bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B119: Triptolide abrogates expression of the Met and epidermal growth factor receptors in pancreatic cancer
Authors: Sangwan Veena , Jensen Kelsey M. , Dudeja Vikas , Chugh Rohit , Banerjee Sulagna , Vickers Selwyn M. , Park Morag , Saluja Ashok K.
Published: October 2015

Background: Minnelide, a pro-drug of the Chinese herb triptolide, is currently in Phase I clinical trials against pancreatic cancer. Preclinical studies with Minnelide have demonstrated its efficacy in preventing tumor formation and causing tumor regression in multiple animal models of pancreatic cancer. However, its mechanism of action remains unclear. Pancreatic cancer cells overexpress several receptor tyrosine kinases including the Met and EGF receptors which drive proliferation, migration and invasion of these cells. Here, using human pancreatic cancer cells as well as the KRasG12D; Trp53R172H; Pdx-1 Cre (KPC) animal model, we show the ability of triptolide, or its water soluble pro-drug, Minnelide, to down-regulate the Met and EGF receptors, both in vitro and in vivo.

Methods:Pancreatic cancer cells were treated with triptolide for varying times (0-24h) and receptor levels evaluated using western blotting or confocal microscopy. The KPC mouse model recapitulates human disease progression and is therefore the most relevant model for chemotherapeutic drug testing. KPC animals, which spontaneously form pancreatic tumors, were treated with Minnelide for one week and tumors harvested. mRNA expression was analyzed using real time PCR and protein expression assessed by immunohistochemistry.

Results: Treatment with triptolide causes an increase in tyrosine phosphorylation at earlier time points (0.5 - 6h), accompanied by an increase in levels of the Met and EGF receptor tyrosine kinases. However, longer treatments (12-24h) resulted in marked decrease in levels of both Met and EGF receptors. Further investigation using tumors from KPC animals treated with Minnelide show a decrease in gene expression of both the Met and EGF receptors compared with tumors from saline injected animals. Furthermore, immunohistochemical analysis of formalin fixed paraffin embedded sections from these tumors show a decrease in levels of the Met receptor.

Conclusion: Treatment of cells or KPC pancreatic tumor bearing animals with triptolide or Minnelide leads to decreased expression of the Met and EGF receptor tyrosine kinases. These results lend further insight into the mechanism of action of Minnelide, a pro-drug currently in clinical trials against pancreatic cancer.

Citation Format: Veena Sangwan, Kelsey M. Jensen, Vikas Dudeja, Rohit Chugh, Sulagna Banerjee, Selwyn M. Vickers, Morag Park, Ashok K. Saluja. Triptolide abrogates expression of the Met and epidermal growth factor receptors in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B119.
Abstract B12: Circulating stroma-related molecules as potential biomarkers for pancreatic ductal adenocarcinoma
Authors: Belotti Dorina , Resovi Andrea , Taraboletti Giulia , Lawlor Rita T. , Scarpa Aldo , Giavazzi Raffaella
Published: October 2015

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited treatment options. Early diagnostic serological markers capable of detecting the disease in its asymptomatic early stage can change the fate of PDAC patients. PDAC is characterized by a relevant stroma formation. This study investigates the potential value of circulating stroma-related molecules as PDAC biomarkers.

To select candidate stroma-associated biomarkers for pancreatic cancer, a review of literature regarding proteomic analysis of PDAC was performed. Eight proteomic studies of differentially expressed sera proteins in PDAC patients and in genetically engineered mice (GEM) developing cancer in the pancreas were analyzed and 176 proteins were identified as potential PDAC biomarkers. Of these, 61 were selected as potentially interesting based on: a) presence in at least 2 independent analysis and/or b) relation to tumor/stroma interaction by Gene Ontology. These included extracellular matrix proteins and proteolytic fragments, matrix-degrading enzymes and their inhibitors, growth factors and adhesion molecules. Among them, 37 proteins could be explored by ELISA (BioRad Bio-plex System) in plasma of 25 early stage PDAC patients and 16 control subjects. Fourteen molecules were significantly modulated, with ten molecules up-regulated and four down-regulated.

This preliminary screening identified 14 potential plasma biomarkers. Specificity and sensitivity of these selected biomarkers are being validated on a larger number of PDAC patients and appropriate controls, including pancreatitis patients and on PDAC mouse models. A combination of some of these molecules might provide a useful tool for early PDAC diagnosis.

Supported by AIRC grant n. 2172

Citation Format: Dorina Belotti, Andrea Resovi, Giulia Taraboletti, Rita T. Lawlor, Aldo Scarpa, Raffaella Giavazzi. Circulating stroma-related molecules as potential biomarkers for pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B12.
Abstract B17: Tumor-associated stellate cells promote an invasive phenotype of pancreatic cancer cells
Authors: Karnevi Emelie , Rosendahl Ann H. , Saleem Moin A. , Andersson Roland
Published: October 2015

At the time of diagnosis, almost 80% of pancreatic cancer patients present with either new-onset type 2 diabetes or impaired glucose tolerance. Pancreatic cancer is associated with a highly abundant stroma, which is believed to influence the pathogenesis of the disease. In the local tumor microenvironment, both elevated glucose levels and the presence of tumor-associated stellate cells are hypothesized to promote the tumor progression and invasion by tumor cells. In this study, the influence by the microenvironment on pancreatic cancer cell invasion was investigated in vitro. Epithelial-to-mesenchymal transition (EMT) of human pancreatic cancer cells co-cultured in normal (5mM) or high (25 mM) glucose conditions with tumor-associated pancreatic stellate cells (TPSCs) was monitored by Western immunoblotting. In addition, a three-dimensional organotypic model was established to study and visualize the pancreatic cancer cell invasion. After co-culture, the expression of several EMT-markers was altered. The levels of E-cadherin were reduced by more than 95% (P<0.001) while vimentin was increased by 45% (P<0.05). In addition, high glucose conditions reduced the levels of ZO-1 and β-catenin compared to normal glucose. TGF-β stimulation, a known inducer of EMT, resulted in a similar modulation of EMT markers. The organotypic model showed differences in the extent of invasion between the cell lines investigated, of which PANC-1 human pancreatic cells were shown to be the most invasive and also formed a highly proliferative epithelium. In high glucose conditions, the invasion of PANC-1 cells appeared to increase both in number and distance covered by the cells. Immunofluorescent staining of EMT-markers in organotypic sections displayed a lack of E-cadherin and extensive expression of vimentin in the tumor epithelium. In conclusion, this study show TPSCs to induce changes in pancreatic cancer cells associated with enhanced invasiveness. In addition, a three-dimensional model visualized the invasive potential of the pancreatic cancer cells, which was further enhanced by high glucose conditions. This study contributes to further elucidate the interplay between, and influence of, the cell types present in the local tumor microenvironment, which promotes the tumor cell invasion as an important step in the pancreatic tumor progression.

Citation Format: Emelie Karnevi, Ann H. Rosendahl, Moin A. Saleem, Roland Andersson. Tumor-associated stellate cells promote an invasive phenotype of pancreatic cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B17.
Abstract B44: The histone deacetylase SIRT6 regulates metabolism in pancreatic ductal adenocarcinoma
Authors: Kugel Sita , Sebastián Carlos , Perera Rushika M. , Bardeesy Nabeel , Mostoslavsky Raul
Published: October 2015

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death and one of the most aggressive and deadly malignancies, with limited therapeutic options. Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase that functions as a novel tumor suppressor, which regulates aerobic glycolysis in cancer cells. Whether glycolysis plays a role in pancreatic cancer development remains a topic of intense study. Importantly, we found SIRT6 to be downregulated in human PDAC and most pancreatic cancer cell lines, resulting in increased expression of glycolytic genes. To determine the role of SIRT6 in pancreatic cancer we utilized human PDAC cell lines that demonstrated low expression of SIRT6 compared to a human pancreatic ductal epithelial (HPDE) control cell line. Restoration of SIRT6 expression decreased the levels of glycolytic gene expression, reduced glucose uptake, and inhibited cell growth. Conversely, knockdown of SIRT6 in HPDE cells increased glycolytic gene expression, glucose uptake and enhanced cell growth. To further explore the role of SIRT6 in a genetically defined PDAC model, we used an autochthonous mouse model with conditional alleles for KRASG12D, p53, and SIRT6, together with a p48-Cre allele to delete SIRT6 and p53 while expressing oncogenic Ras exclusively in the pancreas. SIRT6null, KRASG12D, p53+/- p48 tumor cells also exhibited increased expression of glycolytic genes and had enhanced glucose uptake compared to SIRT6+/+, KRASG12D, p53+/- p48 tumor cells, a phenotype which is reversed by restoration of wild-type but not catalytically inactive SIRT6 expression. Understanding how SIRT6 regulates PDAC metabolism through the modulation of chromatin dynamics will hopefully lead to new therapies to tackle aberrant metabolism in this devastating disease.

