title: Computational drug treatment simulations on projections of dysregulated protein networks derived from the myelodysplastic mutanome match clinical response in patients.
abstract: Although the majority of MDS patients fail to achieve clinical improvement to approved therapies, some patients benefit from treatment. Predicting patient response prior to therapy would improve treatment effectiveness, avoid treatment-related adverse events and reduce healthcare costs. Three separate cohorts of MDS patients were used to simulate drug response to lenalidomide alone, hypomethylating agent (HMA) alone, or HMA plus lenalidomide. Utilizing a computational biology program, genomic abnormalities in each patient were used to create an intracellular pathway map that was then used to screen for drug response. In the lenalidomide treated cohort, computer modeling correctly matched clinical responses in 37/46 patients (80%). In the second cohort, 15 HMA patients were modeled and correctly matched to responses in 12 (80%). In the third cohort, computer modeling correctly matched responses in 10/10 patients (100%). This computational biology network approach identified GGH overexpression as a potential resistance factor to HMA treatment and paradoxical activation of beta-catenin (through Csnk1a1 inhibition) as a resistance factor to lenalidomide treatment. We demonstrate that a computational technology is able to map the complexity of the MDS mutanome to simulate and predict drug response. This tool can improve understanding of MDS biology and mechanisms of drug sensitivity and resistance.
authors.affiliation: Department of Hematology Oncology: 1600 SW Archer Rd. PO box 100278, Gainesville, FL 32610, USA.
authors.forename: Leylah
authors.initials: L
authors.lastname: Drusbosky
authors.affiliation: Department of Hematology Oncology: 1600 SW Archer Rd. PO box 100278, Gainesville, FL 32610, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Medina
authors.affiliation: Department of Hematology Oncology: 1600 SW Archer Rd. PO box 100278, Gainesville, FL 32610, USA.
authors.forename: Regina
authors.initials: R
authors.lastname: Martuscello
authors.affiliation: Department of Hematology Oncology: 1600 SW Archer Rd. PO box 100278, Gainesville, FL 32610, USA.
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Hawkins
authors.affiliation: Department of Biostatistics: 2004 Mowry Road, PO box 117450, Gainesville, FL 32611, USA.
authors.forename: Myron
authors.initials: M
authors.lastname: Chang
authors.affiliation: Department of Pharmacotherapy and Translational Research: 1225 Center Drive, PO box 100486, Gainesville, FL 32610 USA.
authors.forename: Jatinder K
authors.initials: JK
authors.lastname: Lamba
authors.affiliation: Cellworks Group, Inc., 2033 Gateway Place, Suite 500, San Jose, CA, 95110, USA.
authors.forename: Shireen
authors.initials: S
authors.lastname: Vali
authors.affiliation: Cellworks Group, Inc., 2033 Gateway Place, Suite 500, San Jose, CA, 95110, USA.
authors.forename: Ansu
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Cellworks Group, Inc., 2033 Gateway Place, Suite 500, San Jose, CA, 95110, USA.
authors.forename: Neeraj Kumar
authors.initials: NK
authors.lastname: Singh
authors.affiliation: Cellworks Group, Inc., 2033 Gateway Place, Suite 500, San Jose, CA, 95110, USA.
authors.forename: Taher
authors.initials: T
authors.lastname: Abbasi
authors.affiliation: Leukemia Program, Cleveland Clinic, Cleveland: 9500 Euclid Ave, Mail Code R35, Cleveland, OH 44195 USA.
authors.forename: Mikkael A
authors.initials: MA
authors.lastname: Sekeres
authors.affiliation: MDS Research Group, