title: Chemo-predictive assay for targeting cancer stem-like cells in patients affected by brain tumors.
abstract: Administration of ineffective anticancer therapy is associated with unnecessary toxicity and development of resistant clones. Cancer stem-like cells (CSLCs) resist chemotherapy, thereby causing relapse of the disease. Thus, development of a test that identifies the most effective chemotherapy management offers great promise for individualized anticancer treatments. We have developed an ex vivo chemotherapy sensitivity assay (ChemoID), which measures the sensitivity of CSLCs as well as the bulk of tumor cells to a variety of chemotherapy agents. Two patients, a 21-year old male (patient 1) and a 5-month female (patient 2), affected by anaplastic WHO grade-III ependymoma were screened using the ChemoID assay. Patient 1 was found sensitive to the combination of irinotecan and bevacizumab, which resulted in a prolonged disease progression free period of 18 months. Following recurrence, the combination of various chemotherapy drugs was tested again with the ChemoID assay. We found that benzyl isothiocyanate (BITC) greatly increased the chemosensitivity of the ependymoma cells to the combination of irinotecan and bevacizumab. After patient 1 was treated for two months with irinotecan, bevacizumab and supplements of cruciferous vegetable extracts containing BITC, we observed over 50% tumoral regression in comparison with pre-ChemoID scan as evidenced by MRI. Patient 2 was found resistant to all treatments tested and following 6 cycles of vincristine, carboplatin, cyclophosphamide, etoposide, and cisplatin in various combinations, the tumor of this patient rapidly progressed and proton beam therapy was recommended. As expected animal studies conducted with patient derived xenografts treated with ChemoID screened drugs recapitulated the clinical observation. This assay demonstrates that patients with the same histological stage and grade of cancer may vary considerably in their clinical response, suggesting that ChemoID testing which measures the sensitivity of CSLCs as well as the bulk of tumor cells to a variety of chemotherapy agents could lead to more effective and personalized anticancer treatments in the future.
authors.affiliation: Department of Biochemistry and Microbiology, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America; Translational Genomic Research Institute, Marshall University, Huntington, West Virginia, United States of America.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Mathis
authors.affiliation: Department of Neurosurgery, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America.
authors.forename: Anthony
authors.initials: A
authors.lastname: Alberico
authors.affiliation: Department of Biochemistry and Microbiology, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America; Translational Genomic Research Institute, Marshall University, Huntington, West Virginia, United States of America.
authors.forename: Rounak
authors.initials: R
authors.lastname: Nande
authors.affiliation: Department of Biochemistry and Microbiology, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America; Translational Genomic Research Institute, Marshall University, Huntington, West Virginia, United States of America.
authors.forename: Walter
authors.initials: W
authors.lastname: Neto
authors.affiliation: Department of Biochemistry and Microbiology, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America; Translational Genomic Research Institute, Marshall University, Huntington, West Virginia, United States of America.
authors.forename: Logan
authors.initials: L
authors.lastname: Lawrence
authors.affiliation: Department of Biochemistry and Microbiology, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America; Translational Genomic Research Institute, Marshall University, Huntington, West Virginia, United States of America.
authors.forename: Danielle R
authors.initials: DR
authors.lastname: McCallister
authors.affiliation: Department of Biochemistry and Microbiology, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America; Translational Genomic Research Institute, Marshall University, Huntington, West Virginia, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Denvir
authors.affiliation: Department of Medical Oncology, St. Mary's Hospital, Huntington, West Virginia, United States of America.
authors.forename: Gerrit A
authors.initials: GA
authors.lastname: Kimmey
authors.affiliation: Department of Pediatrics, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Mogul
authors.affiliation: Department of Pathology, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America.
authors.forename: Gerard
authors.initials: G
authors.lastname: Oakley
authors.affiliation: Department of Pathology, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America.
authors.forename: Krista L
authors.initials: KL
authors.lastname: Denning
authors.affiliation: Department of Pathology, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dougherty
authors.affiliation: Department of Biology, Marshall University, Huntington, West Virginia, United States of America.
authors.forename: Jagan V
authors.initials: JV
authors.lastname: Valluri
authors.affiliation: Department of Biochemistry and Microbiology, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America; Translational Genomic Research Institute, Marshall University, Huntington, West Virginia, United States of America; Department of Surgery, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Claudio
mesh_terms: D000328:Adult; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016503:Drug Delivery Systems; D004806:Ependymoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays