Browsing by Subject "Pancreatic Cancer"
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Item An Analysis of Pancreatic Cancer(Office of the Vice Chancellor for Research, 2015-04-17) Wagle, PragatThe pancreas is extremely important in various enzymatic activities, such as the production of numerous enzymes such as insulin. Pancreatic Cancer is an extremely deadly disease, which 40,000 people of the 46,000 diagnosed each year fail to survive. It is the 12th most common type of cancer and the 4th leading cause of cancer related deaths. There are 4 stages to Pancreatic ranging from stage 1 to stage 4, where the cancer has spread to a distant organ. Pancreatic cancer is an extremely difficult to diagnose as early symptoms aren’t suggestive as many other illnesses have similar signs and symptoms. Diagnosis can be done through the use of physical examinations, ct scan, ultrasound, endoscopic ultrasound, PET scan, and most effectively a needle biopsy. Currently in development are numerous different therapies. A collective effort is being put forth to further improve current established methods to combat Pancreatic Cancer. A current four-drug chemotherapy, that had results published in May 2011 has shown a 4-month improvement using a regimen called Folfirinox. Compared to treatment with gemcitabine, which is the current therapy mainly utilized, Folfirinox showed improvement on 16 percent more patients in a phase 3 trial. Another trial with a combination of Nab-Paclitaxel and Gemcitabine was conducted against just gemcitabine. Patients with the combination showed a 1.8 months higher average survival rate than without, and showed a significantly higher survival rate through two years of 13% and 5% respectively. Overall these therapies must be reformed to be compatible with a bigger patient population. Subsequently the side effects of the treatments also need to be improved as the side effects include high risk of neutropenia. Both these treatments demonstrate a more efficient therapy and have been implemented into practice but still require improvement.Item Contribution of Environment and Genetics to Pancreatic Cancer Susceptibility(Public Library of Science, 2014-03-20) Hocevar, Barbara A.; Kamendulis, Lisa M.; Pu, Xinzhu; Perkins, Susan M.; Wang, Zheng-Yu; Johnston, Erica L.; DeWitt, John M.; Li, Lang; Loehrer, Patrick J.; Klaunig, James E.; Chiorean, E. Gabriela; Medicine, School of MedicineSeveral risk factors have been identified as potential contributors to pancreatic cancer development, including environmental and lifestyle factors, such as smoking, drinking and diet, and medical conditions such as diabetes and pancreatitis, all of which generate oxidative stress and DNA damage. Oxidative stress status can be modified by environmental factors and also by an individual's unique genetic makeup. Here we examined the contribution of environment and genetics to an individual's level of oxidative stress, DNA damage and susceptibility to pancreatic cancer in a pilot study using three groups of subjects: a newly diagnosed pancreatic cancer group, a healthy genetically-unrelated control group living with the case subject, and a healthy genetically-related control group which does not reside with the subject. Oxidative stress and DNA damage was evaluated by measuring total antioxidant capacity, direct and oxidative DNA damage by Comet assay, and malondialdehyde levels. Direct DNA damage was significantly elevated in pancreatic cancer patients (age and sex adjusted mean ± standard error: 1.00±0.05) versus both healthy unrelated and related controls (0.70±0.06, p<0.001 and 0.82±0.07, p = 0.046, respectively). Analysis of 22 selected SNPs in oxidative stress and DNA damage genes revealed that CYP2A6 L160H was associated with pancreatic cancer. In addition, DNA damage was found to be associated with TNFA −308G>A and ERCC4 R415Q polymorphisms. These results suggest that measurement of DNA damage, as well as select SNPs, may provide an important screening tool to identify individuals at risk for development of pancreatic cancer.Item IL-6 Trans-Signaling and Crosstalk Among Tumor, Muscle and Fat Mediate Pancreatic Cancer Cachexia(BioRxiv, 