Phase I study of OPB-31121, an oral STAT3 inhibitor, in patients with advanced solid tumors

Cancer Research and Treatment

Volumn 47, Issue 4, 2015, Pages 607-615

  Oh, Do Youn ^a,b   Lee, Se Hoon ^a,b   Han, Sae Won ^a,b   Kim, Mi Jung ^a,c   Kim, Tae Min ^a,b   Kim, Tae You ^a,b   Heo, Dae Seog ^a,b   Yuasa, Miyuki ^d   Yanagihara, Yasuo ^e   Bang, Yung Jue ^a,b  

^a Seoul National University Hospital   (South Korea)

^b Seoul National University   (South Korea)

^c National Cancer Center   (South Korea)

^d Otsuka Pharmaceutical ^*  (Japan)

^e Otsuka Pharmaceutical   (Japan)

Author keywords

OPB 31121; Phase I; Solid tumor; STAT3; STAT3 inhibitor

Indexed keywords

ANTINEOPLASTIC AGENT; CALCIUM; GLUCOSE; OPB 31121; PROTEIN INHIBITOR; SODIUM; THYROTROPIN; UNCLASSIFIED DRUG; STAT3 PROTEIN;

ADULT; ADVANCED CANCER; ADVANCED SOLID TUMOR; AGED; ANEMIA; ANTINEOPLASTIC ACTIVITY; AREA UNDER THE CURVE; ARTICLE; ASTHENIA; BREAST CANCER; CALCIUM BLOOD LEVEL; CANCER CHEMOTHERAPY; CLINICAL ARTICLE; COLON CANCER; COLORECTAL CANCER; CONSTIPATION; CONTROLLED STUDY; DIARRHEA; DISEASE COURSE; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG FEVER; DRUG HALF LIFE; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; DYSPNEA; EDEMA; ELIMINATION HALF-LIFE; ESOPHAGUS CANCER; FEMALE; FOLLOW UP; GLUCOSE BLOOD LEVEL; HUMAN; HYPERGLYCEMIA; HYPOCALCEMIA; HYPONATREMIA; LUNG CANCER; LUNG EMBOLISM; MALE; MAXIMUM PLASMA CONCENTRATION; MAXIMUM TOLERATED DOSE; MELANOMA; MOOD DISORDER; MULTIPLE CYCLE TREATMENT; NAUSEA; NEUTROPENIA; OPEN STUDY; PANCREAS CANCER; PARESTHESIA; PAROTID GLAND CANCER; PHASE 1 CLINICAL TRIAL; PITTING EDEMA; RASH; RECTUM CANCER; SIDE EFFECT; SKIN CANCER; SODIUM BLOOD LEVEL; SOLID TUMOR; STOMACH CANCER; THROMBOCYTOPENIA; THYROTROPIN BLOOD LEVEL; TIME TO MAXIMUM PLASMA CONCENTRATION; TREATMENT DURATION; TREATMENT OUTCOME; TREATMENT RESPONSE; UTERINE CERVIX CANCER; VOMITING; ANTAGONISTS AND INHIBITORS; CLINICAL TRIAL; DOSE RESPONSE; METABOLISM; MIDDLE AGED; NEOPLASMS; PATHOLOGY; SAFETY; YOUNG ADULT;

ADULT; AGED; ANTINEOPLASTIC AGENTS; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; HUMANS; MALE; MAXIMUM TOLERATED DOSE; MIDDLE AGED; NEOPLASMS; SAFETY; STAT3 TRANSCRIPTION FACTOR; YOUNG ADULT;

EID: 84942941353     PISSN: 15982998     EISSN: 20059256     Source Type: Journal    
DOI: 10.4143/crt.2014.249     Document Type: Article

References (25)