Citation Format: Sita Kugel, Carlos Sebastián, Rushika M. Perera, Nabeel Bardeesy, Raul Mostoslavsky. The histone deacetylase SIRT6 regulates metabolism in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B44.
Abstract B48: Pancreatic cancer cells exhibit heterogeneous glucose and glutamine metabolic dependencies
Authors: Bryant Kirsten L. , Maitra Anirban , Der Channing J.
Published: October 2015

Pancreatic cancer cells demonstrate altered metabolism that is consistent with amplified aerobic glycolysis, fueled by increased glucose uptake. Concurrently, additional studies have established an enhanced dependence on glutamine to power anabolic processes. Recently, there has been a renewed interest in understanding the altered metabolic requirements of cancer cells with the goal of targeting differential nutrient dependencies for therapeutic gain. We screened a panel of twelve well established and widely studied KRAS mutant pancreatic tumor-derived cell lines, as well as seven low passage KRAS mutant pancreatic patient-derived xenograft (PDX)-established tumor cell lines for the ability to proliferate in growth media deficient in glucose and/or glutamine. While 11 of 12 established cell lines were unable to proliferate in these nutrient-depleted conditions, we identified one (Capan-2) that was capable of proliferation in the complete absence of glucose. By comparison, of the seven PDX-derived cell lines screened, four demonstrated complete glucose or glutamine dependency, whereas one was capable of proliferation in the absence of glutamine and two proliferated in the absence of glucose. Our ongoing studies are focused on elucidating the mechanistic basis for glucose or glutamine independent growth. Defining these mechanisms may identify pharmacologic approaches that target metabolic pathways for the treatment of KRAS mutant pancreatic cancer.

Citation Format: Kirsten L. Bryant, Anirban Maitra, Channing J. Der. Pancreatic cancer cells exhibit heterogeneous glucose and glutamine metabolic dependencies. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B48.
Abstract B64: A Lys-Ala-Leu-Ala (KALA) repeated peptide modification in DNA nanoparticles of DOPE/CHEMS, follows GPCR mediated transgene expression in dendritic cell
Authors: Shaheen Sharif Mohammad , Akita Hidetaka , Harashima Hideyoshi
Published: October 2015

Cellular uptake process of cationic peptide modified liposome is still obscured in perspective of cell biology. The mechanisms responsible for the internalization of oligo arginine, oligo-lysine, TAT and other arginine or lysine enriched peptide have focused on macropinocytosis. No information was reported about the uptake process of repeated cationic arginine or lysine (hydrophilic moiety) followed by leucine or alanine (hydrophobic moiety) with lipid bilayer based DNA nanocargoes. Here we orchestrated the concept of repeated lys-ala-leu-ala (KALA) peptide modified DNA-protamine-lipid nanoparticle, proclaimed a promising transfection activity in dendritic cell, following GPCR mediated endocytosis. Chemical inhibitors studies of chlorpromazine, Fillipin, and Amiloride did not support the concept of macropinocytosis, clathrin mediated endocytosis and cavaeola mediated endocytosis. Cetirizine hydrochloride, a GPCR blocker shut down the KALA mediated transgene expression. Confocal studies showed no liposomal uptake in KALA modification rather than R8 modification, which implies to receptor mediated endocytosis and thereby transgene expression. Low concentration of KALA pretreatment allowed a R8 MEND (usually non-expressed) to that of the same expression of KALA MEND and vice versa of high concentration KALA pretreatment. In a nut-shell performance of KALA ensured an engulfment of GPCR based endocytosis as well as GPCR activation thereby, that outcomes a boom transgene expression in dendritic cell.

Citation Format: Sharif Mohammad Shaheen, Hidetaka Akita, Hideyoshi Harashima. A Lys-Ala-Leu-Ala (KALA) repeated peptide modification in DNA nanoparticles of DOPE/CHEMS, follows GPCR mediated transgene expression in dendritic cell. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B64.
Abstract B74: Minimally invasive ablative therapy for mucinous cystic neoplasms (MCN) in a genetically engineered mouse model
Authors: Cuevas Carlos , Dotson Ashley M. , Hingorani Sunil R.
Published: October 2015

Pancreatic cystic neoplasms are an increasing health problem in the adult population due to their inherent potential to progress to invasive adenocarcinomas. The only available treatment is resection with the consequential significant morbidity and mortality associated with pancreatic surgery. Direct percutaneous injection of an ablative substance represents a potential new approach to this problem. Limited studies performed in human subjects speak to the potential feasibility of this approach, but no systematic or rigorous assessment of agents and outcomes has been possible. We have undertaken an effort to evaluate the effectiveness of intracystic injections of different chemical ablative substances (including ethanol and sodium tetradecyl sulfate) or chemotherapeutic drugs (including gemcitabine and paclitaxel) for the treatment of mucinous cystic neoplasms (MCN) in a murine model of the disease. We have developed a genetically engineered mouse model of MCN (KrasLSL-G12D;Dpc4fl/fl;Cre) that recapitulates the prototypical features of the human correlate, including development of an ovarian-type stroma with estrogen receptor (ER) and progesterone receptor (PR)-positive cells. An MCN is first identified in the mouse with high-resolution ultrasound imaging (HRUS) and the cyst fluid aspirated; the cyst is then injected with one of the treatment regimens. Study feasibility was first established with image-guided India ink injections followed by necropsy to evaluate successful aspiration and injection. Following treatment, disease response is evaluated by serial HRUS and detailed histopathologic and molecular analyses on recovered tissues at study termination. Through these studies we hope to define the optimal therapeutic regimen for non-surgical management of MCN in anticipation of a future clinical trial. We have successfully identified, aspirated and injected MCN with either saline (control) or ablative substances under real time ultrasound guidance in a longitudinal cohort. Challenges to this approach are also discussed including the posterior localization of the treated lesions within the diffusely abnormal pancreas typically found in this animal model.

