KRAS, CDKN2A, SMAD4, and TP53 Gene Mutations Linked to Pancreatic Cancer Patient Survival Time

Alterations in four main genes are responsible for how long patients survive with pancreatic cancer, according to a new study.

via Pancreatic cancer survival linked to four genes — Pancreatic Cancer News — ScienceDaily

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The inaugural issue of Biobanking Weekly is coming to you just as the Global Biobank Week is closing providing leaders at the cutting edge of Biobanking to set the agenda for the months ahead. Important developments in biobanking this week include contributions to understanding of type 1 diabetes, the risks of 9/11 responders to fall victim to human papilloma virus (HPV) related head and neck cancers, new targets for osteoporosis treatment, advances in banking prostate cancer samples, the use of cystic fibrosis biobanks, the testing of drones for sample delivery, and the adoption of lean sigma six for efficient management and distribution of samples. Very exciting developments with plenty more forecast for the coming weeks.

Curcumin analogues extracted from Alpinia officinarum and Alnus japonica inhibited the FoxM1 signalling axis in a pancreatic cancer cell line

 

Alpinia officinarum or lesser galangal (高良姜), is a member of the ginger family, which originates from China and is now cultivated throughout Southeast Asia (Figure 1). The roots are known as galangal and are used in cooking, perfumes and are also known for their medicinal properties. Alnus japonica or East Asian alder (日本桤木), is a species of tree found in Japan, Korea, and eastern China, stretching to Russia. Diarylheptanoids, the family of which the anti-cancer agent curcumin from turmeric is a member, can be extracted from these plants. Diarylheptanoid compounds from these medicinal plants were found to inhibit the growth of the PANC-1 (KRAS heterozygous G12D, TP53 homozygous P72R and R273H) pancreatic cancer cell line [1, 2]. The mechanism was proposed to derive from inhibiting the FoxM1 transcription factor signalling axis.

 

8232821986_3788e5f202_z
Figure 1: Alpinia officinarum. Credit: Biodiversity Heritage Library. No changes were made. Creative Commons Attribution 2.0 Generic (CC BY 2.0).

 

FoxM1 is a transcription factor of central importance to pancreatic cancer [3]. It promotes the transcription of genes involved in cell cycle progression and cell survival as well as migration and invasion [4]. FoxM1 transcription has been demonstrated to be promoted by the sonic hedgehog pathway in colorectal cancer and furthermore the hedgehog pathway is almost universally upregulated in pancreatic cancer [5, 6]. Dong et al. proposed that FoxM1 target genes are downregulated in response to the diarylheptanoid compounds due to Gli1/2 protein downregulation. Interestingly Stat3 signalling has been found to be downregulated by other diarylheptanoid compounds such as HO-3867 and Stat3 transcription can be indirectly upregulated by Gli1 via IL-6 [7, 8]. The extent to which different diarylheptanoid compounds could inhibit both FoxM1 and Stat3 axes in pancreatic cancer  is an open question.  

 

Refs

  1. Dong GZ, Jeong JH, Lee YI, Lee SY, Zhao HY, Jeon R, Lee HJ, Ryu JH. Diarylheptanoids suppress proliferation of pancreatic cancer PANC-1 cells through modulating shh-Gli-FoxM1 pathway. Arch Pharm Res. 2017 Apr;40(4):509-517. Doi: 10.1007/s12272-017-0905-2. PubMed PMID: 28258481.
  2. Gradiz R, Silva HC, Carvalho L, Botelho MF, Mota-Pinto A. MIA PaCa-2 and PANC-1 – pancreas ductal adenocarcinoma cell lines with neuroendocrine differentiation and somatostatin receptors. Sci Rep. 2016 Feb 17;6:21648. Doi: 10.1038/srep21648. PubMed PMID: 26884312.
  3. Akbari B, Mohammadnia A, Yaqubi M, Wee P, Mahdiuni H. Comprehensive Dissection of Transcriptome Data and Regulatory Factors in Pancreatic Cancer Cells. J Cell Biochem. 2017 Apr 12. doi: 10.1002/jcb.26053. PubMed PMID: 28401644.
  4. Quan M, Wang P, Cui J, Gao Y, Xie K. The roles of FOXM1 in pancreatic stem cells and carcinogenesis. Mol Cancer. 2013 Dec 10;12:159. Doi: 10.1186/1476-4598-12-159. Review. PubMed PMID: 24325450.
  5. Wang D, Hu G, Du Y, Zhang C, Lu Q, Lv N, Luo S. Aberrant activation of hedgehog signaling promotes cell proliferation via the transcriptional activation of forkhead Box M1 in colorectal cancer cells. J Exp Clin Cancer Res. 2017 Feb 2;36(1):23. doi: 10.1186/s13046-017-0491-7. PubMed PMID: 28148279.
  6. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008 Sep 26;321(5897):1801-6. Doi: 10.1126/science.1164368. PubMed PMID: 18772397.
  7. Hu Y, Zhao C, Zheng H, Lu K, Shi D, Liu Z, Dai X, Zhang Y, Zhang X, Hu W, Liang G. A novel STAT3 inhibitor HO-3867 induces cell apoptosis by reactive oxygen species-dependent endoplasmic reticulum stress in human pancreatic cancer cells. Anticancer Drugs. 2017 Apr;28(4):392-400. Doi: 10.1097/CAD.0000000000000470. PubMed PMID: 28067673.
  8. Mills LD, Zhang Y, Marler RJ, Herreros-Villanueva M, Zhang L, Almada LL, Couch F, Wetmore C, Pasca di Magliano M, Fernandez-Zapico ME. Loss of the transcription factor GLI1 identifies a signaling network in the tumor microenvironment mediating KRAS oncogene-induced transformation. J Biol Chem. 2013 Apr 26;288(17):11786-94. doi: 10.1074/jbc.M112.438846. PubMed PMID:23482563.

