Merkel Cell Carcinoma with a Suppressor of Fused (SUFU) Mutation: Case Report and Potential Therapeutic Implications

Dermatology and Therapy

Volumn 5, Issue 2, 2015, Pages 129-143

  Cohen, Philip R ^a   Kurzrock, Razelle ^b,c  

^a San Diego   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c UNIVERSITY OF CALIFORNIA SAN DIEGO   (United States)

Author keywords

Carcinoma; Cell; Hedgehog; Merkel; Pathway; Signaling; Suppressor of fused (SUFU)

Indexed keywords

CARBOPLATIN; CD56 ANTIGEN; CHROMOGRANIN; CYTOKERATIN 20; CYTOKERATIN AE1; ETOPOSIDE; SONIC HEDGEHOG PROTEIN; SYNAPTOPHYSIN;

AGED; ARTICLE; BASOPHIL; CASE REPORT; COMPUTER ASSISTED TOMOGRAPHY; CONTROLLED STUDY; ERYTHEMA; FOLLOW UP; GENE MUTATION; HUMAN; HUMAN CELL; HUMAN TISSUE; IMMUNOHISTOCHEMISTRY; INGUINAL HERNIA; LYMPH NODE BIOPSY; MALE; MERKEL CELL TUMOR; ONCOGENE; PARAAORTIC LYMPH NODE; PATHOGENESIS; POSITRON EMISSION TOMOGRAPHY; PRIORITY JOURNAL; SUBCUTANEOUS NODULE; SUPPRESSOR GENE; SUPPRESSOR OF FUSED;

EID: 84935856294     PISSN: 21938210     EISSN: 21909172     Source Type: Journal    
DOI: 10.1007/s13555-015-0074-5     Document Type: Article

References (72)