Citation Format: Carlos Cuevas, Ashley M. Dotson, Sunil R. Hingorani. Minimally invasive ablative therapy for mucinous cystic neoplasms (MCN) in a genetically engineered mouse model. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B74.
Abstract B93: A data base of N of 1 case reports from pancreatic cancer patients enrolled in First-in-man studies 2002 through 2012
Authors: Garrido-Laguna Ignacio , Tometich Danielle , Boucher Kenneth , Sharma Sunil
Published: October 2015

Background: First-in-man (FIM) studies test different doses of novel therapeutics for the first time in humans. The purpose of this work was to develop a data base with FIM studies published in the last decade and to identify extraordinary responses to therapy in patients with advanced pancreatic cancer.

Methods: We conducted a search in Scopus of all FIM studies published between 2002 and 2012. We collected the following information: author, date and journal of publication, class of drug, route of administration, dose escalation design, patient demographic information, grade 3-4 toxicities, dose limiting toxicities, deaths during trial (including treatment related deaths), radiologic response, trial location and tumor types included in each trial.

Results: We identified 3065 references through the Scopus search. Among these we found 118 FIM studies enrolling 5369 patients with advanced cancers from 2002 through 2012. The most common tumor types were colorectal cancer 1055 (19.6%), lung cancer 456 (8.4%), melanoma 475 (8.8%), breast cancer 319 (5.9%) and pancreatic ductal adenocarcinoma 296 (5.5%). There were 194 deaths including 17 (0.3%) treatment related deaths. 12 patients (0.2%) had complete response as best response to therapy including a patient with pancreatic cancer treated with bosutinib (a novel Src/abl tyrosin kinase inhibitor). 1 patient with pancreatic cancer had partial response to CHR-3996 (a novel histone deacetylase inhibitor) with a progression free survival (PFS) of 12 months. A second patient had a partial response to trametinib (MEK inhibitor) with a PFS of 11.75 months. Interestingly histone deacetylases are components of core signaling pathways in pancreatic cancer such Cell cycle and Notch pathway. Moreover, Src is commonly activated in pancreatic cancer.

Conclusions: Novel approaches are urgently needed to treat pancreatic cancer. This includes identifying novel treatment opportunities through N of 1 case reports. We have retrospectively identified extraordinary responses to therapy in patients with advanced pancreatic enrolled in FIM studies with Src, HDAC and MEK inhibitors. Efforts should be now focused on understanding the underpinning biology of the disease in these patients.

Citation Format: Ignacio Garrido-Laguna, Danielle Tometich, Kenneth Boucher, Sunil Sharma. A data base of N of 1 case reports from pancreatic cancer patients enrolled in First-in-man studies 2002 through 2012. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B93.
Abstract IA13: Acinar cell transdifferentiation sets the stage for early tumor heterogeneity
Authors: Takeuchi Kenneth K. , Delgiorno Kathleen E. , Halbrook Christopher J. , Crawford Howard C.
Published: October 2015

Prior to PanIN formation, acinar cells harboring oncogenic Kras gradually lose their acinar character and take on a ductal phenotype in a process known as acinar-to-ductal metaplasia. Rather than mimicking a normal pancreatic duct, metaplastic ducts take on a proliferative biliary progenitor phenotype, marked by the expression of SOX17 and PDX1 and the presence of numerous tuft cells, recently identified as a PanIN initiating cells. Manipulation of SOX17 and PDX1 in vivo reveal them to be a transdifferentiation promoter and suppressor, respectively, both greatly affecting tuft cell genesis and tumor formation. These opposing roles of developmental transcription factors during tumorigenesis implicate the usurpation of a differentiation program that significantly contributes to cellular heterogeneity within early pre-cancerous lesions of the pancreas.

Citation Format: Kenneth K. Takeuchi, Kathleen E. Delgiorno, Christopher J. Halbrook, Howard C. Crawford. Acinar cell transdifferentiation sets the stage for early tumor heterogeneity. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr IA13.
Abstract IA15: Circulating tumor DNA
Authors: Diaz Luis A.
Published: October 2015

The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction–based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.

Citation Format: Luis A. Diaz. Circulating tumor DNA. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr IA15.
Abstract IA26: Pancreatic adenocarcinoma and altered whole-body metabolism
Authors: Wolpin Brian M.
Published: October 2015

Pancreatic cancer is the fourth leading cause of cancer mortality in the United States, and the vast majority of patients live less than 12 months. A defining feature of pancreatic ductal adenocarcinoma (PDAC) is its relationship with altered systemic metabolism. The risk of developing PDAC is increased among individuals with chronic obesity, hyperglycemia, and hyperinsulinemia. Furthermore, weight loss and new-onset diabetes frequently develop within the 2 years before diagnosis, and PDAC is strongly associated with development of cachexia and muscle loss (sarcopenia), which impair patient quality of life and survival.

