187
Views
2
CrossRef citations to date
0
Altmetric
Review

Epigenetic-based targeted therapies for well-differentiated pancreatic neuroendocrine tumors: recent advances and future perspectives

, &
Pages 295-307 | Received 13 Aug 2021, Accepted 15 Sep 2021, Published online: 23 Sep 2021

References

  • Schimmack S, Svejda B, Lawrence B, et al. The diversity and commonalities of gastroenteropancreatic neuroendocrine tumors. Langenbeck Arch Surg. 2011;396:273–298.
  • Inzani F, Petrone G, Rindi G. The new world health organization classification for pancreatic neuroendocrine neoplasia. Endocrinol Metab Clin North Am. 2018;47(3):463–470
  • Pea A, Hruban RH, Wood LD. Genetics of pancreatic neuroendocrine tumors: implications for the clinic. Expert Rev Gastroenterol Hepatol. 2015;9(11):1407–1419.
  • Leotlela PD, Jauch A, Holtgreve-Grez H, et al. Genetics of neuroendocrine and carcinoid tumours. Endocr Relat Cancer. 2003;10:437450.
  • Stevenson M, Lines KE, Thakker RV. Molecular genetic studies of pancreatic neuroendocrine tumors: new therapeutic approaches. Endocrinol Metab Clin N Am. 2018;47:525–548.
  • Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063–3072.
  • Kulke MH, Siu LL, Tepper JE, et al. Future directions in the treatment of neuroendocrine tumors: consensus report of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting. J Clin Oncol. 2011;29:934–943.
  • Pavel M, Öberg K, Falconi M, et al., on the behalf of the ESMO Guidelines Committee. Gastroenteropancreatic neuroendocrine neoplasms: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(7):844–860.
  • Lakis V, Lawlor RT, Newell F, et al. DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association. Commun Biol. 2021;4(1):155.
  • Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331:1199–1203.
  • Brandi ML, Agarwal SK, Perrier ND, et al. Multiple endocrine neoplasia type 1: latest insights. Endocr Rev. 2021;42:133–170.
  • Jensen RT, Norton JA. Treatment of pancreatic neuroendocrine tumors in multiple endocrine neoplasia-type 1(MEN1): some clarity but continued controversy. Pancreas. 2017;46:589–594.
  • Tonelli F. Zollinger-ellison syndrome in men1 patients: medical or surgical treatment? Ann Surg. 2006;244:61–70.
  • Marini F, Giusti F, Tonelli F, et al. Pancreatic neuroendocrine neoplasms in multiple endocrine neoplasia type 1. Int J Mol Sci. 2021;22(8):4041.
  • Scarpa A, Chang DK, Nones K, et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature. 2017;543(7643):65–71.
  • Lin W, Watanabe H, Peng S, et al. Dynamic epigenetic regulation by menin during pancreatic islet tumor formation. Mol Cancer Res. 2015;13(4):689–698.
  • Hoelper D, Huang H, Jain AY, et al. Structural and mechanistic insights into ATRX-dependent and -independent functions of the histone chaperone DAXX. Nat Commun. 2017;8(1):1193.
  • Dyer MA, Qadeer ZA, Valle-Garcia D, et al. ATRX and DAXX: mechanisms and mutations. Cold Spring Harb Perspect Med. 2017;7(3):a026567.
  • Klieser E, Urbas R, Stättner S, et al. Comprehensive immunohistochemical analysis of histone deacetylases in pancreatic neuroendocrine tumors: HDAC5 as a predictor of poor clinical outcome. Hum Pathol. 2017;65:41–52.
  • Choi IS, Estecio MR, Nagano Y, et al. Hypomethylation of LINE-1 and Alu in well-differentiated neuroendocrine tumors (pancreatic endocrine tumors and carcinoid tumors). Mod Pathol. 2007;20:802–810.
  • Marinoni I, Wiederkeher A, Wiedmer T, et al. Hypo-methylation mediates chromosomal instability in pancreatic NET. Endocr Relat Cancer. 2017;24(3):137–146.
  • Stefanoli M, La Rosa S, Sahnane N, et al. Prognostic relevance of aberrant DNA methylation in g1 and g2 pancreatic neuroendocrine tumors. Neuroendocrinology. 2014;100(1):26–34.
  • Conemans EB, Lodewijk L, Moelans CB, et al. DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment. Eur J Endocrinol. 2018;179(3):153–160.
  • Yuan Z, Sánchez Claros C, Suzuki M, et al. Loss of MEN1 activates DNMT1 implicating DNA hypermethylation as a driver of MEN1 tumorigenesis. Oncotarget. 2016;7(11):12633–12650.
  • Tirosh A, Mukherjee S, Lack J, et al. Distinct genome-wide methylation patterns in sporadic and hereditary nonfunctioning pancreatic neuroendocrine tumors. Cancer. 2019;125(8):1247–1257.
  • Di Domenico A, Pipinikas CP, Maire RS, et al. Epigenetic landscape of pancreatic neuroendocrine tumours reveals distinct cells of origin and means of tumour progression. Commun Biol. 2020;3(1):740.
  • Dammann R, Schagdarsurengin U, Liu L, et al. Frequent RASSF1A promoter hypermethylation and K-ras mutations in pancreatic carcinoma. Oncogene. 2003;22(24):3806–3812.
  • Liu L, Broaddus RR, Yao JC, et al. Epigenetic alterations in neuroendocrine tumors: methylation of RAS-association domain family 1, isoform A and p16 genes are associated with metastasis. Mod Pathol. 2005;18(12):1632–1640.
  • Malpeli G, Amato E, Dandrea M, et al. Methylation-associated down-regulation of RASSF1A and up-regulation of RASSF1C in pancreatic endocrine tumors. BMC Cancer. 2011;11:351.
  • Serrano J, Goebel SU, Peghini PL, et al. Alterations in the p16INK4a/CDKN2A tumor suppressor gene in gastrinomas. J Clin Endocrinol Metab. 2000;85(11):4146–4156.
  • House MG, Herman JG, Guo MZ, et al. Aberrant hypermethylation of tumor suppressor genes in pancreatic endocrine neoplasms. Ann Surg. 2003;238(3):423–431. discussion 431-432.
  • Wild A, Ramaswamy A, Langer P, et al. Frequent methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene in pancreatic endocrine tumors. J Clin Endocrinol Metab. 2003;88(3):1367–1373.
  • Mei M, Deng D, Liu T-H, et al. Clinical implications of microsatellite instability and MLH1 gene inactivation in sporadic insulinomas. J Clin Endocrinol Metab. 2009;94(9):3448–3457.
  • Arnold CN, Sosnowski A, Schmitt-Gräff A, et al. Analysis of molecular pathways in sporadic neuroendocrine tumors of the gastro-entero-pancreatic system. Int J Cancer. 2007;120(10):2157–2164.
  • Korotaeva A, Mansorunov D, Apanovich N, et al. MiRNA expression in neuroendocrine neoplasms of frequent localization. Noncoding RNA. 2021;7:38.
  • Li S-C, Essaghir A, Martijn C, et al. Global microRNA profiling of well-differentiated small intestinal neuroendocrine tumors. Mod Pathol. 2013;26:685–696.
  • Michael IP, Saghafinia S, Hanahan D. A set of microRNAs coordinately controls tumorigenesis, invasion, and metastasis. Proc Natl Acad Sci USA. 2019;116:24184–24195.
  • Roldo C, Missiaglia E, Hagan JP, et al. MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior. J Clin Oncol. 2006;24(29):4677–4684.
  • Lee YS, Kim H, Kim HW, et al. High expression of MicroRNA-196a indicates poor prognosis in resected pancreatic neuroendocrine tumor. Medicine (Baltimore). 2015;94:e2224.
  • Noonan EJ, Place RF, Pookot D, et al. miR-449a targets HDAC-1 and induces growth arrest in prostate cancer. Oncogene. 2009;28(14):1714–1724.
  • Zheng Y, Yang X, Wang C, et al. HDAC6, modulated by miR-206, promotes endometrial cancer progression through the PTEN/AKT/mTOR pathway. Sci Rep. 2020;10(1):3576.
  • Conte M, Dell’Aversana C, Sgueglia G, et al. HDAC2-dependent miRNA signature in acute myeloid leukemia. FEBS Lett. 2019;593(18):2574–2584.
  • Huang JH, Xu Y, Lin FY. The inhibition of microRNA-326 by SP1/HDAC1 contributes to proliferation and metastasis of osteosarcoma through promoting SMO expression. J Cell Mol Med. 2020;24(18):10876–10888.
  • Klieser E, Urbas R, Swierczynski S, et al. HDAC-linked “Proliferative” miRNA expression pattern in pancreatic neuroendocrine tumors. Int J Mol Sci. 2018 Sep 15;19(9):2781.
  • Jin N, Lubner SJ, Mulkerin DL, et al. A phase II trial of a histone deacetylase inhibitor panobinostat in patients with low-grade neuroendocrine tumors. Oncologist. 2016;21(7):785–786.