2020-09-17) Rupert, Joseph E.; Bonetto, Andrea; Narasimhan, Ashok; Liu, Yunlong; O’Connell, Thomas M.; Koniaris, Leonidas G.; Zimmers, Teresa A.; Biochemistry and Molecular Biology, School of MedicineMost patients with pancreatic adenocarcinoma (PDAC) suffer unintentional weight loss, or cachexia. Interleukin-6 causes cachexia in mice and associates with mortality in PDAC. Here we show that tumor cell-derived IL-6 mediates crosstalk between tumor and peripheral tissues to promote cachexia. Tumor-cell IL-6 elicits expression of IL-6 in fat and IL-6 and IL-6 receptor (IL6R) in muscle, concomitantly raising both in blood. Inflammation-induced adipose lipolysis elevates circulating fatty acids, which cooperate with IL-6 to induce skeletal muscle dysmetabolism and wasting. Thus, PDAC induces crosstalk among tumor, fat and muscle via a feed-forward, IL-6 signaling loop. Tumor talks to muscle and fat through IL-6, and muscle to fat via IL6R trans-signaling, and fat to muscle through lipids and fatty acids. Disruption of this crosstalk by depletion of tumor-derived IL-6 halved fat wasting and abolished muscle loss, supporting IL-6, IL-6R and lipids as causal nodes for tissue crosstalk in PDAC cachexia. Significance PDAC-associated cachexia significantly increases patient morbidity and mortality. This study identifies muscle and fat crosstalk via IL6R trans-signaling in concert with muscle steatosis as a main driver of PDAC-associated cachexia.Item Long-Term Gemcitabine Treatment Reshapes the Pancreatic Tumor Microenvironment and Sensitizes Murine Carcinoma to Combination Immunotherapy(American Association for Cancer Research, 2020-08-01) Principe, Daniel R.; Narbutis, Matthew; Kumar, Sandeep; Park, Alex; Viswakarma, Navin; Dorman, Matthew J.; Kamath, Suneel D.; Grippo, Paul J.; Fishel, Melissa L.; Hwang, Rosa F.; Thummuri, Dinesh; Underwood, Patrick W.; Munshi, Hidayatullah G.; Trevino, Jose G.; Rana, Ajay; Pediatrics, School of MedicinePancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death with a median survival time of 6–12 months. Most patients present with disseminated disease and the majority are offered palliative chemotherapy. With no approved treatment modalities for patients who progress on chemotherapy, we explored the effects of long-term Gemcitabine on the tumor microenvironment in order to identify potential therapeutic options for chemo-refractory PDAC. Using a combination of mouse models, primary cell line-derived xenografts, and established tumor cell lines, we first evaluated chemotherapy-induced alterations in the tumor secretome and immune surface proteins by high throughput proteomic arrays. In addition to enhancing antigen presentation and immune checkpoint expression, Gemcitabine consistently increased the synthesis of CCL/CXCL chemokines and TGFβ-associated signals. These secreted factors altered the composition of the tumor stroma, conferring Gemcitabine resistance to cancer-associated fibroblasts in vitro and further enhancing TGFβ1 biosynthesis. Combined Gemcitabine and anti-PD-1 treatment in transgenic models of murine PDAC failed to alter disease course unless mice also underwent genetic or pharmacologic ablation of TGFβ signaling. In the setting of TGFβ signaling deficiency, Gemcitabine and anti-PD-1 led to a robust CD8+ T-cell response and decrease in tumor burden, markedly enhancing overall survival. These results suggest that Gemcitabine successfully primes PDAC tumors for immune checkpoint inhibition by enhancing antigen presentation only following disruption of the immunosuppressive cytokine barrier. Given the current lack of third-line treatment options, this approach warrants consideration in the clinical management of Gemcitabine-refractory PDAC.Item Longitudinal Bioluminescence Imaging of Primary Versus Abdominal Metastatic Tumor Growth in Orthotopic Pancreatic Tumor Models in NSG Mice(LWW, 2015-01) Shannon, Harlan E.; Fishel, Melissa L.; Xie, Jingwu; Gu, Dongsheng; McCarthy, Brian P.; Riley, Amanda A.; Sinn, Anthony L.; Silver, Jayne M.; Peterman, Kacie; Kelley, Mark R.; Hanenberg, Helmut; Korc, Murray; Pollok, Karen E.; Territo, Paul R.; Department of Pediatrics, School of MedicineObjectives: The purpose of the present study was to develop and validate noninvasive bioluminescence imaging methods for differentially monitoring primary and abdominal metastatic tumor growth in mouse orthotopic models of pancreatic cancer. Methods: A semiautomated maximum entropy segmentation method was implemented for the primary tumor region of interest, and a rule-based method for manually drawing a region of interest for the abdominal metastatic region was developed for monitoring tumor growth in orthotopic models of pancreatic cancer. The 2 region-of-interest methods were validated by having 2 observers independently segment Panc-1 tumors, and the results were compared with the number of mesenteric lymph node nodules and histopathologic assessment of liver metastases. The findings were extended to orthotopic tumors of the more metastatic MIA PaCa-2 and AsPC-1 cells where separate groups of animals were implanted with different numbers of cells. Results: The results demonstrated that the segmentation methods were highly reliable, reproducible, and robust and allowed statistically significant discrimination in the growth rates of primary and abdominal metastatic tumors of different cell lines implanted with different numbers of cells. Conclusions: The present results demonstrate that primary tumors and abdominal metastatic foci in orthotopic pancreatic cancer models can be reliably quantified separately and noninvasively over time with bioluminescence imaging.Item Musculoskeletal Effects of Oncostatin M in Pancreatic Cancer Cachexia(2022-07) Jengelley, Daenique Heather Andrene; Zimmers, Teresa A.; Goebl, Mark G.; Mayo, Lindsey D.; Nakshatri, Harikrishna; Ostrowski, Michael C.Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancerrelated deaths with a five-year survival rate of 11%. PDAC tumors are characterized by a dense desmoplastic stromal microenvironment, mediated in part through local cytokine production. PDAC tumors also elicit a systemic inflammatory response in the host; this, combined with a loss of body weight due to muscle and fat wasting, is characteristic of cachexia. Understanding the molecular mechanisms that drive malignant inflammation is critical to improve PDAC therapy and increase patient survival. Oncostatin M (OSM) belongs to the IL-6/GP130 family of cytokines, members of which have been shown to promote PDAC tumor development, inflammation, and cachexia. Much less is known of OSM. My central hypothesis was that OSM promotes pancreatic cancer and cachexia by inducing local and systemic inflammation, fibrosis, and wasting via OSM signaling through the receptor, OSM receptor (OSMR). We investigated effects of exogenous OSM administration in wildtype and IL-6 null mice without cancer. OSM induced systemic fibrosis, bone loss, local muscle wasting, and cardiac dysfunction in presence and absence of IL-6. We further defined the roles of OSM/OSMR in the pancreatic cancer microenvironment and macroenvironment. OSM activated genes involved in inflammation, fibrosis, and tumor progression in both tumor cells and fibroblasts and altered the tumor microenvironment, promoting a dense compaction of tumor cells and cancer associated fibroblasts. Loss of systemic OSM signaling altered tumor metabolism and reduced the stromal compartment without affecting tumor size. Loss of OSMR signaling in tumor cells reduced tumor size and promoted survival. However, systemic loss of OSM or OSMR in host cells did not halt effects of cachexia including muscle dysfunction, atrophy, or inflammation/anemia. Overall, OSM/OSMR signaling in the microenvironment is necessary in modulating tumor phenotype and promoting survival in PDAC but may not be necessary for pancreatic cancer cachexia.Item Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models(AACR, 2016-11-01) Logsdon, Derek P.; Grimard, Michelle; Luo, Meihua; Shahda, Safi; Jiang, Yanlin; Tong, Yan; Yu, Zhangsheng; Zyromski, Nicholas; Schipani, Ernestina; Carta, Fabrizio; Supuran, Claudiu T.; Korc, Murray; Ivan, Mircea; Kelley, Mark R.; Fishel, Melissa L.; Department of Pediatrics, School of MedicinePancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related mortality in the United States. Aggressive