Latest Pancreatic Genomics Papers

In this weeks batch of papers, we have some interesting clinical trials results concerning the Ras inhibitor Salirasib and the Hedgehog inhibitor Vismodegib.  From the world of biologics, we have news of a CD40 antibody used in conjunction with gemcitabine.

If you’d like to help review and curate the papers in the Pancreatic Cancer Genomics collection in Mendeley, feel free to join the group.

  • Salirasib in the treatment of pancreatic cancer.

    Future oncology (London, England) (2010). Volume: 6, Issue: 6. Pages: 885-91.Ernesto Bustinza-Linares, Razelle Kurzrock, Apostolia-Maria Tsimberidou et al.The Ras family of genes is involved in the cellular regulation of proliferation, differentiation, cell adhesion and apoptosis. The K-ras gene is mutated in over 90% of pancreatic cancer cases. Salirasib (S-trans,trans-farnesylthiosalycilic acid [FTS]) is a synthetic small molecule that acts as a potent Ras inhibitor. It is a farnesylcysteine mimetic that selectively disrupts the association of active RAS proteins with the plasma membrane. Animal studies demonstrated that salirasib inhibited tumor growth, downregulated gene expression in the cell cycle and Ras signaling pathways. In a clinical study of salirasib combined with standard doses of gemcitabine, it was demonstrated that the two drugs have no overlapping pharmacokinetics. The salirasib recommended dose was 600 mg twice daily and the progression-free survival was 4.7 months. Future studies will determine whether salirasib adds to the anti-tumor activity of drugs approved by the US FDA for pancreatic cancer.

  • Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors.

    Clinical cancer research : an official journal of the American Association for Cancer Research (2011). Volume: 17, Issue: 8. Pages: 2502-11.Patricia M LoRusso, Charles M Rudin, Josina C Reddy, Raoul Tibes, Glen J Weiss, Mitesh J Borad, Christine L Hann, Julie R Brahmer, Ilsung Chang, Walter C Darbonne, Richard A Graham, Kenn L Zerivitz, Jennifer A Low, Daniel D Von Hoff et al.The hedgehog (Hh) signaling pathway, a key regulator of cell growth and differentiation during development is implicated in pathogenesis of certain cancers. Vismodegib (GDC-0449) is a small-molecule inhibitor of smoothened, a key component of Hh signaling. This phase I trial assessed GDC-0449 treatment in patients with solid tumors refractory to current therapies or for which no standard therapy existed.

  • Dynamics of the immune reaction to pancreatic cancer from inception to invasion.

    Cancer research (2007). Volume: 67, Issue: 19. Pages: 9518-27.Carolyn E Clark, Sunil R Hingorani, Rosemarie Mick, Chelsea Combs, David A Tuveson, Robert H Vonderheide et al.The dynamics of cancer immunosurveillance remain incompletely understood, hampering efforts to develop immunotherapy of cancer. We evaluated the evolving in vivo immune response to a spontaneous tumor in a genetically defined mouse model of pancreatic ductal adenocarcinoma from the inception of preinvasive disease to invasive cancer. We observed a prominent leukocytic infiltration even around the lowest grade preinvasive lesions, but immunosuppressive cells, including tumor-associated macrophages, myeloid-derived suppressor cells (MDSC), and regulatory T cells (Treg), dominated the early response and persisted through invasive cancer. Effector T cells, however, were scarce in preinvasive lesions, found in only a subset of advanced cancers, and showed no evidence of activation. The lack of tumor-infiltrating effector T cells strongly correlated with the presence of intratumoral MDSC with a near mutual exclusion. In vitro, we found that MDSC suppressed T-cell proliferation. Overall, our results show that suppressive cells of the host immune system appear early during pancreatic tumorigenesis, preceding and outweighing antitumor cellular immunity, and likely contribute to disease progression. Thus, in contrast to the hypothesis that an early “elimination phase” of cancer immunosurveillance is eventually overwhelmed by a growing invasive tumor, our findings suggest that productive tumor immunity may be undermined from the start. Efforts to test potent inhibitors of MDSC, tumor-associated macrophages, and Treg, particularly early in the disease represent important next steps for developing novel immunotherapy of cancer.

  • CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans.

    Science (New York, N.Y.) (2011). Volume: 331, Issue: 6024. Pages: 1612-6.Gregory L Beatty, Elena G Chiorean, Matthew P Fishman, Babak Saboury, Ursina R Teitelbaum, Weijing Sun, Richard D Huhn, Wenru Song, Dongguang Li, Leslie L Sharp, Drew A Torigian, Peter J O’Dwyer, Robert H Vonderheide et al.Immunosuppressive tumor microenvironments can restrain antitumor immunity, particularly in pancreatic ductal adenocarcinoma (PDA). Because CD40 activation can reverse immune suppression and drive antitumor T cell responses, we tested the combination of an agonist CD40 antibody with gemcitabine chemotherapy in a small cohort of patients with surgically incurable PDA and observed tumor regressions in some patients. We reproduced this treatment effect in a genetically engineered mouse model of PDA and found unexpectedly that tumor regression required macrophages but not T cells or gemcitabine. CD40-activated macrophages rapidly infiltrated tumors, became tumoricidal, and facilitated the depletion of tumor stroma. Thus, cancer immune surveillance does not necessarily depend on therapy-induced T cells; rather, our findings demonstrate a CD40-dependent mechanism for targeting tumor stroma in the treatment of cancer.

  • Hypoxia activates the hedgehog signaling pathway in a ligand-independent manner by upregulation of Smo transcription in pancreatic cancer.

    Cancer science (2011). Volume: 102, Issue: 6. Pages: 1144-50.Hideya Onishi, Masaya Kai, Seiichi Odate, Hironori Iwasaki, Yoshihiro Morifuji, Toshitatsu Ogino, Takafumi Morisaki, Yutaka Nakashima, Mitsuo Katano et al.The hedgehog (Hh) signaling pathway is activated in various types of cancer including pancreatic ductal adenocarcinoma. It has been shown that extremely low oxygen tension (below 1% O2) is found in tumor tissue including pancreatic ductal adenocarcinoma cells (PDAC) and increases the invasiveness of PDAC. To investigate the contribution of the Hh pathway to hypoxia-induced invasiveness, we examined how hypoxia affects Hh pathway activation and the invasiveness of PDAC. In the present study, three human PDAC lines were cultured under normoxic (20% O2) or hypoxic (1% O2) conditions. Hypoxia upregulated the transcription of Sonic hedgehog (Shh), Smoothened (Smo), Gli1 and matrix metalloproteinase9 (MMP9) and increased the invasiveness of PDAC. Significantly, neither the addition of recombinant Shh (rhShh) nor the silencing of Shh affected the transcription of these genes and the invasiveness of PDAC. On the other hand, silencing of Smo decreased the transcription of Gli1 and MMP9 and PDAC invasiveness. Silencing of Gli1 or MMP9 decreased PDAC invasiveness. These results suggest that hypoxia activates the Hh pathway of PDAC by increasing the transcription of Smo in a ligand-independent manner and increases PDAC invasiveness.

  • Hypoxia activates the hedgehog signaling pathway in a ligand-independent manner by upregulation of Smo transcription in pancreatic cancer.

    Cancer science (2011). Volume: 102, Issue: 6. Pages: 1144-50.Hideya Onishi, Masaya Kai, Seiichi Odate, Hironori Iwasaki, Yoshihiro Morifuji, Toshitatsu Ogino, Takafumi Morisaki, Yutaka Nakashima, Mitsuo Katano et al.The hedgehog (Hh) signaling pathway is activated in various types of cancer including pancreatic ductal adenocarcinoma. It has been shown that extremely low oxygen tension (below 1% O2) is found in tumor tissue including pancreatic ductal adenocarcinoma cells (PDAC) and increases the invasiveness of PDAC. To investigate the contribution of the Hh pathway to hypoxia-induced invasiveness, we examined how hypoxia affects Hh pathway activation and the invasiveness of PDAC. In the present study, three human PDAC lines were cultured under normoxic (20% O2) or hypoxic (1% O2) conditions. Hypoxia upregulated the transcription of Sonic hedgehog (Shh), Smoothened (Smo), Gli1 and matrix metalloproteinase9 (MMP9) and increased the invasiveness of PDAC. Significantly, neither the addition of recombinant Shh (rhShh) nor the silencing of Shh affected the transcription of these genes and the invasiveness of PDAC. On the other hand, silencing of Smo decreased the transcription of Gli1 and MMP9 and PDAC invasiveness. Silencing of Gli1 or MMP9 decreased PDAC invasiveness. These results suggest that hypoxia activates the Hh pathway of PDAC by increasing the transcription of Smo in a ligand-independent manner and increases PDAC invasiveness.