 

 

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Journal Publications:

  1. Orchard-Webb D. 2016. Progress Toward Commercial Scale and Efficiency in Cell Therapy Bioprocessing. BioProcess International. October Supplement. http://www.bioprocessintl.com/manufacturing/cell-therapies/manufacturing-cell-therapies-commercial-scale-efficiency/
  1. Orchard-Webb D. 2015. Future Directions in Pancreatic Cancer Therapy. JOP. Journal of the Pancreas 16:249-255.
  1. Orchard-Webb D.J., Lee T.C., Cook G.P., Blair G.E. 2014. CUB Domain Containing Protein 1 (CDCP1) modulates adhesion and motility in colon cancer cells. BMC Cancer. 14:754.
  1. Orchard-Webb D; Fox N; Elghazawy RM; Speirs V; Smith AM; Lodge JPA; Melcher AA; Verbeke CS; Blair GE. 2012. Development of a Chimaeric Oncolytic Adenovirus Vector for Pancreatic Cancer Biotherapy. Journal of pathology. 228: S18-S18.
  1. Elghazawy RM; Fox N; Orchard-Webb D; Speirs V; Smith AM; Lodge JPA; Verbeke CS; Blair GE. 2012. An Ex-Vivo Model of Human Pancreatic Cancer. Journal of pathology. 228: S19-S19.
  1. Orchard-Webb, D. 2011. The cancer cell biology of the integral membrane protein CUB domain containing protein 1 (CDCP1). University of Leeds. Thesis.
  1. Orchard-Webb, D. J., Cook, G. P., and Blair, G. E. 2010. Poster 482: Characterising the role of the metastasis associated cell surface glycoprotein CDCP1 in cancer cell lines – possible roles in cell adhesion and survival. EJC Supplements 8: 123.
  1. Fini, M.A., Orchard-Webb, D., Kosmider, B., Amon, J.D., Kelland, R., Shibao, G., and Wright, R.M. 2008. Migratory Activity of Human Breast Cancer Cells is Modulated by Differential Expression of Xanthine Oxidoreductase.  J. Cell. Biochem.  105: 1008-1026.

 

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  1. Orchard-Webb D. 2014. Next generation treatments for type I diabetes. http://www.apptheneum.com/next-generation-treatments-type-diabetes/

 

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  1. Niebuhr M., Scharonow H., Gathmann M., Mamerow D., Werfel T. 2010. Staphylococcal exotoxins are strong inducers of IL-22: A potential role in atopic dermatitis. J Allergy Clin Immunol. 126: 1176-1183.e4. http://www.jacionline.org/article/S0091-6749(10)01264-9/abstract

 

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Resource – STAT3 – Pancreatic Cancer

 

STAT3 plays a pivotal role in pancreatic cancer and is drawing increased attention as a potential drug target for the disease. This post will be updated periodically.

 

STAT3 inhibitorsRefs

MIR506 – Sun L, Hu L, Cogdell D, Lu L, Gao C, Tian W, Zhang Z, Kang Y, Fleming JB, Zhang W. MIR506 induces autophagy-related cell death in pancreatic cancer cells by targeting the STAT3 pathway. Autophagy. 2017 Jan 25:0. doi: 10.1080/15548627.2017.1280217. PubMed PMID: 28121485.