1. Hughes MP, Hardee ME, Cornelius LA, Hutchins LF, Becker JC, Gao L. Merkel cell carcinoma: epidemiology, target, and therapy. Curr Dermatol Rep. 2014;3:46–53 (PMID = 24587977).
2. Amakye D, Jagani Z, Dorsch M. Unraveling the therapeutic potential of the Hedgehog pathway in cancer. Nat Med. 2013;19:1410–22 (PMID = 24202394).
3. Park JY, Kricka LJ, Fortina P. Next-generation sequencing in the clinic. Nat Biotechnol. 2013;31:990–2 (PMID = 24213773).
4. Foundation Medicine, Inc., Cambridge. http://www.foundationmedicine.com. Accessed Mar 25, 2015.
5. Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, He J, Schnall-Levin M, White J, Sanford EM, An P, Sun J, Juhn F, Brennan K, Iwanik K, MAillet A, Buell J, White E, Zhao M, Balasubramanian S, Terzic S, Richards T, Banning V, Garcia L, Mahoney K, Zwirko Z, Donahue A, Beltran H, Mosquera JM, Rubin MA, Dogan S, Hedvat CV, Berger MF, Pusztai L, Lechner M, Boshoff C, Jarosz M, Vietz C, Parker A, Miller VA, Ross JS, Curran J, Cronin MT, Stephens PJ, Lipson D, Yelensky R. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 2013;31:1023–1031. (PMID = 24142049).
6. Marek L, Grzanka A, Chmielowska E, Jankowski M, Schwartz RA, Czajkowski R. Merkel cell carcinoma: an illustrative case and review. Postepy Dermatol Alergol. 2014;31:325–8 (PMID = 25395930).
7. Schwartz JL, Wong SL, McLean SA, Hayman JA, Lao CD, Kozlow JH, Malloy KM, Bradford CR, Frohm ML, Fullen DR, Lowe L, Bichakjian CK. NCCN guidelines implementation in the multidisciplinary Merkel cell carcinoma program at the university of Michigan. J Natl Compr Cancer Netw. 2014;12:434–41 (PMID = 24616547).
8. Raju S, Vazirnia A, Totri C, Hata TR. Treatment of Merkel cell carcinoma of the head and neck: a systematic review. Dermatol Surg. 2014;40:1273–83 (PMID = 25350122).
9. Erstad DJ, Cusack JC Jr. Mutational analysis of Merkel cell carcinoma. Cancers (Basal). 2014;6:2116–36 (PMID = 25329450).
10. Treglia G, Kakhki VR, Giovanella L, Sadeghi R. Diagnostic performance of fluorine-18-fluorodeoxyglucose positron emission tomography in patients with Merkel cell carcinoma: a systematic review and meta-analysis. Am J Clin Dermatol. 2013;14:437–47 (PMID = 23959776).
11. Ibrahim SF, Ahronowitz I, McCalmont TH, Hernandez Pampaloni M, Ryan JL, Yu SS. 18F-flurodeoxyglucose positron emission tomography-computed tomography imaging in the management of Merkel cell carcinoma: a single-institution retrospective study. Dermatol Surg. 2013;39:1323–33 (PMID = 23777452).
12. Aldabagh B, Joo J, Yu SS. Merkel cell carcinoma: current status of targeted and future potential for immunotherapies. Semin Cutan Med Surg. 2014;33:76–82 (PMID = 25085666).
13. Patel RV, Frankel A, Goldenberg G. An update on nonmelanoma skin cancer. J Clin Aesthet Dermatol. 2011;4(2):20–7 (PMID = 21386954).
14. Czapiewski P, Biernat W. Merkel cell carcinoma—recent advances in the biology, diagnositics and treatment. Int J Biochem Cell Biol. 2014;53:536–46 (PMID = 24811434).
15. Ma JE, Brewer JD. Merkel cell carcinoma in immunosuppressed patients. Cancers (Basel). 2014;6:1328–50 (PMID = 24978436).
16. Sastre-Garau X, Peter M, Avril M-F, Laude H, Couturier J, Rozenberg F, Almeida A, Boitier F, Carlotti A, Courturaud B, Dupin N. Merkel cell carcinoma of the skin: pathological and molecular evidence for a causative role of MCV in oncogenesis. J Pathol. 2009;218:48–56 (PMID = 19291712).
17. Samimi M, Touze A. Merkel cell carcinoma: the first human cancer shown to be associated with a polyomavirus. Presse Med. 2014;43:e405–11 (PMID = 25455636).
18. Leroux-Kozal V, Leveque N, Brodard V, Lesage C, Dudez O, Makeieff M, Kanagaratnam L, Diebold M-D. Merkel cell carcinoma: histopathologic and prognostic features according to the immunohistochemical expression of Merkel cell polyomavirus Large T antigen correlated with viral load. Hum Pathol. 2015;46:443–53 (PMID = 25623078).