  • The patterns and dynamics of genomic instability in metastatic pancreatic cancer.

    Nature (2010). Volume: 467, Issue: 7319. Pages: 1109-13.Peter J Campbell, Shinichi Yachida, Laura J Mudie, Philip J Stephens, Erin D Pleasance, Lucy A Stebbings, Laura A Morsberger, Calli Latimer, Stuart McLaren, Meng-Lay Lin, David J McBride, Ignacio Varela, Serena A Nik-Zainal, Catherine Leroy, Mingming Jia, Andrew Menzies, Adam P Butler, Jon W Teague, Constance A Griffin, John Burton, Harold Swerdlow, Michael A Quail, Michael R Stratton, Christine Iacobuzio-Donahue, P Andrew Futreal et al.Pancreatic cancer is an aggressive malignancy with a five-year mortality of 97-98%, usually due to widespread metastatic disease. Previous studies indicate that this disease has a complex genomic landscape, with frequent copy number changes and point mutations, but genomic rearrangements have not been characterized in detail. Despite the clinical importance of metastasis, there remain fundamental questions about the clonal structures of metastatic tumours, including phylogenetic relationships among metastases, the scale of ongoing parallel evolution in metastatic and primary sites, and how the tumour disseminates. Here we harness advances in DNA sequencing to annotate genomic rearrangements in 13 patients with pancreatic cancer and explore clonal relationships among metastases. We find that pancreatic cancer acquires rearrangements indicative of telomere dysfunction and abnormal cell-cycle control, namely dysregulated G1-to-S-phase transition with intact G2-M checkpoint. These initiate amplification of cancer genes and occur predominantly in early cancer development rather than the later stages of the disease. Genomic instability frequently persists after cancer dissemination, resulting in ongoing, parallel and even convergent evolution among different metastases. We find evidence that there is genetic heterogeneity among metastasis-initiating cells, that seeding metastasis may require driver mutations beyond those required for primary tumours, and that phylogenetic trees across metastases show organ-specific branches. These data attest to the richness of genetic variation in cancer, brought about by the tandem forces of genomic instability and evolutionary selection.

  • Pancreatic cancer risk and ABO blood group alleles: results from the pancreatic cancer cohort consortium.

    Cancer research (2010). Volume: 70, Issue: 3. Pages: 1015-23.Brian M Wolpin, Peter Kraft, Myron Gross, Kathy Helzlsouer, H Bas Bueno-de-Mesquita, Emily Steplowski, Rachael Z Stolzenberg-Solomon, Alan A Arslan, Eric J Jacobs, Andrea Lacroix, Gloria Petersen, Wei Zheng, Demetrius Albanes, Naomi E Allen, Laufey Amundadottir, Garnet Anderson, Marie-Christine Boutron-Ruault, Julie E Buring, Federico Canzian, Stephen J Chanock, Sandra Clipp, John Michael Gaziano, Edward L Giovannucci, G?ran Hallmans, Susan E Hankinson, Robert N Hoover, David J Hunter, Amy Hutchinson, Kevin Jacobs, Charles Kooperberg, Shannon M Lynch, Julie B Mendelsohn, Dominique S Michaud, Kim Overvad, Alpa V Patel, Aleksandar Rajkovic, Maria-Jos? Sanch?z, Xiao-Ou Shu, Nadia Slimani, Gilles Thomas, Geoffrey S Tobias, Dimitrios Trichopoulos, Paolo Vineis, Jarmo Virtamo, Jean Wactawski-Wende, Kai Yu, Anne Zeleniuch-Jacquotte, Patricia Hartge, Charles S Fuchs et al.A recent genome-wide association study (PanScan) identified significant associations at the ABO gene locus with risk of pancreatic cancer, but the influence of specific ABO genotypes remains unknown. We determined ABO genotypes (OO, AO, AA, AB, BO, and BB) in 1,534 cases and 1,583 controls from 12 prospective cohorts in PanScan, grouping participants by genotype-derived serologic blood type (O, A, AB, and B). Adjusted odds ratios (ORs) for pancreatic cancer by ABO alleles were calculated using logistic regression. Compared with blood type O, the ORs for pancreatic cancer in subjects with types A, AB, and B were 1.38 [95% confidence interval (95% CI), 1.18-1.62], 1.47 (95% CI, 1.07-2.02), and 1.53 (95% CI, 1.21-1.92), respectively. The incidence rates for blood types O, A, AB, and B were 28.9, 39.9, 41.8, and 44.5 cases per 100,000 subjects per year. An increase in risk was noted with the addition of each non-O allele. Compared with OO genotype, subjects with AO and AA genotype had ORs of 1.33 (95% CI, 1.13-1.58) and 1.61 (95% CI, 1.22-2.18), whereas subjects with BO and BB genotypes had ORs of 1.45 (95% CI, 1.14-1.85) and 2.42 (1.28-4.57). The population attributable fraction for non-O blood type was 19.5%. In a joint model with smoking, current smokers with non-O blood type had an adjusted OR of 2.68 (95% CI, 2.03-3.54) compared with nonsmokers of blood type O. We concluded that ABO genotypes were significantly associated with pancreatic cancer risk.

  • A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33.

    Nature genetics (2010). Volume: 42, Issue: 3. Pages: 224-8.Gloria M Petersen, Laufey Amundadottir, Charles S Fuchs, Peter Kraft, Rachael Z Stolzenberg-Solomon, Kevin B Jacobs, Alan A Arslan, H Bas Bueno-de-Mesquita, Steven Gallinger, Myron Gross, Kathy Helzlsouer, Elizabeth A Holly, Eric J Jacobs, Alison P Klein, Andrea LaCroix, Donghui Li, Margaret T Mandelson, Sara H Olson, Harvey A Risch, Wei Zheng, Demetrius Albanes, William R Bamlet, Christine D Berg, Marie-Christine Boutron-Ruault, Julie E Buring, Paige M Bracci, Federico Canzian, Sandra Clipp, Michelle Cotterchio, Mariza de Andrade, Eric J Duell, J Michael Gaziano, Edward L Giovannucci, Michael Goggins, G?ran Hallmans, Susan E Hankinson, Manal Hassan, Barbara Howard, David J Hunter, Amy Hutchinson, Mazda Jenab, Rudolf Kaaks, Charles Kooperberg, Vittorio Krogh, Robert C Kurtz, Shannon M Lynch, Robert R McWilliams, Julie B Mendelsohn, Dominique S Michaud, Hemang Parikh, Alpa V Patel, Petra H M Peeters, Aleksandar Rajkovic, Elio Riboli, Laudina Rodriguez, Daniela Seminara, Xiao-Ou Shu, Gilles Thomas, Anne Tj?nneland, Geoffrey S Tobias, Dimitrios Trichopoulos, Stephen K Van Den Eeden, Jarmo Virtamo, Jean Wactawski-Wende, Zhaoming Wang, Brian M Wolpin, Herbert Yu, Kai Yu, Anne Zeleniuch-Jacquotte, Joseph F Fraumeni, Robert N Hoover, Patricia Hartge, Stephen J Chanock et al.We conducted a genome-wide association study of pancreatic cancer in 3,851 affected individuals (cases) and 3,934 unaffected controls drawn from 12 prospective cohort studies and 8 case-control studies. Based on a logistic regression model for genotype trend effect that was adjusted for study, age, sex, self-described ancestry and five principal components, we identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Two correlated SNPs, rs9543325 (P = 3.27 x 10(-11), per-allele odds ratio (OR) 1.26, 95% CI 1.18-1.35) and rs9564966 (P = 5.86 x 10(-8), per-allele OR 1.21, 95% CI 1.13-1.30), map to a nongenic region on chromosome 13q22.1. Five SNPs on 1q32.1 map to NR5A2, and the strongest signal was at rs3790844 (P = 2.45 x 10(-10), per-allele OR 0.77, 95% CI 0.71-0.84). A single SNP, rs401681 (P = 3.66 x 10(-7), per-allele OR 1.19, 95% CI 1.11-1.27), maps to the CLPTM1L-TERT locus on 5p15.33, which is associated with multiple cancers. Our study has identified common susceptibility loci for pancreatic cancer that warrant follow-up studies.

  • Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer.

    Nature genetics (2009). Volume: 41, Issue: 9. Pages: 986-90.Laufey Amundadottir, Peter Kraft, Rachael Z Stolzenberg-Solomon, Charles S Fuchs, Gloria M Petersen, Alan A Arslan, H Bas Bueno-de-Mesquita, Myron Gross, Kathy Helzlsouer, Eric J Jacobs, Andrea LaCroix, Wei Zheng, Demetrius Albanes, William Bamlet, Christine D Berg, Franco Berrino, Sheila Bingham, Julie E Buring, Paige M Bracci, Federico Canzian, Fran?oise Clavel-Chapelon, Sandra Clipp, Michelle Cotterchio, Mariza de Andrade, Eric J Duell, John W Fox, Steven Gallinger, J Michael Gaziano, Edward L Giovannucci, Michael Goggins, Carlos A Gonz?lez, G?ran Hallmans, Susan E Hankinson, Manal Hassan, Elizabeth A Holly, David J Hunter, Amy Hutchinson, Rebecca Jackson, Kevin B Jacobs, Mazda Jenab, Rudolf Kaaks, Alison P Klein, Charles Kooperberg, Robert C Kurtz, Donghui Li, Shannon M Lynch, Margaret Mandelson, Robert R McWilliams, Julie B Mendelsohn, Dominique S Michaud, Sara H Olson, Kim Overvad, Alpa V Patel, Petra H M Peeters, Aleksandar Rajkovic, Elio Riboli, Harvey A Risch, Xiao-Ou Shu, Gilles Thomas, Geoffrey S Tobias, Dimitrios Trichopoulos, Stephen K Van Den Eeden, Jarmo Virtamo, Jean Wactawski-Wende, Brian M Wolpin, Herbert Yu, Kai Yu, Anne Zeleniuch-Jacquotte, Stephen J Chanock, Patricia Hartge, Robert N Hoover et al.We conducted a two-stage genome-wide association study of pancreatic cancer, a cancer with one of the lowest survival rates worldwide. We genotyped 558,542 SNPs in 1,896 individuals with pancreatic cancer and 1,939 controls drawn from 12 prospective cohorts plus one hospital-based case-control study. We conducted a combined analysis of these groups plus an additional 2,457 affected individuals and 2,654 controls from eight case-control studies, adjusting for study, sex, ancestry and five principal components. We identified an association between a locus on 9q34 and pancreatic cancer marked by the SNP rs505922 (combined P = 5.37 x 10(-8); multiplicative per-allele odds ratio 1.20; 95% confidence interval 1.12-1.28). This SNP maps to the first intron of the ABO blood group gene. Our results are consistent with earlier epidemiologic evidence suggesting that people with blood group O may have a lower risk of pancreatic cancer than those with groups A or B.

  • Gemcitabine Plus nab-Paclitaxel Is an Active Regimen in Patients With Advanced Pancreatic Cancer: A Phase I/II Trial

    Journal of Clinical Oncology (2011).D. D. Von Hoff, R. K. Ramanathan, M. J. Borad, D. A. Laheru, L. S. Smith, T. E. Wood, R. L. Korn, N. Desai, V. Trieu, J. L. Iglesias, H. Zhang, P. Soon-Shiong, T. Shi, N. V. Rajeshkumar, A. Maitra, M. Hidalgo et al.PURPOSEThe trial objectives were to identify the maximum-tolerated dose (MTD) of first-line gemcitabine plus nab-paclitaxel in metastatic pancreatic adenocarcinoma and to provide efficacy and safety data. Additional objectives were to evaluate positron emission tomography (PET) scan response, secreted protein acidic and rich in cysteine (SPARC), and CA19-9 levels in relation to efficacy. Subsequent preclinical studies investigated the changes involving the pancreatic stroma and drug uptake. PATIENTS AND METHODSPatients with previously untreated advanced pancreatic cancer were treated with 100, 125, or 150 mg/m(2) nab-paclitaxel followed by gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 every 28 days. In the preclinical study, mice were implanted with human pancreatic cancers and treated with study agents.ResultsA total of 20, 44, and three patients received nab-paclitaxel at 100, 125, and 150 mg/m(2), respectively. The MTD was 1,000 mg/m(2) of gemcitabine plus 125 mg/m(2) of nab-paclitaxel once a week for 3 weeks, every 28 days. Dose-limiting toxicities were sepsis and neutropenia. At the MTD, the response rate was 48%, with 12.2 median months of overall survival (OS) and 48% 1-year survival. Improved OS was observed in patients who had a complete metabolic response on [(18)F]fluorodeoxyglucose PET. Decreases in CA19-9 levels were correlated with increased response rate, progression-free survival, and OS. SPARC in the stroma, but not in the tumor, was correlated with improved survival. In mice with human pancreatic cancer xenografts, nab-paclitaxel alone and in combination with gemcitabine depleted the desmoplastic stroma. The intratumoral concentration of gemcitabine was increased by 2.8-fold in mice receiving nab-paclitaxel plus gemcitabine versus those receiving gemcitabine alone. CONCLUSIONThe regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.

