Project title: Carcinoid Cancer Genome Study

Matthew Meyerson, MD, PhD Dana-Farber Cancer Institute

Matthew Meyerson, MD, PhD
  • Status: Completed
  • Year(s): 2009
  • Research Type: Basic
  • Primary Site: Small intestine
  • Area of Inquiry: Mapping NET dependencies

General Description

The goal of this study is to find novel targets for treatment and to facilitate the development of new targeted therapies and better diagnostics for patients. This is the first genomic study of this magnitude for neuroendocrined tumors. The first goal of this project is to identify which genes are altered in carcinoid, by studying carcinoid DNA with the most powerful new methods available, and comparing these genes sequences to genes from normal tissue. The second goal is to decipher which of these genes can promote tumor growth. The long-term goal is to find new drugs that block the effects of carcinoid-causing genes and thereby kill carcinoid cells.

Results

Dr. Meyerson and his team determined the genetic landscape of small intestine neuroendocrine tumors utilizing exome and whole genome sequencing. In particular, Meyerson’s analysis revealed somatic mutations in the CDKN1B gene among patients with small intestine neuroendocrine tumors and identified CDKN1B as a probable tumor suppressor suggesting that the mutation could lead to unregulated cell growth. This discovery could lead to new treatment strategies, including inhibitory therapies already being developed. Meyerson also found that carcinoid tumors have a very low mutation rate, which is similar to findings in pancreatic neuroendocrine tumors.

Publications

Francis JM, Kiezun A, Ramos AH, Serra S, Pedamallu CS, Qian ZR, Banck MS, Kanwar R, Kulkarni AA, Karpathakis A, Manzo V, Contractor T, Philips J, Nickerson E, Pho N, Hooshmand SM, Brais LK, Lawrence MS, Pugh T, McKenna A, Sivachenko A, Cibulskis K, Carter SL, Ojesina AI, Freeman S, Jones RT, Voet D, Saksena G, Auclair D, Onofrio R, Shefler E, Sougnez C, Grimsby J, Green L, Lennon N, Meyer T, Caplin M, Chung DC, Beutler AS, Ogino S, Thirlwell C, Shivdasani R, Asa SL, Harris CR, Getz G, Kulke M, Meyerson M. Somatic mutation of CDKN1B in small intestine neuroendocrine tumorsNat Genet. 2013 Dec;45(12):1483-6. doi: 10.1038/ng.2821. Epub 2013 Nov 3.    
  1. Luo Y, Zhu H, Tan T, He J. Current Standards and Recent Advances in Biomarkers of Major Endocrine Tumors. Front Pharmacol. 2018 Sep 10;9:963. doi: 10.3389/fphar.2018.00963.
    eCollection 2018. Review.

  2. Mishra R, Haldar S, Placencio V, Madhav A, Rohena-Rivera K, Agarwal P, Duong F, Angara B, Tripathi M, Liu Z, Gottlieb RA, Wagner S, Posadas EM, Bhowmick NA. Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming. J Clin Invest. 2018 Oct 1;128(10):4472-4484. doi: 10.1172/JCI99397. Epub 2018 Jul 26.

  3. Lee L, Ito T, Jensen RT. Everolimus in the treatment of neuroendocrine tumors: efficacy, side-effects, resistance, and factors affecting its place in the treatment sequence. Expert Opin Pharmacother. 2018 Jun;19(8):909-928. doi: 10.1080/14656566.2018.1476492. Epub 2018 May 24.

  4. Zhang T, Guo J, Li H, Wang J. Meta-analysis of the prognostic value of p-4EBP1 in human malignancies. Oncotarget. 2017 Dec 7;9(2):2761-2769. doi: 10.18632/oncotarget.23031. eCollection 2018 Jan 5.