We hypothesized that alterations in whole-body metabolism could be detected in patients with pancreatic cancer prior to diagnosis, with potential utility for disease screening and identifying novel treatment approaches. To investigate this hypothesis, circulating metabolites were profiled in prediagnostic plasma from pancreatic cancer cases and matched controls using a liquid chromatography-tandem mass spectrometry (LC-MS) metabolomics platform. In nearly 1,500 participants from four prospective cohort studies, we identified metabolites associated with future pancreatic cancer diagnosis independent of known measures of obesity, energy balance and insulin resistance. Experimental studies indicate that multiple years elapse between formation of the initial PDAC clone and development of cells with the capacity for metastatic spread. Thus, we considered whether the circulating metabolites identified in humans were also seen in mice with early pancreatic cancers and used labeled metabolites to trace the source of metabolic alterations in model systems. This work indicates that systemic metabolic alterations can be seen in humans and model systems prior to pancreatic cancer diagnosis, with implications for understanding the biology of early pancreatic tumors and host-tumor interactions.

Citation Format: Brian M. Wolpin. Pancreatic adenocarcinoma and altered whole-body metabolism. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr IA26.
Abstract IA5: Translating genetic discoveries to patient care
Authors: Hruban Ralph H.
Published: October 2015

Next-generation sequencing technologies have changed the speed at which cancer genetics research can be performed and this research has fundamentally changed our understanding of pancreatic cancer.

1. Families: It has been estimated that 10% of pancreatic cancer has an inherited basis. Whole-exome and whole-genome sequencing studies have led to the discovery of several new familial pancreatic cancer genes including PALB2 and ATM. It is hoped that new multi-institutional collaborative efforts will dramatically increase the pace of discovery. Patients found to harbor a genetic alteration that predisposes them to pancreatic cancer will be the first to benefit from early detection efforts.

2. Cystic neoplasms: Some cystic lesions in the pancreas are harmless benign tumors, while others are precancerous. Lives can be saved if significant precursor lesions can be identified and removed, but there is a risk of over-treatment if the benign harmless cysts are removed. Whole-exome sequencing all of the four major types of cystic neoplasms of the pancreas has revealed a pattern of mutations specific for each cyst type. In the future, cyst fluid can be sampled and cyst type determined by sequencing.

3. Early detection: The genetic alterations in a cancer and in its precursor lesions offer extremely sensitive and highly specific markers for the early detection of pancreatic neoplasia. These genetic alterations can be detected in pancreatic juice collected at endoscopy and even in the plasma.

4. Invasive cancer: Genetic alterations in a cancer can be the basis for individualized therapies.

5. Metastatic cancer: The sequencing of metastatic cancer has helped define the timeline of tumor progression in the pancreas.

In sum, and in short, these are exciting times in the war against pancreatic cancer. The translation of discoveries made by sequencing pancreatic tumors to patient care holds the promise for reducing mortality from this terrible disease.

Citation Format: Ralph H. Hruban. Translating genetic discoveries to patient care. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr IA5.
Abstract IA9: Vitamin D: Shining light on pancreatic cancer
Authors: Sherman Mara H. , Ding Ning , Collisson Eric A. , Downes Michael , Evans Ronald M.
Published: October 2015

Pancreatic ductal adenocarcinoma (PDAC) occurs in the context of an exuberant desmoplastic response that produces a ‘living chimera’ of tumor and activated stromal components. A prominent feature of the stromal response is the transformation of the Vitamin A storing pancreatic stellate cell (PSC) to activated myofibroblasts. We hypothesized that restoration of the quiescent PSC phenotype could disrupt tumor-stroma crosstalk and thus improve response to chemotherapy. Recently, we have shown that the vitamin D receptor (VDR) is expressed at high levels in activated human pancreatic tumor stroma and, in response to ligand, acts as a master transcriptional regulator of PSCs to reprise the quiescent state. In vivo, a synthetic VDR agonist (Cal) induced signal-dependent transcriptional remodeling of tumor stroma, enhancing the anti-tumor effects of gemcitabine by increasing intratumoral concentration to reduce tumor growth.

Secreted factors are key drivers of the communication between tumor and stroma. To explore the impact of PSC secreted factors on gene expression in pancreatic cancer, PDAC cell lines were grown in the presence of stromal conditioned media (StCM). Addition of StCM was sufficient to induce expression of thousands of PDAC genes linked to epigenetic reprograming including genome wide histone hyperacetylation. The gene expression profile induced by stromal factors overlap with those previously identified following oncogenic Kras, suggesting functional complementarity between cell-autonomous and micro-environmental cues. As epigenome modification results in changes in gene expression through histone modifications, we tested a small molecule inhibitors epigenetic regulators for the capacity to inhibit gene expression changes downstream of stromal factors. Paracrine induction of pro-growth and inflammatory genes was inhibited by this small molecule, suggesting that acetyl-lysine readers serve as key transducers of stromal inputs to drive alterations in gene expression in pancreatic cancer cells. This work describes a molecular strategy through which transcriptional reprogramming of tumors and tumor stroma by Vitamin D or epigenetic regulators may serve as a therapeutic portal in the treatment of pancreatic cancer.

Citation Format: Mara H. Sherman, Ning Ding, Eric A. Collisson, Michael Downes, Ronald M. Evans. Vitamin D: Shining light on pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr IA9.
Abstract PR14: PTEN-Long and gemcitabine combination treatment as a therapeutic for pancreatic cancer
Authors: Ahmed Roshan Ara , Hopkins Benjamin , Palermo Carmine , Sastra Steve A. , Rapp Zachary , Parsons Ramon , Olive Kenneth P.
Published: October 2015

PTEN is the second most frequently altered tumor suppressor found in human cancer, and is downregulated in a majority of pancreatic tumors. PTEN-Long is an endogenously expressed translational variant of this tumor suppressor that is identical to PTEN with the exception of an additional N-terminal region that gives this variant the ability to cross the cell membrane. Purified PTEN-Long can be used therapeutically to restore lost PTEN function, and has provoked profound regressions in PTEN null xenograft models. Here we explore the effect of PTEN-Long therapy in pancreatic cancer, both in the presence and absence of endogenous PTEN.

In preliminary data, we found that combining PTEN-Long with chemotherapy extended overall survival in a clinically predictive genetically engineered mouse model of PDA (K-rasLSL.G12D/+; p53LSL.R172H/+;PdxCre, called KPC). To explore PTEN-Long’s ability to enter various tissues we performed pharmacokinetic and pharmacodynamic experiments. We also utilized a surgical biopsy technique to obtain paired pre- and post-treatment tumor samples. These experiments demonstrated that PTEN-Long is able to alter canonical PTEN/PI3K signaling within pancreatic tumor tissues. Finally, we treated PTEN deficient mice (K-rasLSL.G12D/+; PTENFlox/+; PdxCre) with PTEN-Long in an attempt to model the therapeutic response of the ~5% of human pancreatic tumors that are genetically PTEN null. Longitudinal ultrasound imaging of the first of these mice suggests that these mice have more significant and prolonged regressions compared to KPC mice following PTEN-Long treatment.

This abstract is also presented as Poster A86.

Citation Format: Roshan Ara Ahmed, Benjamin Hopkins, Carmine Palermo, Steve A. Sastra, Zachary Rapp, Ramon Parsons, Kenneth P. Olive. PTEN-Long and gemcitabine combination treatment as a therapeutic for pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr PR14.
Abstract A21: Developing a model for engaging underserved breast cancer survivors: Expanding a financial assistance program to include support and education
Authors: Henry Catherine Creme , Hanson Arin Ahlum , Guglielmino Janine
Published: October 2015

Background: Living Beyond Breast Cancer's grant assists with the financial hardship of breast cancer treatment. Since 2006, the grant has funded more than 1,200 women by paying household bills. $1.1 million has been distributed in the Philadelphia region. 90% of recipients earn less than 300% of the federal poverty line; 63% are women of color. A 2010 needs assessment indicated that recipients were unfamiliar with LBBC's programs and had limited interactions with the organization. Personal and financial crises made seeking information and support a low priority.

Methods: Interventions developed increase contact time with recipients and provide personalized invitations to other LBBC education and support programs. Applicants receive a peer support phone call from an LBBC Breast Cancer Helpline volunteer to share information about upcoming programs and refer to resources to meet their needs. Special invitations to recipients offer registration fee waivers to LBBC conferences and invite them to tailored programs for low-income families.

Results: 65% of applicants were previously unaware of Living Beyond Breast Cancer and its programs. All applicants receive 10-20 minutes of phone peer support and invitations to two local programs. Applicants receive breast cancer publications on topics related to their concerns or experience. A nutrition-on-a-budget series was piloted in 2013 to address recipients' other wellness needs and provide meals. 14 women participated and reported that the program increased their knowledge of other nutrition resources available and increased their likelihood of using other LBBC services.

Conclusions: A financial assistance program provides a unique opportunity to engage underserved breast cancer survivors who may not otherwise seek support and education from an organization. The addition of peer support interventions helps assess and alleviate other concerns and connects recipients to a support system that they can access throughout their experience. These interventions can act as a model for other regional and national grant programs.