HO-3867

Nexrutine®

Renalase

AM0010

AZD9150 – AZD9150 With MEDI4736 in Patients With Advanced Pancreatic, Non-Small Lung and Colorectal Cancer. ClinicalTrials.gov Identifier: NCT02983578

 

 

 

Paeonol an anti-cancer agent with potential for synergy with immunotherapeutics

 

Paeonol, 1-(2-Hydroxy-4-methoxyphenyl) ethanone (figure 1) is a phenolic compound found in peonies such as Paeonia suffruticosa (moutan cortex), in Arisaema erubescens, and in Dioscorea japonica. It is a component of some traditional Chinese medicines [1].

 

paeonol
Figure 1: Paeonol, 1-(2-Hydroxy-4-methoxyphenyl) ethanone.

 

Paeonol has been demonstrated to induce apoptosis in a wide range of cancers including ovarian, gastric, colon, esophageal, hepatocellular, breast, melanoma, prostate and lung [2, 3, 4, 5, 6, 7, 8, 9, 10].

 

Paeonol appears to have anti-inflammatory and possibly anti-fibrotic capacity. In CW-2 large intestine carcinoma cell line paeonol inhibited tumor necrosis factor alpha (TNFα)-induced transcriptional activity of NF-κB and interferon gamma (IFNγ) induction of STAT1 [11]. It may also have an inhibitory effect on STAT3 [3]. In colon cancer cells paeonol was found to increase RUNX3 expression levels. RUNX3 has a complex role in the fibrosis promoting process of epithelial to mesenchymal transition (EMT), however at least in certain contexts RUNX3 prevents EMT [12, 13]. Drug resistance and immunosuppression are associated with EMT.

 

Importantly paeonol was found to alleviate drug resistance. It enhanced the efficacy of cisplatin [14], doxorubicin [15], and paclitaxel [16]. These effects may be mediated through inhibition of the Akt pathway [17] in addition to any anti-fibrotic mechanism of action.

 

Paeonol can potentially “heat up” the immunosuppressive microenvironment of immunotherapy resistant tumours as it has been found to reduce the expression of Cyclooxygenase-2 (COX-2) and therefore reduce the levels of its metabolite prostaglandin E2 (PGE2) [18]. PGE2 is known to promote the presence of active myeloid-derived suppressor cells (MDSC) within the tumour microenvironment which inhibit CD4+ and CD8+ T cells [19]. Paeonol may therefore be synergistic with the new class of cancer immunotherapeutics.

 

Refs

 