  5. Chu PY, Jiang SS, Shan YS, Hung WC, Chen MH, Lin HY, Chen YL, Tsai HJ, Chen LT. Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) regulates the cell metabolism of pancreatic neuroendocrine tumors (pNET) and de-sensitizes pNET to mTOR inhibitors. Oncotarget. 2017 Oct 9;8(61):103613-103625. doi: 10.18632/oncotarget.21665. eCollection 2017 Nov 28.

  6. Chang TM, Shan YS, Chu PY, Jiang SS, Hung WC, Chen YL, Tu HC, Lin HY, Tsai HJ, Chen LT. The regulatory role of aberrant Phosphatase and Tensin Homologue and Liver Kinase B1 on AKT/mTOR/c-Myc axis in pancreatic neuroendocrine tumors. Oncotarget. 2017 Sep 16;8(58):98068-98083. doi: 10.18632/oncotarget.20956. eCollection 2017 Nov 17.

  7. Lamberti G, Ceccarelli C, Brighi N, Maggio I, Santini D, Mosconi C, Ricci C, Biasco G, Campana D. Determination of Mammalian Target of Rapamycin Hyperactivation as Prognostic Factor in Well-Differentiated Neuroendocrine Tumors. Gastroenterol Res Pract. 2017;2017:7872519. doi: 10.1155/2017/7872519. Epub 2017 Oct 29.

  8. Aristizabal Prada ET, Auernhammer CJ. Targeted therapy of gastroenteropancreatic neuroendocrine tumours: preclinical strategies and future targets. Endocr Connect. 2018 Jan;7(1):R1-R25. doi: 10.1530/EC-17-0286. Epub 2017 Nov 16. Review.

  9. Shi Y, Qian ZR, Zhang S, Li W, Masugi Y, Li T, Chan JA, Yang J, Da Silva A, Gu M, Liu L, Hamada T, Kosumi K, Dutton T, Brais LK, Nishihara R, Fuchs CS, Ogino S, Kulke MH. Cell Cycle Protein Expression in Neuroendocrine Tumors: Association of CDK4/CDK6, CCND1, and Phosphorylated Retinoblastoma Protein With Proliferative Index. Pancreas. 2017 Nov/Dec;46(10):1347-1353. doi: 10.1097/MPA.0000000000000944.

  10. Nölting S, Rentsch J, Freitag H, Detjen K, Briest F, Möbs M, Weissmann V, Siegmund B, Auernhammer CJ, Aristizabal Prada ET, Lauseker M, Grossman A, Exner S, Fischer C, Grötzinger C, Schrader J, Grabowski P; GERMAN NET-Z study group.. The selective PI3Kα inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: Results from multiple cell line models. PLoS One. 2017 Aug 11;12(8):e0182852. doi: 10.1371/journal.pone.0182852. eCollection 2017.

  11. Chen B, Yang L, Zhang R, Gan Y, Zhang W, Liu D, Chen H, Tang H. Hyperphosphorylation of RPS6KB1, rather than overexpression, predicts worse prognosis in non-small cell lung cancer patients. PLoS One. 2017 Aug 9;12(8):e0182891. doi: 10.1371/journal.pone.0182891. eCollection 2017. Hilal T. Current understanding and approach to well differentiated lung neuroendocrine tumors: an update on classification and management. Ther Adv Med Oncol. 2017 Mar;9(3):189-199. doi: 10.1177/1758834016678149. Epub 2016 Nov 17. Review.

  12. Chan DL, Segelov E, Singh S. Everolimus in the management of metastatic neuroendocrine tumours. Therap Adv Gastroenterol. 2017 Jan;10(1):132-141. doi: 10.1177/1756283X16674660. Epub 2016 Oct 25. Review.

  13. Cho SY, Choi M, Ban HJ, Lee CH, Park S, Kim H, Kim YS, Lee YS, Lee JY. Cervical small cell neuroendocrine tumor mutation profiles via whole exome sequencing. Oncotarget. 2017 Jan 31;8(5):8095-8104. doi: 10.18632/oncotarget.14098.

  14. Soler A, Figueiredo AM, Castel P, Martin L, Monelli E, Angulo-Urarte A, Milà-Guasch M, Viñals F, Baselga J, Casanovas O, Graupera M. Therapeutic Benefit of Selective Inhibition of p110α PI3-Kinase in Pancreatic Neuroendocrine Tumors. Clin Cancer Res. 2016 Dec 1;22(23):5805-5817. Epub 2016 May 25.

  15. Qian ZR, Li T, Ter-Minassian M, Yang J, Chan JA, Brais LK, Masugi Y, Thiaglingam A, Brooks N, Nishihara R, Bonnemarie M, Masuda A, Inamura K, Kim SA, Mima K, Sukawa Y, Dou R, Lin X, Christiani DC, Schmidlin F, Fuchs CS, Mahmood U, et al. Association Between Somatostatin Receptor Expression and Clinical Outcomes in Neuroendocrine Tumors. Pancreas. 2016 Nov;45(10):1386-1393.

  16. Lee MS, O’Neil BH. Summary of emerging personalized medicine in neuroendocrine tumors: are we on track? J Gastrointest Oncol. 2016 Oct;7(5):804-818. Review. Lee E, Wei Y, Zou Z, Tucker K, Rakheja D, Levine B, Amatruda JF. Genetic inhibition of autophagy promotes p53 loss-of-heterozygosity and tumorigenesis. Oncotarget. 2016 Oct 18;7(42):67919-67933. doi: 10.18632/oncotarget.12084.

  17. Olsen IH, Langer SW, Federspiel BH, Oxbøl J, Loft A, Berthelsen AK, Mortensen J, Oturai P, Knigge U, Kjær A. (68)Ga-DOTATOC PET and gene expression profile in patients with neuroendocrine carcinomas: strong correlation between PET tracer uptake and gene expression of somatostatin receptor subtype 2. Am J Nucl Med Mol Imaging. 2016 Jan 28;6(1):59-72. eCollection 2016.

  18. Circelli L, Sciammarella C, Guadagno E, Tafuto S, del Basso de Caro M, Botti G, Pezzullo L, Aria M, Ramundo V, Tatangelo F, Losito NS, Ieranò C, D’Alterio C, Izzo F, Ciliberto G, Colao A, Faggiano A, Scala S. CXCR4/CXCL12/CXCR7 axis is functional in neuroendocrine tumors and signals on mTOR. Oncotarget. 2016 Apr 5;7(14):18865-75. doi: 10.18632/oncotarget.7738.

  19. Robbins HL, Hague A. The PI3K/Akt Pathway in Tumors of Endocrine Tissues. Front Endocrinol (Lausanne). 2016 Jan 11;6:188. doi: 10.3389/fendo.2015.00188. eCollection 2015. Review. Kleist B, Poetsch M. Neuroendocrine differentiation: The mysterious fellow of colorectal cancer. World J Gastroenterol. 2015 Nov 7;21(41):11740-7. doi: 10.3748/wjg.v21.i41.11740. Review.

  20. Harter PN, Jennewein L, Baumgarten P, Ilina E, Burger MC, Thiepold AL, Tichy J, Zörnig M, Senft C, Steinbach JP, Mittelbronn M, Ronellenfitsch MW. Immunohistochemical Assessment of Phosphorylated mTORC1-Pathway Proteins in Human Brain Tumors. PLoS One. 2015 May 19;10(5):e0127123. doi: 10.1371/journal.pone.0127123. eCollection 2015.

  21. Yi YW, You K, Bae EJ, Kwak SJ, Seong YS, Bae I. Dual inhibition of EGFR and MET induces synthetic lethality in triple-negative breast cancer cells through downregulation of ribosomal protein S6. Int J Oncol. 2015 Jul;47(1):122-32. doi: 10.3892/ijo.2015.2982. Epub 2015 May 4. 

Additional Details

  • City: Boston
  • Grant Duration: 3 years
  • Awards: No information
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