1. Yu H, Jove R. The STATs of cancer: new molecular targets come of age. Nat Rev Cancer. 2004;4:97-105.
2. Mankan AK, Greten FR. Inhibiting signal transducer and activator of transcription 3: rationality and rationale design of inhibitors. Expert Opin Investig Drugs. 2011;20:1263-75.
3. Sansone P, Bromberg J. Targeting the interleukin-6/Jak/stat pathway in human malignancies. J Clin Oncol. 2012;30: 1005-14.
4. Calvisi DF, Ladu S, Gorden A, Farina M, Conner EA, Lee JS, et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology. 2006;130:1117-28.
5. Jove R. Preface: STAT signaling. Oncogene. 2000;19:2466-7.
6. Levy DE, Inghirami G. STAT3: a multifaceted oncogene. Proc Natl Acad Sci U S A. 2006;103:10151-2.
7. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009;9: 798-809.
8. Alvarez JV, Greulich H, Sellers WR, Meyerson M, Frank DA. Signal transducer and activator of transcription 3 is required for the oncogenic effects of non-small-cell lung cancer-associated mutations of the epidermal growth factor receptor. Cancer Res. 2006;66:3162-8.
9. Grandis JR, Drenning SD, Zeng Q, Watkins SC, Melhem MF, Endo S, et al. Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo. Proc Natl Acad Sci U S A. 2000;97:4227-32.
10. Mizutani Y, Bonavida B, Koishihara Y, Akamatsu K, Ohsugi Y , Yoshida O. Sensitization of human renal cell carcinoma cells to cis-diamminedichloroplatinum(II) by anti-interleukin 6 monoclonal antibody or anti-interleukin 6 receptor monoclonal antibody. Cancer Res. 1995;55:590-6.
11. Alas S, Bonavida B. Inhibition of constitutive STAT3 activity sensitizes resistant non-Hodgkin's lymphoma and multiple myeloma to chemotherapeutic drug-mediated apoptosis. Clin Cancer Res. 2003;9:316-26.
12. Li WC, Ye SL, Sun RX, Liu YK, Tang ZY, Kim Y, et al. Inhibi tion of growth and metastasis of human hepatocellular carcinoma by antisense oligonucleotide targeting signal transducer and activator of transcription 3. Clin Cancer Res. 2006;12: 7140-8.
13. Verstovsek S. Therapeutic potential of JAK2 inhibitors. Hematology Am Soc Hematol Educ Program. 2009:636-42.
14. Kim MJ, Nam HJ, Kim HP, Han SW, Im SA, Kim TY, et al. OPB-31121, a novel small molecular inhibitor, disrupts the JAK2/STAT3 pathway and exhibits an antitumor activity in gastric cancer cells. Cancer Lett. 2013;335:145-52.
15. Bendell JC, Hong DS, Burris HA 3rd, Naing A, Jones SF, Falchook G, et al. Phase 1, open-label, dose-escalation, and pharmacokinetic study of STAT3 inhibitor OPB-31121 in subjects with advanced solid tumors. Cancer Chemother Pharmacol. 2014;74:125-30.
16. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387-97.
17. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365: 1054-61.
18. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779-90.
19. James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434:1144-8.
20. Motte N, Saulnier P, Le Couedic JP, Soria JC, Delaloge S, Boige V, et al. Mutations in JAK2V617F homologous domain of JAK genes are uncommon in solid tumors. Int J Cancer. 2007;121: 2113-5.
21. Lin L, Liu A, Peng Z, Lin HJ, Li PK, Li C, et al. STAT3 is necessary for proliferation and survival in colon cancer-initiating cells. Cancer Res. 2011;71:7226-37.
22. Morikawa T, Baba Y, Yamauchi M, Kuchiba A, Nosho K, Shima K, et al. STAT3 expression, molecular features, inflammation patterns, and prognosis in a database of 724 colorectal cancers. Clin Cancer Res. 2011;17:1452-62.
23. Chen J, Wang J, Lin L, He L, Wu Y, Zhang L, et al. Inhibition of STAT3 signaling pathway by nitidine chloride suppressed the angiogenesis and growth of human gastric cancer. Mol Cancer Ther. 2012;11:277-87.
24. Deng JY, Sun D, Liu XY, Pan Y, Liang H. STAT-3 correlates with lymph node metastasis and cell survival in gastric cancer. World J Gastroenterol. 2010;16:5380-7.
25. Gong W, Wang L, Yao JC, Ajani JA, Wei D, Aldape KD, et al. Expression of activated signal transducer and activator of transcription 3 predicts expression of vascular endothelial growth factor in and angiogenic phenotype of human gastric cancer. Clin Cancer Res. 2005;11:1386-93.