19. Salehi-Vaziri M, Sadeghi F, Alamsi-Hashiani A, Haeri H, Monavari SH, Keyvani H. Merkel cell polyomavirus and human papillomavirus infections in cervical disease in Iranian women. Arch Virol. 2015. [Epub ahead of print]. (PMID = 25721299).
20. Trizuljak J, Srovnal J, Plevova K, Brychtova Y, Semerad L, Bakesova D, Letalova E, Benedikova A, Mayer J, Hajduch M, Posposilova S, Doubek M. Analysis of prognostic significance of Merkel cell polyomavirus in chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk. 2015. doi:10.1016/j.clml.2015.02.003 [Epub ahead of print]. (PMID = 25758600).
21. Falchook GS, Rady P, Hymes S, Nguyen HP, Trying SK, Prieto VG, Hong DS, Kurzrock R. Merkel cell polyomavirus and HPV-17 associated with cutaneous squamous cell carcinoma arising in a patient with melanoma treated with the BRAF inhibitor dabrafenib. JAMA Dermatol. 2013;149:322–6 (PMID = 23552670).
22. Gormley RH, Kim EJ, Rook AH, Kovarik CL, Sun A, Rady P, Tyring SK. Merkel cell polyomavirus in low levels in folliculotropic mycosis fungoides represents a passenger, not a driver. Int J Dermatol. 2015. doi:10.1111/ijd.12754 [Epub ahead of print]. (PMID = 25661198).
23. Du-Thanh A, Dereure O, Guillot B, Foulongne V. Merkel cell polyomavirus: its putative involvement in a particular subset of cutaneous lymphoma with possibly unfavorable outcome. J Clin Virol. 2014;61:161–5 (PMID = 25049207).
24. Murakami I, Matsushita M, Iwasaki T, Kuwamoto S, Kato M, Horie Y, Hayashi K, Gogusev J, Jaubert F, Nakamoto S, Yamakawa H, Takata K, Oka T, Yoshino T. High viral load of Merkel cell polyomavirus DNA sequences in Langerhans cell sarcoma tissues. Infect Agent Cancer. 2014;9:15. doi:10.1186/1750-9378-9-15 (eCollections 2014). (PMID = 24834110).
25. Hourdequin KC, Lefferts JA, Brennick JB, Ernstoff MS, Tsongalis GJ, Pipas JM. Merkel cell polyomavirus and extrapulmonary small cell carcinoma. Oncol Lett. 2013;6:1049–52 (PMID = 24137462).
26. Fisher CA, Harms PW, McHugh JB, Edwards PC, Siddiqui J, Palanisamy N, Bichakjian CK, Benavides E, Danciu TE. Small cell carcinoma in the parotid harboring Merkel cell polyomavirus. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014;118:703–12 (PMID = 25457888).
27. Xu S, Jiang J, Yu X, Sheng D, Zhu T, Jin M. Association of Merkel cell polyomavirus infection with EGFR mutation status in Chinese non-small cell lung cancer patients. Lung Cancer. 2014;83:341–6 (PMID = 24485957).
28. Iwasaki T, Matsushita M, Nonaka D, Kuwamoto S, Kato M, Murakami I, Nagata K, Nakajima H, Sano S, Hayashi K. Comparison of Akt/mTOR/4E-BP1 pathway signaling activation and mutations of PIK3CA in Merkel cell polyomavirus-negative carcinomas. Hum Pathol. 2015;46:210–6 (PMID = 25466966).
29. Xie H, Liu T, Wang N, Bjornhagen V, Hoog A, Larsson C, Lui WO, Xu D. TERT promoter mutations and gene amplification: promoting TERT expression in Merkel cell carcinoma. Oncotarget. 2014;5:10048–57 (PMID = 25301727).
30. Garneski KM, Lemos BD, Feng B, Jaimes N, Penas PF, Bi X, Maher E, Cohen L, Leonard JH, Granter SR, Chin L, Nghiem P. Array-CGH reveals recurrent genomic changes in Merkel cell carcinoma including amplification of L-Myc. J Invest Dermatol. 2009;129:1547–55 (PMID = 19020549).
31. Brunner M, Thurnher D, Pammer J, Heiduschka G, Petzelbauer P, Schmid C, Schneider S, Erovic BM. Expression of hedgehog signaling molecules in Merkel cell carcinoma. Head Neck. 2010;32:333–40 (PMID = 19644931).
32. Jai Y, Wang Y, Xie J. The Hedgehog pathway: role in cell differentiation, polarity and proliferation. Arch Toxicol. 2015 [Epub ahead of print]. (PMID = 25559776).
33. Cowey CL. Targeted therapy for advanced basal-cell carcinoma: vismodegib and beyond. Dermatol Ther (Heidelb). 2013;3:17–31 (PMID = 23888252).
34. Lyons TG, O’Kane GM, Kelly CM. Efficacy and safety of vismodegib: a new therapeutic agent in the treatment of basal cell carcinoma. Expert Opin Drug Saf. 2014;13:1125–32 (PMID = 25033383).
35. Scales SJ, de Sauvage FJ. Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci. 2009;30:303–12 (PMID = 19443052).
36. Abidi A. Hedgehog signaling pathway: a novel target for cancer therapy: vismodegib, a promising therapeutic option in treatment of basal cell carcinomas. Indian J Pharmacol. 2014;46:3–12 (PMID = 24550577).
37. Ruiz-Salas V, Alegre M, Lopez-Ferrer A, Garces JR. Vismodegib: a review. Actas Dermosifiliogr. 2014;105:744–51 (PMID = 24359667).
38. McMillan R, Matsui W. Molecular pathways: the hedgehog signaling pathway in cancer. Clin Cancer Res. 2012;18:4883–8 (PMID = 22718857).
39. Dlugosz AA, Talaz M. Following the hedgehog to new cancer therapies. N Engl J Med. 2008;361:1202–5 (PMID = 19726764).
40. Meiss F, Zeiser R. Vismodigib. Recent Results Cancer Res. 2014;201:405–17 (PMID = 24756807).
41. Aditya S, Rattan A. Vismodegib: a smoothened inhibitor for the treatment of advanced basal cell carcinoma. Indian Dermatol Online J. 2013;4:365–8 (PMID = 24350028).
42. Harms KL, Dlugosz AA. Harnessing hedgehog for the treatment of basal cell carcinoma. JAMA Dermatol. 2013;149:607–8 (PMID = 23677088).
43. Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, Solomon JA, Yoo S, Arron ST, Friedlander PA, Marmur E, Rudin CM, Chang ALS, Low JA, Mackey HM, Yauch RL, Graham RA, Reddy JC, Hauschild A. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366:2171–9.
44. Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, Fu L, Holcomb T, Stinson J, Gould SE, Coleman B, LoRusso PM, Von Hoff DD, de Sauvage FJ, Low JA. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med. 2009;361:1173–8 (PMID = 19726761).
45. Von Hoff DD, LoRusso PM, Rudin CM, Redy JC, Yauch RL, Tibes R, Weiss GJ, Borad MJ, Hann CL, Brahmer JR, Mackey HM, Lum BL, Darbonne WC, Marsters JC Jr, de Sauvage FJ, Low JA. N Engl J Med. 2009;361:1164–72 (PMID = 19726763).
46. Brinkhuizen T, Reinders MG, van Geel M, Hendriksen AJ, Paulussen AD, Winnepenninckx VJ, Keymeulen KB, Soetekouw PM, van Steensel MA, Mosterd K. Acquired resistance to the Hedgehog pathway inhibitor vismodegib due to smoothened mutations in treatment of locally advanced basal cell carcinoma. J Am Acad Dermatol. 2014;71:1005–8 (PMID = 25199678).
47. Atwood SX, Chang AL, Oro AE. Hedgehog pathway inhibition and the race against tumor evolution. J Cell Biol. 2012;199:193–7 (PMID = 23071148).
48. Smith MJ, Beetz C, Williams SG, Bhaskar SS, O’Sullivan J, Anderson B, Baly SB Urquhart JE, Bholah Z, Oudit D, Cheesman E, Kelsey A, McCabe MG, Newman WG, Evans DG. Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations. J Clin Oncol. 2014;32:4155–4161. (PMID = 25403219).
49. Lin C, Yao E, Wang K, Nozawa Y, Shimizu H, Johnson JR, Chen JN, Krogan NJ, Chuang PT. Regulation of Sufu activity by p66B and Mycbp provides new insight into vertebrate Hedgehog signaling. Genes Dev. 2014;28:2547–63 (PMID = 25403183).
50. Cherry AL, Finta C, Karlstrom M, Jin Q, Schwend T, Astorga-Wells J, Zubarev RA, Del Campo M, Criswell AR, de Sanctis D, Jovine L, Toftgard R. Structural basis of SUFU-GLI interaction in human Hedgehog signaling regulation. Acta Crystallogr D Biol Crystallogr. 2013;69:2563–79 (PMID = 24311597).
51. Toster U, Finta C, Rahman MF, Shimokawa T, Zaphiropoulos PG. Novel mechanism of action on Hedgehog signaling by a suppressor of fused carboxy terminal variant. PLoS One. 2012;7:e37761 (PMID = 22666390).
52. Kan Z, Jaiswal BS, Stinson J, Janakiraman V, Bhatt D, Stern HM, Yue P, Haverty PM, Bourgon R, Zheng J, Moorhead M, Chaudhuri S, Tomsho LP, Peters BA, Pujara K, Cordes S, Davis DP, Carlton VE, Yuan W, Li L, Wang W, Eigenbrot C, Kaminker JS, Eberhard DA, Waring P, Schuster SC, Modrusan Z, Zhang Z, Stokoe D, de Sauvage FJ, Faham M, Seshagiri S. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature. 2010;466:869–73 (PMID = 20668451).