treatment regimens have not changed the disease course, and the median survival has just recently reached a year. Several mechanisms are proposed to play a role in PDAC therapeutic resistance, including hypoxia, which creates a more aggressive phenotype with increased metastatic potential and impaired therapeutic efficacy. AP Endonuclease-1/Redox Effector Factor 1 (APE1/Ref-1) is a multifunctional protein possessing a DNA repair function in base excision repair and the ability to reduce oxidized transcription factors, enabling them to bind to their DNA target sequences. APE1/Ref-1 regulates several transcription factors involved in survival mechanisms, tumor growth, and hypoxia signaling. Here, we explore the mechanisms underlying PDAC cell responses to hypoxia and modulation of APE1/Ref-1 redox signaling activity, which regulates the transcriptional activation of hypoxia-inducible factor 1 alpha (HIF1α). Carbonic anhydrase IX (CA9) is regulated by HIF1α and functions as a part of the cellular response to hypoxia to regulate intracellular pH, thereby promoting cell survival. We hypothesized that modulating APE1/Ref-1 function will block activation of downstream transcription factors, STAT3 and HIF1α, interfering with the hypoxia-induced gene expression. We demonstrate APE1/Ref-1 inhibition in patient-derived and established PDAC cells results in decreased HIF1α–mediated induction of CA9. Furthermore, an ex vivo three-dimensional tumor coculture model demonstrates dramatic enhancement of APE1/Ref-1–induced cell killing upon dual targeting of APE1/Ref-1 and CA9. Both APE1/Ref-1 and CA9 are under clinical development; therefore, these studies have the potential to direct novel PDAC therapeutic treatment.Item Targeting Protein Arginine Methyltransferase 5 as a Novel Therapeutic Approach in Pancreatic & Colorectal Cancer(2018-12) Prabhu, Lakshmi Milind; Lu, Tao; Safa, Ahmad; Pollok, Karen; Skaar, Todd; Zhang, Jian-TingPancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are among the most commonly diagnosed forms of cancer in the United States. Due to their widespread prevalence and high mortality rate, it is vital to develop effective therapeutic drugs to combat these deadly diseases. In both PDAC and CRC, the multifunctional factor nuclear factor kappa B (NF-kB), a central coordinator of cellular immune responses, is activated abnormally, leading to tumorigenesis and cancer progression. Therefore, controlling NF-kB activity is critical in the treatment of these cancers. In a previous study, we identified a new mechanism by which NF-kB activity is regulated by an epigenetic enzyme known as protein arginine methyltransferase 5 (PRMT5). We showed that overexpression of PRMT5 not only activated NF-kB, but also significantly promoted several characteristics associated with cancer, including increased cell proliferation, migration, and anchorage-independent growth in both PDAC and CRC cells. Moreover, in order to examine the therapeutic potential of PRMT5 in these cancers, we adapted the state-of-the-art AlphaLISA technique into a high throughput screen (HTS) platform to screen for PRMT5 inhibitors. As a result, we successfully identified the small molecule PR5-LL-CM01 as our lead hit. Further validation experiments confirmed that PR5-LL-CM01 is a potent and specific PRMT5 inhibitor that exhibits significant anti-tumor efficacy in both in vitro and in vivo models of PDAC and CRC. Additionally, in a second screen, we discovered two natural compounds, P1608K04 and P1618J22, that can also function as the PRMT5 inhibitors. These findings further highlight the robustness of the PRMT5- specific AlphaLISA HTS technique. To conclude, we describe here for the first time a novel role of PRMT5 as a tumor-promoting factor in PDAC and CRC through NF-kB activation. By successfully developing and applying an innovative AlphaLISA HTS technique, we discovered PR5-LL-CM01, P1608K04, and P1618J22 as novel PRMT5 inhibitors, with PR5-LL-CM01 showing the strongest potency in both PDAC and CRC models. Therefore, we demonstrated that PRMT5 is a promising therapeutic target in PDAC and CRC, and the novel PRMT5 inhibitor PR5-LL-CM01 could serve as a promising