  1. Deng C, Yao N, Wang B, Zhang X. Development of microwave-assisted extraction followed by headspace single-drop microextraction for fast determination of paeonol in traditional Chinese medicines. J Chromatogr A. 2006 Jan 20;1103(1):15-21. PubMed PMID: 16309693.
  2. Xu Y, Zhu JY, Lei ZM, Wan LJ, Zhu XW, Ye F, Tong YY. Anti-proliferative effects of paeonol on human prostate cancer cell lines DU145 and PC-3. J Physiol Biochem. 2016 Nov 10. PubMed PMID: 27834040.
  3. Zhang L, Tao L, Shi T, Zhang F, Sheng X, Cao Y, Zheng S, Wang A, Qian W, Jiang L, Lu Y. Paeonol inhibits B16F10 melanoma metastasis in vitro and in vivo via disrupting proinflammatory cytokines-mediated NF-κB and STAT3 pathways. IUBMB Life. 2015 Oct;67(10):778-88. doi: 10.1002/iub.1435. PubMed PMID: 26452780.
  4. Ou Y, Li Q, Wang J, Li K, Zhou S. Antitumor and Apoptosis Induction Effects of Paeonol on Mice Bearing EMT6 Breast Carcinoma. Biomol Ther (Seoul). 2014 Jul;22(4):341-6. doi: 10.4062/biomolther.2013.106. PubMed PMID: 25143814.
  5. Lei Y, Li HX, Jin WS, Peng WR, Zhang CJ, Bu LJ, Du YY, Ma T, Sun GP. The radiosensitizing effect of Paeonol on lung adenocarcinoma by augmentation of radiation-induced apoptosis and inhibition of the PI3K/Akt pathway. Int J Radiat Biol. 2013 Dec;89(12):1079-86. doi: 10.3109/09553002.2013.825058. PubMed PMID: 23875954.
  6. Yin J, Wu N, Zeng F, Cheng C, Kang K, Yang H. Paeonol induces apoptosis in human ovarian cancer cells. Acta Histochem. 2013 Oct;115(8):835-9. Doi: 10.1016/j.acthis.2013.04.004. PubMed PMID: 23768958.
  7. Li N, Fan LL, Sun GP, Wan XA, Wang ZG, Wu Q, Wang H. Paeonol inhibits tumor growth in gastric cancer in vitro and in vivo. World J Gastroenterol. 2010 Sep 21;16(35):4483-90. PubMed PMID: 20845518.
  8. Xing G, Zhang Z, Liu J, Hu H, Sugiura N. Antitumor effect of extracts from moutan cortex on DLD-1 human colon cancer cells in vitro. Mol Med Rep. 2010 Jan-Feb;3(1):57-61. doi: 10.3892/mmr_00000218. PubMed PMID: 21472200.
  9. Sun GP, Wan X, Xu SP, Wang H, Liu SH, Wang ZG. Antiproliferation and apoptosis induction of paeonol in human esophageal cancer cell lines. Dis Esophagus. 2008;21(8):723-9. doi: 10.1111/j.1442-2050.2008.00840.x. PubMed PMID: 18522637.
  10. Chunhu Z, Suiyu H, Meiqun C, Guilin X, Yunhui L. Antiproliferative and apoptotic effects of paeonol on human hepatocellular carcinoma cells. Anticancer Drugs. 2008 Apr;19(4):401-9. doi: 10.1097/CAD.0b013e3282f7f4eb. PubMed PMID: 18454050.
  11. Ishiguro K, Ando T, Maeda O, Hasegawa M, Kadomatsu K, Ohmiya N, Niwa Y, Xavier R, Goto H. Paeonol attenuates TNBS-induced colitis by inhibiting NF-kappaB and STAT1 transactivation. Toxicol Appl Pharmacol. 2006 Nov 15;217(1):35-42. PubMed PMID: 16928387.
  12. Whittle MC, Izeradjene K, Rani PG, Feng L, Carlson MA, DelGiorno KE, Wood LD, Goggins M, Hruban RH, Chang AE, Calses P, Thorsen SM, Hingorani SR. RUNX3 Controls a Metastatic Switch in Pancreatic Ductal Adenocarcinoma. Cell. 2015 Jun 4;161(6):1345-60. doi: 10.1016/j.cell.2015.04.048. PubMed PMID: 26004068.
  13. Voon DC, Wang H, Koo JK, Nguyen TA, Hor YT, Chu YS, Ito K, Fukamachi H, Chan SL, Thiery JP, Ito Y. Runx3 protects gastric epithelial cells against epithelial-mesenchymal transition-induced cellular plasticity and tumorigenicity. Stem Cells. 2012 Oct;30(10):2088-99. doi: 10.1002/stem.1183. PubMed PMID: 22899304.
  14. Xu SP, Sun GP, Shen YX, Peng WR, Wang H, Wei W. Synergistic effect of combining paeonol and cisplatin on apoptotic induction of human hepatoma cell lines. Acta Pharmacol Sin. 2007 Jun;28(6):869-78. PubMed PMID: 17506946.
  15. Fan L, Song B, Sun G, Ma T, Zhong F, Wei W. Endoplasmic reticulum stress-induced resistance to doxorubicin is reversed by paeonol treatment in human hepatocellular carcinoma cells. PLoS One. 2013 May 3;8(5):e62627. Doi: 10.1371/journal.pone.0062627. PubMed PMID: 23658755.
  16. Cai J, Chen S, Zhang W, Hu S, Lu J, Xing J, Dong Y. Paeonol reverses paclitaxel resistance in human breast cancer cells by regulating the expression of transgelin 2. Phytomedicine. 2014 Jun 15;21(7):984-91. doi: 10.1016/j.phymed.2014.02.012. PubMed PMID: 24680370.
  17. Zhang W, Cai J, Chen S, Zheng X, Hu S, Dong W, Lu J, Xing J, Dong Y. Paclitaxel resistance in MCF-7/PTX cells is reversed by paeonol through suppression of the SET/phosphatidylinositol 3-kinase/Akt pathway. Mol Med Rep. 2015 Jul;12(1):1506-14. doi: 10.3892/mmr.2015.3468. PubMed PMID: 25760096.
  18. Li M, Tan SY, Wang XF. Paeonol exerts an anticancer effect on human colorectal cancer cells through inhibition of PGE₂ synthesis and COX-2 expression. Oncol Rep. 2014 Dec;32(6):2845-53. doi: 10.3892/or.2014.3543. PubMed PMID: 25322760.
  19. Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res. 2007 May 1;67(9):4507-13. PubMed PMID: 17483367.