53. Taylor MD, Liu L, Raffel C, Hui C-C, Mainprize TG, Zhang X, Agatep R, Chiappa S, Gao L, Lowrance A, Hao A, Goldstein AM, Theodora S, Scherer SW, Dura WT, Wainwright B, Squire JA, Rutka JT, Hogg D. Mutations in SUFU predispose to medulloblastoma. Nat Genet. 2002;31:306–10 (PMID = 12068298).
54. Aaikko M, Li SP, Saarinen S, Alhopuro P, Kaasinen E, Morgunova E, Li Y, Vesanen K, Smith MJ, Evans DG, Poyhonen M, Kiuru A, Auvinen A, Aaltonen LA, Taipale J, Vahteristo P. Loss of SUFU function in familial multiple meningioma. Am J Hum Genet. 2012;91:520–6 (PMID = 22958902).
55. Brugieres L, Remenieras A, Pierron G, Varlet P, Forget S, Byrde B, Bombled J, Puget S, Caron O, Dufour C, Delatte O, Bressac-de-Paillerets B, Grill J. High frequency of germline SUFU mutations in children with desmoplastic/nodular medulloblastoma younger than 3 years of age. J Clin Oncol. 2012;30:2087–93 (PMID = 22508808).
56. Lee Y, Kawagoe R, Sasai K, Li Y, Russell HR, Curran T, McKinnon PJ. Loss of suppressor-of-fused function promotes tumorigenesis. Oncogene. 2007;26:6442–7 (PMID = 17452975).
57. Heby-Henricson K, Bergstrom A, Rozell B, Toftgard R, Teglund S. Loss of Trp53 promotes medulloblastoma development but not skin tumorigenesis in Sufu heterozygous mutant mice. Mol Carcinog. 2012;51:754–60 (PMID = 21882258).
58. Northcott PA, Jones DT, Kool M, Robinson GW, Gilbertson RJ, Cho YJ, Pomeroy SL, Korshunov A, Lichter P, Taylor MD, Pfister SM. Medulloblastomics: the end of the beginning. Nat Rev Cancer. 2012;12:818–34 (PMID = 23175120).
59. Pugh TJ, Weeraratne SD, Archer TC, Pomeranz Krummel DA, Auclair D, Bochicchio J, Cameiro MO, Carter SL, Cibulskis K, Erlich RL, Greulich H, Lawrence MS, Lennon NJ, McKenna A, Meldrim J, Ramos AH, Ross MG, Russ C, Shefler E, Sivachenko A, Sogoloff B, Stojanov P, Tamayo P, Mesirov JP, Amani V, Teider N, Sengupta S, Francois JP, Northcott PA, Taylor MD, Yu F, Crabtree GR, Kautzman AG, Gabriel SB, Getz G, Jager N, Jones DT, Lichter P, Pfister SM, Roberts TM, Meyerson M, Pomeroy SL, Cho YJ. Medulloblastomas exome sequencing uncovers subtype-specific somatic mutations. Nature. 2012;488:106–110. (PMID = 22820256).
60. Robinson G, Parker M, Kranenburg TA, Lu C, Chen X, Ding L, Phoenix TN, Hedlund E, Wei L, Zhu X, Chalhoub N, Baker SJ, Huether R, Kriwacki R, Curley N, Thiruvenkatam R, Wang J, Wu G, Rusch M, Hong X, Becksfort J, Gupta P, Ma J, Easton J, Vadodaria B, Onar-Thomas A, Lin T, Li S, Pounds S, Paugh S, Zhao D, Kawauchi D, Roussel MF, Finkelstein D, Ellison DW, Lau CC, Bouffet E, Hassall T, Gurarangan S, Cohn R, Fulton RS, Fulton LL, Dooling DJ, Ochoa K, Gajjar A, Mardis ER, Wilson RK, Downing JR, Zhang J, Gilbertson RJ. Novel mutations target distinct subgroups of medulloblastoma. Nature. 2012;488:43–48. (PMID = 22722829).
61. Jones DT, Jager n, Kool M, Zichner T, Hutter B, Sultan M, Cho YJ, Hovestadt V, Stutz AM, Rausch T, Warnatz HJ, Ryzhova M, Bender S Strum D, Pleier S, Cin H, Pfaff E, Seiber L, Wittmann A, Remke M, Witt H, Hutter S, Tzaridis T, Weischenfeldt J, Raeder B, Avci M, Amstislavskiy V, Zapatka M, Weber UD, Wang Q, Lasitschka B, Bartholomae CC, Schmidt M, von Kalle C, Ast V, Lawrenz C, Eils J, Kabbe R, Benes V, van Sluis P, Koster J, Volckmann R, Shih D, Betts MJ, Russell RB, Coco S, Tonini GP, Schuller U, Hans V, Graf N, Kim YJ, Monoranu C, Roggendorf W, Unterberg A, Herold-Mende C, Milde T, Kuozik AE, von Deimling A, Witt O, Maass E, Rossler J, Ebinger M, Schuhmann MU, Fruhwald MC, Hasselblatt M, Jabado N, Rutkowski S, von Bueren AO, Williamson D, Clifford SC, MCabe MG, Collins VP, Wolf S, Wiemann S, Lehrach H, Brors B, Scheurlen W, Felsberg J, Reifenberger G, Northcott PA, Taylor MD, Meyerson M, Pomeroy SL, Yaspo ML, Korbel JO, Korshunov A, Eils R, Pfister SM, Lichter P, ICGC PedBrain Tumor Project. Dissecting the genomic complexity underlying medulloblastoma. Nature. 2012;488:100–105. (PMID = 22832583).