basis for new drug development in PDAC and CRC.Item Targeting Ref-1/APE1 Pathway Inhibition in Pancreatic Cancer Using APX3330 for Clinical Trials(Office of the Vice Chancellor for Research, 2016-04-08) Fishel, Melissa L.; Logsdon, Derek P.; Supuran, Claudiu T.; Zyromski, Nicholas; Ivan, Mircea; Kelley, Mark R.; Shah, FenilPancreatic ductal adenocarcinoma is the 4th leading cause of cancer-related mortality in the US. Most patients present with advanced disease and ~95% die within five years, most surviving under six months. Targeted therapies offer modest improvement in survival, albeit at an increase in side effects and unwanted toxicities. Ref-1 regulates transcription factors involved in pancreatic cancer cell survival signaling due to its redox-coactivator activity, such as HIF-1α, NFκB, NRF2 and STAT3. High expression levels of Ref-1 indicate decreased survival in PDAC and other cancers. APX3330, a specific Ref-1 inhibitor, has been shown in multiple in vitro and in vivo pancreatic cancer models to be effective in reducing tumor growth and metastases. The safety and dose administration of APX3330 have been previously established, including toxicology, phase I, and phase II clinical evaluation in non-cancer patients in Japan (Eisai). We have partnered with ApeX Therapeutics to develop APX3330 for cancer treatment (phase I trial anticipated early 2016). We studied interactions of Ref-1, APX3330, convergent pathways; i.e. HIF-1α and STAT3, and downstream targets like CAIX. We performed in vivo studies demonstrating single and combination effects of APX3330 with Gemcitabine (Gem) showing significantly decreased tumor volume in the combination treatments. We also tested single and combination studies of APX3330 in an ex vivo 3-D tumor-stroma model system using patient derived tumor cells along with patient derived cancer-associated fibroblasts. We used the CAIX inhibitor SLC-0111 and JAK2 inhibitor, Ruxolitinib; both in clinical trials. In our system, APX3330 decreases the tumor area and intensity in a dose-dependent manner. The combination of APX3330 with Gem demonstrated an additive enhancement effect in the tumor, and APX3330 with SLC-0111/Ruxolitinib enhanced tumor killing. These data demonstrate APX3330 single agent efficacy in our 3D patient model and enhanced tumor killing when pathways regulated by Ref-1, HIF-1 and STAT3 are blocked.Item Tumor-stroma interaction mediated by tissue transglutaminase in pancreatic cancer(2015-08) Lee, Jiyoon; Matei, Daniela Elena; Harrington, Maureen A.; Herbert, Brittney-Shea; Xie, JingwuPancreatic ductal adenocarcinoma (PDA) is a deadly disease due to early metastasis and resistance to chemotherapy. PDA is commonly associated with a dense desmoplastic stroma, which forms a protective niche for cancer cells. Tissue transglutaminase (TG2), a Ca2+-dependent enzyme, is abundantly expressed in pancreatic cancer cells and crosslinks proteins through acyl-transfer transamidation between glutamine and lysine residues. The objective of the study was to determine the functions of TG2 in the pancreatic stroma. Orthotopic pancreatic xenografts and co-culture systems tested the mechanisms by which the enzyme modulates tumor-stroma interactions. We showed that TG2 secreted by cancer cells is enzymatically active and renders the stroma denser by crosslinking collagen, which in turn activates fibroblasts and stimulates their proliferation. Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are transcription factors involved in mechanotransduction. The TG2-mediated fibrosis-rich, stiff microenvironment conveys mechanical cues to cancer cells leading to activation of YAP and TAZ, promoting cell proliferation and tumor growth. Stable knockdown of TG2 in pancreatic cancer cells led to decreased size of pancreatic xenografts and increased sensitivity of xenografts to gemcitabine. Taken together, our results demonstrate that TG2 secreted in the tumor microenvironment orchestrates the crosstalk between cancer cells and the stroma, fundamentally impacting tumor growth and response to chemotherapy. Our study supports TG2 inhibition in the pancreatic stroma as a novel strategy to block pancreatic cancer progression.