title: Targeting nodal in conjunction with dacarbazine induces synergistic anticancer effects in metastatic melanoma.
abstract: Metastatic melanoma is a highly aggressive skin cancer with a poor prognosis. Despite a complete response in fewer than 5% of patients, the chemotherapeutic agent dacarbazine (DTIC) remains the reference drug after almost 40 years. More recently, FDA-approved drugs have shown promise but patient outcome remains modest, predominantly due to drug resistance. As such, combinatorial targeting has received increased attention, and will advance with the identification of new molecular targets. One attractive target for improving melanoma therapy is the growth factor Nodal, whose normal expression is largely restricted to embryonic development, but is reactivated in metastatic melanoma. In this study, we sought to determine how Nodal-positive human melanoma cells respond to DTIC treatment and to ascertain whether targeting Nodal in combination with DTIC would be more effective than monotherapy. A single treatment with DTIC inhibited cell growth but did not induce apoptosis. Rather than reducing Nodal expression, DTIC increased the size of the Nodal-positive subpopulation, an observation coincident with increased cellular invasion. Importantly, clinical tissue specimens from patients with melanomas refractory to DTIC therapy stained positive for Nodal expression, both in pre- and post-DTIC tumors, underscoring the value of targeting Nodal. In vitro, anti-Nodal antibodies alone had some adverse effects on proliferation and apoptosis, but combining DTIC treatment with anti-Nodal antibodies decreased cell growth and increased apoptosis synergistically, at concentrations incapable of producing meaningful effects as monotherapy.
  
  
  CONCLUSIONS
  Targeting Nodal in combination with DTIC therapy holds promise for the treatment of metastatic melanoma.
authors.affiliation: Program in Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute at Ann and Robert H. Lurie Children's Hospital of Chicago, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Katharine M
authors.initials: KM
authors.lastname: Hardy
authors.affiliation: Program in Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute at Ann and Robert H. Lurie Children's Hospital of Chicago, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Luigi
authors.initials: L
authors.lastname: Strizzi
authors.affiliation: Program in Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute at Ann and Robert H. Lurie Children's Hospital of Chicago, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Naira V
authors.initials: NV
authors.lastname: Margaryan
authors.affiliation: Program in Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute at Ann and Robert H. Lurie Children's Hospital of Chicago, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Howard Hughes Medical Institute NU Bioscientist Program, Weinberg College of Arts and Sciences, Northwestern University, Evanston, Illinois.
authors.forename: Kanika
authors.initials: K
authors.lastname: Gupta
authors.affiliation: Department of Pathology, Harvard Medical School, Brigham & Women's Hospital, Boston, Massachusetts.
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.affiliation: Melanoma Institute Australia; Sydney Medical School, The University of Sydney; and Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: Program in Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute at Ann and Robert H. Lurie Children's Hospital of Chicago, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois. m-hendrix@northwestern.edu.
authors.forename: Mary J C
authors.initials: MJ
authors.lastname: Hendrix
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000494:pharmacology*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D055457:Nodal Protein / Q000276:immunology / Q000378:metabolism*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; C526007:NODAL protein, human; D055457:Nodal Protein; D003606:Dacarbazine