62. The Cancer Genome Atlas Data Portal. http://tcga-data.nci.nih.gov/tcga/. Accessed Dec 21, 2014.
63. Kool M, Jones DT, Jager N, Northcott PA, Pugh TJ, Hovestadt V, Piro RM, Esparza LA, Markant SL, Remke M, Milde T, Bourdeaut F, Ryzhova M, Strum D, Pfaff E, Stark S, Hutter S, Seker-Cin H, Johann P, Bender S, Schmidt C, Rausch T, Shih D, Reimand J, Sieber L, Wittmann A, Linke L, Witt H, Weber UD, Zapatka M, Konig R, Beroukim R, Bergthold G, van Sluis P, Volckmann R, Koster J, Versteeg R, Schmidt S, Wolf S, Lawerenz C, Bartholomae CC, von Kalle C, Unterberg A, Herold-Mende C, Hofer S, Kulozik AE, von Deimlig A, Scheurten W, Felsberg J, Reifenberger G, Hasselblatt M, Crawford JR, Grant GA, Jabado N, Perry A, Cowdrey C, Croul S, Zadeh G, Korbel JO, Doz F, Delattre O, Bader GD, McCabe MG, Collins VP, Kieran MW, Cho YJ, Pomeroy SL, Witt O, Brors B, Taylor MD, Schuller U, Korshunov A, Eils R, Wechsler-Reya RJ, Lichter P, Pfister SM, ICGC PedBrain Tumor Project. Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell. 2014;25:393–405. (PMID = 24651015).
64. Ruch JM, Kim EJ. Hedgehog signaling pathway and cancer therapeutics: progress to date. Drugs. 2013;73:613–23 (PMID = 23605693).
65. Lauth M, Bergstrom A, Shimokawa T, Toftgard R. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc Natl Acad Sci. 2007;104:8455–60 (PMID = 17494766).
66. Hyman JM, Firestone AJ, Heine VM, Zhao Y, Ocasio CA, Han K, Sun M, Rack PG, Sinha S, Wu JJ, Solow-Cordero DE, Jiang J, Rowitch DH, Chen JK. Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade. Proc Natl Acad Sci. 2009;106:14132–7 (PMID = 19666565).
67. Kim J, Aftab BT, Tang JY, Kim D, Lee AH, Rezaee M, Kim J, Chen B, King EM, Borodovsky A, Riggins GJ, Epstein EH Jr, Beachy PA, Rudin CM. Itraconazole an arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer Cell. 2013;23:23–34 (PMID = 23291299).
68. Beauchamp EM, Ringer L, Bulut G, Saiwan KP, Hall MD, Lee YC, Peaceman D, Ozdemirli M, Rodriguez O, Macdonald TJ, Albanese C, Toretsky JA, Uren A. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. J Clin Invest. 2011;121:148–60 (PMID = 21183792).
69. Kim J, Lee JJ, Kim J, Gardner D, Beachy PA. Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector. Proc Natl Acad Sci. 2010;107:13432–7 (PMID = 206234968).
70. Tang Y, Gholamin S, Schubert S, Willardson M, Lee A, Bandopadhayay P, Bergthold G, Masoud S, Nguyen B, Vue N, Balansay B, Yu F, Oh S, Woo P, Chen S, Ponnuswami A, Monje M, Atwood SX, Whitson RJ, Mitra S, Cheshier SH, Qi J, Beroukhim R, Tang JY, Wechsler-Reva R, Oro AE, Link BA, Bradner JE, Cho YJ. Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nat Med. 2014;20:732–40 (PMID = 24973920).
71. Dombret H, Preudhomme C, Berthon C, Raffoux E, Thomas X, Vey N, Gomez-Roco C, Ethell M, Yee K, Bourdel F, Herait P Michallet M, Recher C, Roumier C, Quesnel B. A phase 1 study of the BET-bromodomain inhibitor OTX015 in patients with advanced acute leukemia [Abstract 117]. In: 56th ASH Annual Meeting and Exposition. San Francisco. 2014. https://ash.confex.com/ash/2014/webprogram/Paper70684.html. Accessed Jan 24, 2015.
72. Thieblemont C, Stathis A, Inghirami G, Korlin L, Morschhauser F, Gleeson M, Broussais F, Amorim S, Salles G, Facon T, Cunningham D, Vey N, Bourdel F, Herait P, Zucca E. A phase 1 study of the BET-bromodomain inhibitor OTX015 in patients with non-leukemic hematologic malignancies [Abstract 4417]. In: 56th ASH Annual Meeting and Exposition. San Francisco. 2014. https://ash.confex.com/ash/2014/webprogram/Paper70510.html. Accessed Jan 24, 2015.