  • Cecconi D, Donadelli M, Rinalducci S, et al. Proteomic analysis of pancreatic endocrine tumor cell lines treated with the histone deacetylase inhibitor trichostatin A. Proteomics. 2007;7(10):1644–1653.
  • Lines KE, Stevenson M, Filippakopoulos P, et al., Epigenetic pathway inhibitors represent potential drugs for treating pancreatic and bronchial neuroendocrine tumors. Oncogenesis. 2017;6(5):e332.
  • Stockhausen MT, Sjolund J, Manetopoulos C, et al. Effects of the histone deacetylase inhibitor valproic acid on Notch signalling in human neuroblastoma cells. Br J Cancer. 2005;92:751–759.
  • Arvidsson Y, Johanson V, Pfragner R, et al. Cytotoxic effects of valproic acid on neuroendocrine tumour cells. Neuroendocrinology. 2016;103(5):578–591.
  • Mohammed TA, Holen KD, Jaskula-Sztul R, et al. A pilot phase II study of valproic acid for treatment of low-grade neuroendocrine carcinoma. Oncologist. 2011;16(6):835–843.
  • Yee AJ, Raje NS. Panobinostat and multiple myeloma in 2018. Oncologist. 2018;23(5):516–517.
  • Schmitz RL, Weissbach J, Kleilein J, et al. Targeting HDACs in pancreatic neuroendocrine tumor models. Cells. 2021;10(6):1408.
  • Matrood S, de Prisco N, Wiowski T, et al. Modulation of pancreatic neuroendocrine neoplastic cell fate by autophagy mediated death. Neuroendocrinology. 2020 Oct 27. Online ahead of print. DOI: https://doi.org/10.1159/000512567.
  • Montalbano R, Waldegger P, Quint K, et al. Endoplasmic reticulum stress plays a pivotal role in cell death mediated by the pan-deacetylase inhibitor panobinostat in human hepatocellular cancer cells. Transl Oncol. 2013;6(2):143–157.
  • Klieser E, Illig R, Státtner S, et al. Endoplasmic reticulum stress in pancreatic neuroendocrine tumors is linked to clinicopathological parameters and possible epigenetic regulations. Anticancer Res. 2015;35(11):6127–6136.
  • Wanek J, Gaisberger M, Beyreis M, et al. Pharmacological inhibition of class IIA HDACs by LMK-235 in pancreatic neuroendocrine tumor cells. Int J Mol Sci. 2018;19(10):3128.
  • Lin W, Cao J, Liu J, et al. Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1. Proc Natl Acad Sci U S A. 2011;108(33):13379–13386.
  • Jones PA, Issa JP, Baylin S. Targeting the cancer epigenome for therapy. Nature Rev Genet. 2016;17:630–641.
  • Schmitt AM, Pavel M, Rudolph T, et al. Prognostic and predictive roles of MGMT protein expression and promoter methylation in sporadic pancreatic neuroendocrine neoplasms. Neuroendocrinology. 2014;100(1):35–44.
  • Walter T, van Brakel B, Vercherat C, et al. O6-Methylguanine-DNA methyltransferase status in neuroendocrine tumours: prognostic relevance and association with response to alkylating agents. Br J Cancer. 2015;112(3):523–531.
  • Cros J, Hentic O, Rebours V, et al. MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors. Endocr Relat Cancer. 2016;23(8):625–633.
  • Owen DH, Alexander AJ, Konda B, et al. Combination therapy with capecitabine and temozolomide in patients with low and high grade neuroendocrine tumors, with an exploratory analysis of O(6)-methylguanine DNA methyltransferase as a biomarker for response. Oncotarget. 2017;8(61):104046–104056.
  • Cives M, Ghayouri M, Morse B, et al. Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors. Endocr Relat Cancer. 2016;23(9):759–767.
  • Girot P, Dumars C, Mosnier JF, et al. Short article: evaluation of O6-methylguanine-DNA methyltransferase as a predicting factor of response to temozolomide-based chemotherapy in well-differentiated metastatic pancreatic neuroendocrine tumors. Eur J Gastroenterol Hepatol. 2017;29(7):826–830.
  • Krug S, Boch M, Rexin P, et al. Impact of therapy sequence with alkylating agents and MGMT status in patients with advanced neuroendocrine tumors. Anticancer Res. 2017;37(5):2491–2500.
  • Colao A, de Nigris F, Modica R, et al. Clinical epigenetics of neuroendocrine tumors: the road ahead. Front Endocrinol (Lausanne). 2020;11:604341.
  • Al-Toubah T, Cives M, Strosberg J. Novel immunotherapy strategies for treatment of neuroendocrine neoplasms. Transl Gastroenterol Hepatol. 2020;5:54.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.