title: Targeting melanoma with front-line therapy does not abrogate Nodal-expressing tumor cells.
abstract: Metastatic melanoma is a highly aggressive skin cancer with a poor prognosis. It is the leading cause of skin cancer deaths with a median overall survival for advanced-stage metastatic disease of <6 months. Despite advances in the field with conventional and targeted therapies, the heterogeneity of melanoma poses the greatest ongoing challenge, ultimately leading to relapse and progression to a more drug-resistant tumor in most patients. Particularly noteworthy are recent findings, indicating that these therapies exert selective pressure on tumors resulting in the activation of pathways associated with cancer stem cells that are unresponsive to current therapy. Our previous studies have shown how Nodal, an embryonic morphogen of the transforming growth factor-beta superfamily, is one of these critical factors that is reactivated in aggressive melanoma and resistant to conventional chemotherapy, such as dacarbazine. In the current study, we sought to determine whether BRAF inhibitor (BRAFi) therapy targeted Nodal-expressing tumor cells in uniquely matched unresectable stage III and IV melanoma patient samples before and after therapy that preceded their eventual death due to disease. The results demonstrate that BRAFi treatment failed to affect Nodal levels in melanoma tissues. Accompanying experiments in soft agar and in nude mice showed the advantage of using combinatorial treatment with BRAFi plus anti-Nodal monoclonal antibody to suppress tumor growth and metastasis. These data provide a promising new approach using front-line therapy combined with targeting a cancer stem cell-associated molecule-producing a more efficacious response than monotherapy.
authors: Department of Biology, Shepherd University, Shepherdstown, WV, USA.|Program in Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute at Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.|Robert C. Byrd Health Sciences Center, West Virginia University Cancer Institute, West Virginia University, Morgantown, WV, USA.
authors: Mary Jc
authors: MJ
authors: Hendrix
authors: Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA.
authors: Irawati
authors: I
authors: Kandela
authors: Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA.
authors: Andrew P
authors: AP
authors: Mazar
authors: Program in Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute at Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.|Robert C. Byrd Health Sciences Center, West Virginia University Cancer Institute, West Virginia University, Morgantown, WV, USA.
authors: Elisabeth A
authors: EA
authors: Seftor
authors: Program in Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute at Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.|Robert C. Byrd Health Sciences Center, West Virginia University Cancer Institute, West Virginia University, Morgantown, WV, USA.
authors: Richard Eb
authors: RE
authors: Seftor
authors: Program in Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute at Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.|Robert C. Byrd Health Sciences Center, West Virginia University Cancer Institute, West Virginia University, Morgantown, WV, USA.
authors: Naira V
authors: NV
authors: Margaryan
authors: Program in Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute at Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.|Department of Pathology, Midwestern University, Downers Grove, IL, USA.
authors: Luigi
authors: L
authors: Strizzi
authors: Department of Pathology, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
authors: George F
authors: GF
authors: Murphy
authors: Melanoma Institute Australia and Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors: Georgina V
authors: GV
authors: Long
authors: Melanoma Institute Australia and Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.|Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors: Richard A
authors: RA
authors: Scolyer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods; D009154:Mutation; D055457:Nodal Protein / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D010091:Oximes / Q000008:administration & dosage; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011728:Pyridones / Q000008:administration & dosage; D011744:Pyrimidinones / Q000008:administration & dosage; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D007093:Imidazoles; D055457:Nodal Protein; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib