title: Targeted Blockade of JAK/STAT3 Signaling Inhibits Ovarian Carcinoma Growth.
abstract: Ovarian carcinoma is the fifth leading cause of death among women in the United States. Persistent activation of STAT3 is frequently detected in ovarian carcinoma. STAT3 is activated by Janus family kinases (JAK) via cytokine receptors, growth factor receptor, and non-growth factor receptor tyrosine kinases. Activation of STAT3 mediates tumor cell proliferation, survival, motility, invasion, and angiogenesis, and recent work demonstrates that STAT3 activation suppresses antitumor immune responses and supports tumor-promoting inflammation. We hypothesized that therapeutic targeting of the JAK/STAT3 pathway would inhibit tumor growth by direct effects on ovarian carcinoma cells and by inhibition of cells in the tumor microenvironment (TME). To test this, we evaluated the effects of a small-molecule JAK inhibitor, AZD1480, on cell viability, apoptosis, proliferation, migration, and adhesion of ovarian carcinoma cells in vitro. We then evaluated the effects of AZD1480 on in vivo tumor growth and progression, gene expression, tumor-associated matrix metalloproteinase (MMP) activity, and immune cell populations in a transgenic mouse model of ovarian carcinoma. AZD1480 treatment inhibited STAT3 phosphorylation and DNA binding, and migration and adhesion of cultured ovarian carcinoma cells and ovarian tumor growth rate, volume, and ascites production in mice. In addition, drug treatment led to altered gene expression, decreased tumor-associated MMP activity, and fewer suppressor T cells in the peritoneal TME of tumor-bearing mice than control mice. Taken together, our results show pharmacologic inhibition of the JAK2/STAT3 pathway leads to disruption of functions essential for ovarian tumor growth and progression and represents a promising therapeutic strategy.
authors: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors: Galina
authors: G
authors: Gritsina
authors: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors: Fang
authors: F
authors: Xiao
authors: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors: Shane W
authors: SW
authors: O'Brien
authors: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Kazan (Volga Region) Federal University, Kazan, Russia.
authors: Rashid
authors: R
authors: Gabbasov
authors: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors: Marisa A
authors: MA
authors: Maglaty
authors: Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors: Ren-Huan
authors: RH
authors: Xu
authors: Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors: Roshan J
authors: RJ
authors: Thapa
authors: Biostatistics Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors: Yan
authors: Y
authors: Zhou
authors: Genomics Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors: Emmanuelle
authors: E
authors: Nicolas
authors: Biostatistics Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors: Samuel
authors: S
authors: Litwin
authors: Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors: Siddharth
authors: S
authors: Balachandran
authors: Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors: Luis J
authors: LJ
authors: Sigal
authors: AstraZeneca Oncology iMed, Waltham, Massachusetts.
authors: Dennis
authors: D
authors: Huszar
authors: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Denise.Connolly@fccc.edu.
authors: Denise C
authors: DC
authors: Connolly
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016000:Cluster Analysis; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: C545606:AZD 1480; D000700:Analgesics; D039302:Integrin alphaVbeta3; D011720:Pyrazoles; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; D053612:Janus Kinases; D020782:Matrix Metalloproteinases
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