    Published using Mendeley: The reference manager for researchers

  • Comparing Aurora A and Aurora B as molecular targets for growth inhibition of pancreatic cancer cells.

    Molecular cancer therapeutics (2006). Volume: 5, Issue: 10. Pages: 2450-8.Steven L Warner, Ruben M Munoz, Phillip Stafford, Erich Koller, Laurence H Hurley, Daniel D Von Hoff, Haiyong Han et al.To address the increased need to understand the similarities and differences in targeting Aurora A or Aurora B for the treatment of cancer, we systematically evaluated the relative importance of Aurora A and/or Aurora B as molecular targets using antisense oligonucleotides. It was found that perturbations in Aurora A and Aurora B signaling result in growth arrest and apoptosis preferentially in cancer cells. The biological fingerprints of Aurora A and Aurora B inhibition were compared and contrasted in efforts to identify the superior therapeutic target. Due to the different biological responses, we conclude that each Aurora kinase should be treated as autonomous drug targets, which can be targeted independently or in combination. We observed no advantages to targeting both kinases simultaneously and feel that an Aurora A-targeted therapy may have some beneficial consequences over an Aurora B-targeted therapy, such as mitotic arrest and the rapid induction of apoptosis.

  • Tumor-stroma interactions in pancreatic ductal adenocarcinoma.

    Molecular cancer therapeutics (2007). Volume: 6, Issue: 4. Pages: 1186-97.Daruka Mahadevan, Daniel D Von Hoff et al.The host stromal response to an invasive epithelial carcinoma is frequently called a desmoplastic reaction (DR) and is a universal feature of pancreatic ductal adenocarcinoma (PDA). This DR is characterized by a complex interplay between the normal host epithelial cells, invading tumor cells, stromal fibroblasts, inflammatory cells, proliferating endothelial cells, an altered extracellular matrix, and growth factors activating oncogenic signaling pathways by autocrine and paracrine mechanisms. Hence, the tumor microenvironment is a dynamic process promoting tumor growth and invasion through mechanisms likely to include anoikis resistance, genomic instability, and drug resistance. Cell coculture models, murine models (xenograft and genetic), and gene expression profiling studies on human PDA biopsies have identified several key molecules, such as collagen type I, fibronectin, laminin, matrix metalloproteinases (MMP) and their inhibitors (tissue inhibitors of MMP), growth factors (transforming growth factor beta, platelet-derived growth factor, connective tissue growth factor, and hepatocyte growth factor), chemokines, and integrins as constituents of the DR. Despite these findings, it is unclear which molecular-cellular events initiate and drive desmoplasia in PDA. Accumulating evidence indicates that pancreatic stellate cells when activated switch to a myofibroblast phenotype that produces components of the extracellular matrix, MMPs, and tissue inhibitors of MMPs by activating the mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2) pathway. Based on current evidence, several therapeutic strategies are been evaluated on identified potential therapeutic targets. This review summarizes our current understanding of the mechanisms that potentially drive the DR in PDA and future possibilities for therapeutic targeting of this critical process.

  • Gene expression profiling-based identification of cell-surface targets for developing multimeric ligands in pancreatic cancer.

    Molecular cancer therapeutics (2008). Volume: 7, Issue: 9. Pages: 3071-80.Yoganand Balagurunathan, David L Morse, Galen Hostetter, Vijayalakshmi Shanmugam, Phillip Stafford, Sonsoles Shack, John Pearson, Maria Trissal, Michael J Demeure, Daniel D Von Hoff, Victor J Hruby, Robert J Gillies, Haiyong Han et al.Multimeric ligands are ligands that contain multiple binding domains that simultaneously target multiple cell-surface proteins. Due to cooperative binding, multimeric ligands can have high avidity for cells (tumor) expressing all targeting proteins and only show minimal binding to cells (normal tissues) expressing none or only some of the targets. Identifying combinations of targets that concurrently express in tumor cells but not in normal cells is a challenging task. Here, we describe a novel approach for identifying such combinations using genome-wide gene expression profiling followed by immunohistochemistry. We first generated a database of mRNA gene expression profiles for 28 pancreatic cancer specimens and 103 normal tissue samples representing 28 unique tissue/cell types using DNA microarrays. The expression data for genes that encode proteins with cell-surface epitopes were then extracted from the database and analyzed using a novel multivariate rule-based computational approach to identify gene combinations that are expressed at an efficient binding level in tumors but not in normal tissues. These combinations were further ranked according to the proportion of tumor samples that expressed the sets at efficient levels. Protein expression of the genes contained in the top ranked combinations was confirmed using immunohistochemistry on a pancreatic tumor tissue and normal tissue microarrays. Coexpression of targets was further validated by their combined expression in pancreatic cancer cell lines using immunocytochemistry. These validated gene combinations thus encompass a list of cell-surface targets that can be used to develop multimeric ligands for the imaging and treatment of pancreatic cancer.

  • Copy number alterations in pancreatic cancer identify recurrent PAK4 amplification.

    Cancer biology & therapy (2008). Volume: 7, Issue: 11. Pages: 1793-802.Shuaili Chen, Theresa Auletta, Ostap Dovirak, Christina Hutter, Karen Kuntz, Samira El-ftesi, Jude Kendall, Haiyong Han, Daniel D Von Hoff, Raheela Ashfaq, Anirban Maitra, Christine A Iacobuzio-Donahue, Ralph H Hruban, Robert Lucito et al.Pancreatic cancer is one of the most lethal of all cancers. The median survival is six months and less than 5% of those diagnosed survive five years. Recurrent genetic deletions and amplifications in 72 pancreatic adenocarcinomas, the largest sample set analyzed to date for pancreatic cancer, were defined using comparative genomic hybridization The recurrent genetic alterations identified target a number of previously well-characterized genes, as well as regions that contain possible new oncogenes and tumor suppressor genes. We have focused on chromosome 19q13, a region frequently found amplified in pancreatic cancer and demonstrate how boundaries of common regions of mutation can be mapped and how a gene, in this case PAK4 amplified on chromosome19q13, can be functionally validated. We show that although the PAK4 gene is not activated by mutation in cell lines with gene amplification, an oncogenic form of the KRAS2 gene is present in these cells and oncogenic KRAS2 can activate PAK4. In fact in the three samples we identified with PAK4 gene amplification, the KRAS2 gene was activated and genomically amplified. The kinase activity of the PAK4 protein is significantly higher in cells with genomic amplification as compared to cells without amplification. Our study demonstrates the utility of analyzing copy number data in a large set of neoplasms to identify genes involved in cancer. We have generated a useful dataset which will be particularly useful for the pancreatic cancer community as efforts are undertaken to sequence the pancreatic cancer genome.

  • Gemcitabine plus celecoxib in patients with advanced or metastatic pancreatic adenocarcinoma: results of a phase II trial.

    American journal of clinical oncology (2008). Volume: 31, Issue: 2. Pages: 157-62.Tomislav Dragovich, Howard Burris, Patrick Loehrer, Daniel D Von Hoff, Sherry Chow, Steven Stratton, Sylvan Green, Yrma Obregon, Irene Alvarez, Michael Gordon et al.Cycloxygenase-2 (COX-2) is overexpressed in pancreatic tumors where it may be involved in inflammation, carcinogenesis, and the regulation of neoangiogenesis. The purpose of this trial was to evaluate the combination of intravenous gemcitabine with selective COX-2 inhibitor, celecoxib for effect on survival, disease progression, and tolerability in patients with advanced pancreatic cancer. In addition, limited pharmacokinetic and pharmacodynamic analyses were preformed.

  • Genome-wide analysis of pancreatic cancer using microarray-based techniques.

    Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] (2009). Volume: 9, Issue: 1-2. Pages: 13-24.Tomohiko Harada, Claude Chelala, Tatjana Crnogorac-Jurcevic, Nicholas R Lemoine et al.Microarray-based comparative genomic hybridisation (CGH) has allowed high-resolution analysis of DNA copy number alterations across the entire cancer genome. Recent advances in bioinformatics tools enable us to perform a robust and highly sensitive analysis of array CGH data and facilitate the discovery of novel cancer-related genes.

  • Therapeutic antibodies for the treatment of pancreatic cancer.

    TheScientificWorldJournal (2010). Pages: 1107-20.Patrick Chames, Brigitte Kerfelec, Daniel Baty et al.Pancreatic cancer is a devastating disease with the worst mortality rate and an overall 5-year survival rate lower than 5%. In the U.S., this disease is the fourth leading cause of death and represents 6% of all cancer-related deaths. Gemcitabine, the current standard first-line treatment, offers marginal benefits to patients in terms of symptom control and prolongation of life. Since 1996, about 20 randomized phase III trials have been performed to improve the efficacy of gemcitabine, with little success regarding a significant improvement in survival outcomes. The need for novel therapeutic strategies, such as target therapy, is obvious. Monoclonal antibodies have finally come of age as therapeutics and several molecules are now approved for cancer therapies. This review aims to give a general view on the clinical results obtained so far by antibodies for the treatment of pancreatic cancer and describes the most promising avenues toward a significant improvement in the treatment of this frustrating disease.

  • Design and activity of a murine and humanized anti-CEACAM6 single-chain variable fragment in the treatment of pancreatic cancer.

    Cancer research (2009). Volume: 69, Issue: 5. Pages: 1933-40.Christopher J Riley, Kevin P Engelhardt, Jose W Saldanha, Wenqing Qi, Laurence S Cooke, Yingting Zhu, Satya T Narayan, Kishore Shakalya, Kimiko Della Croce, Ivan G Georgiev, Raymond B Nagle, Harinder Garewal, Daniel D Von Hoff, Daruka Mahadevan et al.Pancreatic ductal adenocarcinoma (PDA) is a lethal disease, with surgery being the only curative modality for localized disease, and gemcitabine with or without erlotinib remains the standard of therapy for unresectable or metastatic disease. CEACAM6 is overexpressed in human PDA independent of stage or grade and causes anoikis resistance when dysregulated. Because murine monoclonal antibody 13-1 possesses target-specific cytotoxicity in human PDA cell lines, we designed a humanized anti-CEACAM6 single-chain variable fragment (scFv) based on monoclonal antibody 13-1. PEGylation of the glycine-serine linker was used to enhance plasma half-life. These scFvs bound CEACAM6 with high affinity, exhibited cytotoxic activity, and induced dose-dependent poly(ADP-ribose) polymerase cleavage. Murine PDA xenograft models treated with humanized scFv alone elicited tumor growth inhibition, which was enhanced in combination with gemcitabine. Immunohistochemistry showed significant apoptosis, with inhibition of angiogenesis and proliferation, and preservation of the target. Collectively, our results have important implications for the development of novel antibody-based therapies against CEACAM6 in PDA.

  • Identification and characterization of a novel anticancer agent with selectivity against deleted in pancreatic cancer locus 4 (DPC4)-deficient pancreatic and colon cancer cells.

    Pancreas (2009). Volume: 38, Issue: 5. Pages: 551-7.Hong Wang, Bret Stephens, Daniel D Von Hoff, Haiyong Han et al.The deleted in pancreatic cancer locus 4 (DPC4)/SMAD4 tumor suppressor gene is frequently inactivated in pancreatic (approximately 55%) and colorectal cancers (approximately 30%). Like other tumor suppressor genes, the loss-of-function mutations found in the DPC4 gene are specific to cancer cells. This provides an attractive and unique opportunity for therapeutic intervention. The aim of this study was to identify and characterize small molecules that selectively kill DPC4-deficient cancer cells.

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About aspenbio

I write software for scientists. I'm interested in Java/Groovy/Grails, the Semantic Web and Cancer Biology.
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