects of obesity on desmoplasia and inflammation/immune cell infiltration, tumor growth and delivery and response to chemotherapy. RESULTS: We found that obesity aggravates desmoplasia in PDACs in both patient samples and multiple mouse models. In addition, tumors in obese mice presented with elevated levels of activated PSCs and fibrosis, as well as inflammatory cytokines and TANs,. These alterations in the tumor microenvironment in obesity associated with accelerated tumor growth, reduced tumor blood perfusion and increased hypoxia, and impaired delivery and efficacy of chemotherapeutics. Genetic ablation and pharmacological inhibition (losartan) of AT1 signaling reversed obesity-augmented desmoplasia and tumor growth, and improved the response to chemotherapy to the level observed in lean mice. We further discovered the underlying mechanisms: 1) obesity increases intra-tumor adipocytes and IL-1ß secretion by these cells; 2) increased IL-1ß induces TAN recruitment; 3) recruited TANs activate PSCs; and 4) activated PSCs enhance desmoplasia. Conversely, activated PSCs also secrete IL-1ß that recruits further TANs. Of clinical relevance, we found that metformin not only normalizes the abnormal systemic metabolism, but also reprogramms PSCs and immune cells and alleviates the fibroinflammatory microenvironment in pancreatic cancer in obesity/diabetes.. Importantly, the strategies described above were not effective in the normal weight setting. CONCLUSION: Here we successfully demonstrated that targeting desmoplasia, including immunomodulation with anti-IL-1ß, or treatment with generic drugs such as losartan and metformin are potential strategies to potentiate treatments in PDAC patients with excess weight. Citation Format: Joao Incio, Priya Suboj, Shan M. Chin, Chen Ivy, Mei Ng, Hadi Nia, Jelena Grahovac, Hao Liu, Shannon Kao, Suboj Babykutty, Yuhui Huang, Keehoon Jung, Nuh Rahbari, Xiaoxing Han, Vikash Chauhan, John Martin, Julia Kahn, Peigen Huang, Raquel Soares, Yves Boucher, Dai Fukumura, Rakesh Jain. Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 898.

Outcomes of Systematic Nutritional Assessment and Medical Nutrition Therapy in Pancreatic Cancer

We investigated the nutritional and survival outcomes of medical nutrition therapy by a registered dietitian, along with support from a dedicated nutrition and metabolic support team in pancreatic cancer patients requiring enteral or parenteral nutrition. Subjective global assessment (SGA) was used to assess nutritional status in 304 pancreatic cancer patients. Using baseline and last SGA, patients were categorized into 3 groups: improved SGA, deteriorated SGA, and unchanged SGA. Kaplan-Meier and Cox regression were used to calculate survival after controlling for relevant confounders. One-hundred twenty-five (41.1%) patients had their SGA unchanged, 87 (28.6%) patients had "improved SGA," whereas 92 (30.3%) patients had "deteriorated SGA." On univariate survival analysis, the median survival was 7.8, 11.2, and 12.6 months for deteriorated, unchanged, and improved SGA groups, respectively. On multivariate analysis, change in SGA was independently predictive of survival. Patients with deteriorated SGA had 1.5 times (95% confidence interval, 1.1-2.1) greater risk of mortality compared to those with improved SGA. The majority of pancreatic cancer patients (70%) in our study either maintained or improved their nutritional status during cancer treatment. Improvement in SGA correlated with a significantly decreased risk of mortality independent of sex, previous treatment history, and evidence of biological anticancer activity.

Piperlongumine Enhances Chemotherapy‐Induced Pancreatic Cancer Cell Death

Pancreatic cancer is one of the most deadly cancers with a nearly 95% mortality rate. The large majority of pancreatic cancer patients have mutations in the K‐ras oncogene which contribute to uncontrolled cell proliferation. The poor response of K‐ras mutant tumors to currently available chemotherapy and the extremely low survival rate of pancreatic cancer patients point to a critical need for alternative therapeutic strategies. The use of reactive oxygen species (ROS)‐inducing agents has emerged as an innovative and effective strategy to treat K‐ras mutant cancers. We investigated the effects of a known ROS inducer, piperlongumine (PPLGM), a bioactive agent found in long peppers, alone and in combination with chemotherapeutic agents (gemcitabine and erlotinib) on pancreatic cancer cell viability, survival, and apoptosis. MIA PaCa‐2, PANC‐1 (K‐ras mutant), and BxPC‐3 (wild‐type K‐ras) cells were treated with PPLGM, erlotinib, gemcitabine, and their combinations. Cell survival and apoptosis were assessed by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT), clonogenic survival, and histone‐DNA ELISA assays. The combination of PPLGM, erlotinib, and gemcitabine resulted in a greater reduction in cell viability and induction of apoptosis in all three pancreatic cancer cell lines when compared to any agent alone. These results suggest that the use of PPLGM in combination with chemotherapeutic agents could be a successful strategy for achieving better treatment outcomes in K‐ras mutant pancreatic cancer patients.

Treatment of intrathoracic acute fluid collection with thoracotomy and endoscopic sphincterotomy. Report of a case

s / Pancreatology Aims: To devise and pilot a symptom questionnaire to determine the efficacy of existing decision tools in identifying symptoms of pancreatic cancer and to determine the prevalence and timing of associated symptoms. Patients & methods: This was a hospital based case control study which involved the piloting of a novel symptom questionnaire. The questionnaire included symptoms from both current clinical decision tools for pancreatic cancer: the QCancer® tool and the RAT. The frequency of symptoms, the timing of onset as well as the management of condition were retrospectively reviewed via face to face interviews. Results: The median QCancer ® 2013 score is higher in pancreatic cancer patients (2.47%) compared with cholangiocarcinoma patients (0.74%) and benign pancreatobiliary patients (0.44%). Unintentional weight loss, abdominal pain, heartburn, back pain, steatorrhoea, diarrhoea were reported by a majority of pancreatic cancer patients. Conclusion: Patients with pancreatic cancer presenting with key symptoms have the potential to be identified earlier by clinical diagnostic algorithms in primary care.

A triple combination of atorvastatin, celecoxib and tipifarnib strongly inhibits pancreatic cancer cells and xenograft pancreatic tumors

Because K-Ras mutation and cyclooxygenase-2 (COX-2) overexpression are hallmarks of majority of pancreatic cancer patients, an approach to inhibit the progression and growth of pancreatic cancer using the simultaneous administration of agents that inhibit the function of both targets, should be considered. In the present study, we assessed the effects of atorvastatin (Lipitor), celecoxib (Celebrex) and tipifarnib (Zarnestra) on the growth of human pancreatic cancer. In the in vitro studies, we found that treatment of human pancreatic tumor cells with a combination of atorvastatin, celecoxib and tipifarnib had a stronger inhibitory effect on growth and a stronger stimulatory effect on apoptosis than each drug alone or for any combination of two drugs. We also found that treatment of Panc-1 cells with a combination of all three drugs strongly decreased the levels of phosphorylated Erk1/2 and Akt. In an animal model of xenograft tumors in severe combined immunodeficient (SCID) mice, we found that daily i.p. injections of a combination of atorvastatin, celecoxib and tipifarnib had a stronger inhibitory effect on the growth of the tumors in mice than each drug alone or for any combination of two drugs. The results of our study indicate that a combination of atorvastatin, celecoxib and tipifarnib may be an effective strategy for the treatment of pancreatic cancer.