Citation Format: Catherine Creme Henry, Arin Ahlum Hanson, Janine Guglielmino. Developing a model for engaging underserved breast cancer survivors: Expanding a financial assistance program to include support and education. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr A21.
Abstract A77: PVT1 exon 9 overexpression as a potential biomarker of prostate cancer in black men
Authors: Ogunwobi Olorunseun O. , Ilboudo Adeodat
Published: October 2015

Prostate cancer (PC) is disproportionately aggressive in Black men and is associated with single nucleotide polymorphisms around regions 2 and 3 of the 8q24 human chromosomal region. Variants of this region interact with the non-protein coding gene locus, PVT1, in PC. And, PVT1 is overexpressed in PC. The PVT1 gene locus has at least 12 exons that make separate transcripts. It is possible that these transcripts may have different functions. However, the role of PVT1 transcripts in PC is unknown. Our aim is to determine if PVT1 transcripts play a role in aggressiveness and racial disparity in PC. We used a panel of five PC cell lines: PC-3 (from a White man with aggressive androgen-independent PC); MDA PCa 2b (from a Black man with aggressive androgen-dependent PC (ADPC)); RWPE-1 (epithelial prostate cells from normal prostate of a White man); WPE1-NA22 (tumorigenic cells derived from RWPE-1 cells from a White man, tumors are ADPC and indolent), and VCaP (from a White man with ADPC). Ribonucleic acid (RNA) extraction, complimentary deoxyribonucleic acid (cDNA) synthesis, and quantitative polymerase chain reaction (qPCR) were performed to evaluate expression of all twelve PVT1 exons. Each qPCR was performed in quadruplicates. Four separate qPCR experiments were performed. Expression of PVT1 exons was inconsistent except for exon 9. There was no significant difference in exon 9 expression between RWPE1, WPE1-NA22, PC-3, and VCaP cells derived from White men. However, exon 9 expression in the MDA PCa 2b cell line derived from a Black man was significantly higher than in the other four cell lines by at least 61%. Consequently, we observed differential expression of exon 9 of PVT1 in a manner that suggests that exon 9 may be associated with PC in Black men. These data provide a basis for further examining the function and mechanisms of action of PVT1 exon 9 in PC in Black men.

Citation Format: Olorunseun O. Ogunwobi, Adeodat Ilboudo. PVT1 exon 9 overexpression as a potential biomarker of prostate cancer in black men. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr A77.
Abstract A82: Identifying differentially expressed microRNAs as investigational tools in postpartum breast cancer in Hispanic women
Authors: Muñoz-Rodríguez José L. , Vrba Lukas , Hu Chengcheng , Thompson Patricia A. , Martinez Maria Elena , Futscher Bernard W.
Published: October 2015

The risk of breast cancer transiently increases immediately following pregnancy; peaking between 3-7 years. The biology that underlies this risk window and the effect on the natural history of the disease is unknown. MicroRNAs (miRNAs) are small, non-coding RNAs that have been shown to be dysregulated in breast cancer. Utilizing a quantitative RT-PCR approach, we profiled the expression pattern of 355 miRNAs across 56 formalin-fixed, paraffin embedded breast tumor tissue samples from multiparous Hispanic women. Based on a data-driven splitting of the expression pattern of the 355 miRNAs, the case series was separated into two groups based on time since last full-term pregnancy (TSLFTP): a) an early group representing women diagnosed with breast cancer ≤ 5.2 years postpartum (n=12); and b) a late group representing women diagnosed with breast cancer ≥ 5.3 years postpartum (n=44). We identified 15 miRNAs with significant differential expression between the early and late postpartum groups. Ten miRNAs had a two-fold or higher difference in expression, with miR-138, miR-660, miR-31, miR-135b, miR-17, miR-454, and miR-934 overexpressed in the early versus the late group; while miR-892a, miR-199a-5p, and miR-542-5p were overexpressed in the late versus the early postpartum group. Further analysis of the miRNA expression data demonstrated that 60% of the identified differentially expressed miRNAs are encoded on the X chromosome, with several miRNAs found together in miRNA gene clusters. Additionally, DNA methylation, measured using a Sequenom MassARRAY, demonstrated that three out of five tested miRNA genes (mir-31, mir-135b, and mir-138-2) had a lower mean methylation in the early versus late postpartum group, and negatively correlated with miRNA expression. In summary, we have identified miRNAs that are differentially expressed and differentially methylated between tumors of the early versus late postpartum, suggesting that potential differences in epigenetic regulation may exist in the postpartum breast cancers.

