Pharmacokinetic modeling optimizes inhibition of the 'undruggable' EWS-FLI1 transcription factor in ewing sarcoma

Oncotarget

Volumn 5, Issue 2, 2014, Pages 338-350

  Hong, Sung Hyeok ^a   Youbi, Sarah E ^a   Peter Hong, S ^b   Kallakury, Bhaskar ^a   Monroe, Phillip ^b   Erkizan, Hayriye V ^a   Barber Rotenberg, Julie S ^a   Houghton, Peter ^c   üren, Aykut ^a   Toretsky, Jeffrey A ^a  

^a GEORGETOWN UNIVERSITY   (United States)

^b BATTELLE MEMORIAL INSTITUTE   (United States)

^c THE RESEARCH INSTITUTE AT NATIONWIDE CHILDREN S HOSPITAL   (United States)

Author keywords

Ewing sarcoma; EWS FLI1; Pharmacokinetic modeling; Rat xenograft; YK 4 279

Indexed keywords

ANTINEOPLASTIC AGENT; CAVEOLIN 1; RNA BINDING PROTEIN EWS; TRANSCRIPTION FACTOR FLI 1; UNCLASSIFIED DRUG; YK 4 279; EWS-FLI FUSION PROTEIN; INDOLE DERIVATIVE; ONCOPROTEIN; YK 4-279;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; AREA UNDER THE CURVE; ARTICLE; CANCER INHIBITION; CONCENTRATION RESPONSE; CONTINUOUS INFUSION; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG EFFECT; DRUG EFFICACY; DRUG EXPOSURE; DRUG HALF LIFE; ENANTIOMER; EWING SARCOMA; FEMALE; IN VITRO STUDY; IN VIVO STUDY; MALE; NONHUMAN; RAT; TIME TO MAXIMUM PLASMA CONCENTRATION; TUMOR XENOGRAFT; ANIMAL; ANTAGONISTS AND INHIBITORS; BLOOD; C57BL MOUSE; DRUG EFFECTS; DRUG SCREENING; GENETIC TRANSCRIPTION; GENETICS; HUMAN; METABOLISM; MOUSE; PATHOLOGY; RANDOMIZATION; SARCOMA, EWING; SPRAGUE DAWLEY RAT; TUMOR CELL LINE;

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; CELL LINE, TUMOR; FEMALE; HUMANS; INDOLES; MALE; MICE; MICE, INBRED C57BL; ONCOGENE PROTEINS, FUSION; PROTO-ONCOGENE PROTEIN C-FLI-1; RANDOM ALLOCATION; RATS; RATS, SPRAGUE-DAWLEY; RNA-BINDING PROTEIN EWS; SARCOMA, EWING; TRANSCRIPTION, GENETIC; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84896735201     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.1495     Document Type: Article

References (33)

1. Linabery AM and Ross JA. Childhood and adolescent cancer survival in the US by race and ethnicity for the diagnostic period 1975-1999. Cancer. 2008; 113(9):2575-2596.
2. Bernstein ML, Devidas M, Lafreniere D, Souid AK, Meyers PA, Gebhardt M, Stine K, Nicholas R, Perlman EJ, Dubowy R, Wainer IW, Dickman PS, Link MP, Goorin A and Grier HE. Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children's Cancer Group Phase II Study 9457--a report from the Children's Oncology Group. J Clin Oncol. 2006; 24(1):152-159.
3. Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ and Miser JS. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003; 348(8):694-701.
4. Womer RB, West DC, Krailo MD, Dickman PS, Pawel BR, Grier HE, Marcus K, Sailer S, Healey JH, Dormans JP and Weiss AR. Randomized controlled trial of intervalcompressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol. 2012; 30(33):4148-4154.
5. Delattre O, Zucman J, Melot T, Garau XS, Zucker JM, Lenoir GM, Ambros PF, Sheer D, Turc-Carel C, Triche TJ and et al. The Ewing family of tumors--a subgroup of smallround-cell tumors defined by specific chimeric transcripts. N Engl J Med. 1994; 331(5):294-299.
6. Toretsky JA, Erkizan V, Levenson A, Abaan OD, Parvin JD, Cripe TP, Rice AM, Lee SB and Uren A. Oncoprotein EWS-FLI1 activity is enhanced by RNA helicase A. Cancer Res. 2006; 66(11):5574-5581.
7. Erkizan HV, Kong Y, Merchant M, Schlottmann S, Barber-Rotenberg JS, Yuan L, Abaan OD, Chou TH, Dakshanamurthy S, Brown ML, Uren A and Toretsky JA. A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma. Nat Med. 2009; 15(7):750-756.
8. Darnell JE, Jr. Transcription factors as targets for cancer therapy. Nat Rev Cancer. 2002; 2(10):740-749.
9. Dunker AK and Uversky VN. Drugs for 'protein clouds': targeting intrinsically disordered transcription factors. Curr Opin Pharmacol. 2010; 10(6):782-788.
10. Ng KP, Potikyan G, Savene RO, Denny CT, Uversky VN and Lee KA. Multiple aromatic side chains within a disordered structure are critical for transcription and transforming activity of EWS family oncoproteins. Proc Natl Acad Sci U S A. 2007; 104(2):479-484.
11. Uren A, Tcherkasskaya O and Toretsky JA. Recombinant EWS-FLI1 oncoprotein activates transcription. Biochemistry. 2004; 43(42):13579-13589.
12. Erkizan HV, Uversky VN and Toretsky JA. Oncogenic partnerships: EWS-FLI1 protein interactions initiate key pathways of Ewing's sarcoma. Clin Cancer Res. 2010; 16(16):4077-4083.
13. Mittag T, Kay LE and Forman-Kay JD. Protein dynamics and conformational disorder in molecular recognition. J Mol Recognit. 2010; 23(2):105-116.
14. Shan Y, Eastwood MP, Zhang X, Kim ET, Arkhipov A, Dror RO, Jumper J, Kuriyan J and Shaw DE. Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization. Cell. 2012; 149(4):860-870.
15. Boehr DD, Nussinov R and Wright PE. The role of dynamic conformational ensembles in biomolecular recognition. Nature chemical biology. 2009; 5(11):789-796.
16. Wong CC, Cheng KW and Rigas B. Preclinical predictors of anticancer drug efficacy: critical assessment with emphasis on whether nanomolar potency should be required of candidate agents. J Pharmacol Exp Ther. 2012; 341(3):572-578.
17. Hammoudeh DI, Follis AV, Prochownik EV and Metallo SJ. Multiple independent binding sites for small-molecule inhibitors on the oncoprotein c-Myc. J Am Chem Soc. 2009; 131(21):7390-7401.
18. Mustata G, Follis AV, Hammoudeh DI, Metallo SJ, Wang H, Prochownik EV, Lazo JS and Bahar I. Discovery of novel myc-max heterodimer disruptors with a threedimensional pharmacophore model. J Med Chem. 2009; 52(5):1247-1250.
19. Arkin MR and Wells JA. Small-molecule inhibitors of protein-protein interactions: progressing towards the dream. Nature reviews. 2004; 3(4):301-317.
20. Barber-Rotenberg JS, Selvanathan SP, Kong Y, Erkizan HV, Snyder TM, Hong PS, Kobs CL, South NL, Summer S, Monroe PJ, Chruszcz M, Dobrev V, Tosso PN, Scher LJ, Minor W, Brown ML, et al. Single Enantiomer of YK-4-279 Demonstrates Specificity in Targeting the Oncogene EWS-FLI1. Oncotarget. 2012; 3(2):172-182.
21. Chatuphonprasert W, Rermraksakul P, Udomsuk L, Laoong T and Jarukamjorn K. Different profiles of hepatic alkoxyresorufin O-dealkylase activities in small rodents. Journal of applied toxicology : JAT. 2012; 32(12):1002-1007.
22. Tirado OM, Mateo-Lozano S, Villar J, Dettin LE, Llort A, Gallego S, Ban J, Kovar H and Notario V. Caveolin-1 (CAV1) is a target of EWS/FLI-1 and a key determinant of the oncogenic phenotype and tumorigenicity of Ewing's sarcoma cells. Cancer Res. 2006; 66(20):9937-9947.
23. Tirado OM, MacCarthy CM, Fatima N, Villar J, Mateo-Lozano S and Notario V. Caveolin-1 promotes resistance to chemotherapy-induced apoptosis in Ewing's sarcoma cells by modulating PKCalpha phosphorylation. Int J Cancer. 2010; 126(2):426-436.
24. Fuxreiter M, Tompa P, Simon I, Uversky VN, Hansen JC and Asturias FJ. Malleable machines take shape in eukaryotic transcriptional regulation. Nature chemical biology. 2008; 4(12):728-737.
25. Kemp MM, Wang Q, Fuller JH, West N, Martinez NM, Morse EM, Weiwer M, Schreiber SL, Bradner JE and Koehler AN. A novel HDAC inhibitor with a hydroxypyrimidine scaffold. Bioorganic & medicinal chemistry letters. 2011; 21(14):4164-4169.
26. Koehler AN. A complex task? Direct modulation of transcription factors with small molecules. Curr Opin Chem Biol. 2010; 14(3):331-340.
27. Metallo SJ. Intrinsically disordered proteins are potential drug targets. Curr Opin Chem Biol. 2010; 14(4):481-488.
28. Vavouri T, Semple JI, Garcia-Verdugo R and Lehner B. Intrinsic protein disorder and interaction promiscuity are widely associated with dosage sensitivity. Cell. 2009; 138(1):198-208.
29. Yin JJ, Sharma S, Shumyak SP, Wang ZX, Zhou ZW, Zhang Y, Guo P, Li CZ, Kanwar JR, Yang T, Mohapatra SS, Liu W, Duan W, Wang JC, Li Q, Zhang X, et al. Synthesis and biological evaluation of novel folic acid receptor-targeted, beta-cyclodextrin-based drug complexes for cancer treatment. PLoS ONE. 2013; 8(5):e62289.
30. Michel J and Cuchillo R. The impact of small molecule binding on the energy landscape of the intrinsically disordered protein C-myc. PLoS ONE. 2012; 7(7):e41070.
31. Schmahl HJ, Nau H and Neubert D. The enantiomers of the teratogenic thalidomide analogue EM 12: 1. Chiral inversion and plasma pharmacokinetics in the marmoset monkey. Archives of toxicology. 1988; 62(2-3):200-204.
32. Thomas JM and Schug SA. Recent advances in the pharmacokinetics of local anaesthetics. Long-acting amide enantiomers and continuous infusions. Clinical pharmacokinetics. 1999; 36(1):67-83.
33. Sainz-Jaspeado M, Lagares-Tena L, Lasheras J, Navid F, Rodriguez-Galindo C, Mateo-Lozano S, Notario V, Sanjuan X, Garcia Del Muro X, Fabra A and Tirado OM. Caveolin-1 modulates the ability of Ewing's sarcoma to metastasize. Mol Cancer Res. 2010; 8(11):1489-1500.