Citation Format: José L. Muñoz-Rodríguez, Lukas Vrba, Chengcheng Hu, Patricia A. Thompson, Maria Elena Martinez, Bernard W. Futscher. Identifying differentially expressed microRNAs as investigational tools in postpartum breast cancer in Hispanic women. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr A82.
Abstract B27: Overweight/obesity and physical activity rates in an ethnically diverse sample of breast cancer survivors
Authors: Cunningham Joan E. , Bauza Colleen E. , Brown Erika T. , Anthony Alberg J. , Kistner-Griffin Emily , Spruill Ida J. , Bryant Debbie C. , Esnaola Nestor F. , Jefferson Melanie S. , Whitfield Keith , Kramer Rita M. , Bolick Susan , Hurley Deborah , Mosley Catishia , Hazelton Tonya R. , Bea Vivian J. , Burshell Dana R. , Knight Kendrea D. , Ford Marvella E.
Published: October 2015

Background: High body mass index (BMI) is linked to poorer survival after breast cancer diagnosis. Physical activity (PA) could moderate this association.

Objectives/Hypothesis: Prevalence of high BMI (overweight/obesity) and level of PA were evaluated in a statewide sample of women within 18 months of breast cancer diagnosis.

Methods: In an ongoing study, 73 women (35 EA and 38 AA) were identified through the SC Central Cancer Registry, and were interviewed to obtain their self-reported body weight, height, PA and other data.

Results: Age: Age ranged from 26 to 90 years (mean 61 years, SD 13.0), with AAs 2.1 years younger than EAs (p=0.49). Education: 62% had more than a high school (HS) diploma (58% of AAs and 66% of EAs, p=0.49). BMI: 77% were overweight/obese; 42% of AAs and 31% of EAs were overweight, 45% of AAs and 34% of EAs were obese (p=0.03). PA: 23% reported no PA (29% of AAs and 17% of EAs, p=0.23). Only 38% met CDC PA guidelines of at least 150 min/week of moderate PA (29% of AAs and 47% of EAs; p=0.11). PA and BMI: PA <90 min/week was associated with 4-fold higher risk of overweight/ obesity (p=0.023). No significant associations were seen by race. PA and Education: No significant association was observed between >HS education and meeting PA guidelines (p=0.15), or between >HS education and greater PA per week (p=0.57). Education and BMI: No significant association was seen (p=0.77).

Conclusions: Prevalence of overweight/obesity was high, especially among AAs.

Future Recommendations: It is imperative to identify strategies to reduce obesity/overweight in BRCA survivors.

Citation Format: Joan E. Cunningham, Colleen E. Bauza, Erika T. Brown, Alberg J. Anthony, Emily Kistner-Griffin, Ida J. Spruill, Debbie C. Bryant, Nestor F. Esnaola, Melanie S. Jefferson, Keith Whitfield, Rita M. Kramer, Susan Bolick, Deborah Hurley, Catishia Mosley, Tonya R. Hazelton, Vivian J. Bea, Dana R. Burshell, Kendrea D. Knight, Marvella E. Ford. Overweight/obesity and physical activity rates in an ethnically diverse sample of breast cancer survivors. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B27.
Abstract B55: Elevation of oxidative expression proteins in colorectal adenomatous polyps
Authors: Wallace LaShanale M. , Mehrabi Sharifeh , Cohen Shakeria , Aikhionbare Felix O.
Published: October 2015

The optimal management of patients with colorectal adenomatous polyps depends on the accuracy of appropriate staging strategies because patients with similar colorectal adenocarcinoma architecture display heterogeneity in the course and outcome of the disease. Chronic oxidative stress may play a critical role in the pathogenesis of colorectal cancers, given that a major promutagenic threat faced by colonic epithelial cells is that of chronic oxidative stress. Although reactive oxygen species arise in most cells as a result of normal metabolic processes, additional sources of oxidative stress in colonic cells may include enzymes such as cyclooxygenase 2 (COX-2) and ATPase 6 and 8. High levels of COX-2 and ATPase protein expression have been detected in human colorectal polyps, which are lesions that can progress to colorectal carcinomas. This study applied spectrophotometric, dinitrophenylhydrazone (DNPH) assay, two dimensional gel electrophoresis, and Western blot analyses to assess the levels of oxidatively modified carbonyl proteins in 37 pairs of normal/surrounding and colorectal adenomatous polyps and cancer tissues. Our data showed that the levels of reactive protein carbonyl groups increased as level of malignancy increased. The level of carbonyl protein was 58% and 26% less in N/S tissues as compare to tumor tissue in adenocarcinoma, and colorectal adenomatous polyps tissues respectably. The differences between the level of carbonyl potion in N/S and tumor tissues was more pronounced in African American patient than in Caucasians. Also the levels of carbonyl proteins were notably higher in tissue contained higher number of tumor cells in different tissues blocks obtained from same patient. Our results may suggest that oxidative stress is involved in oxidatively modification of carbonyl proteins, leading to increased aggressiveness of colorectal polyps.

This study was supported by NIGMS grant # GM099663- awarded to Dr. Felix O. Aikhionbare

Citation Format: LaShanale M. Wallace, Sharifeh Mehrabi, Shakeria Cohen, Felix O. Aikhionbare. Elevation of oxidative expression proteins in colorectal adenomatous polyps. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B55.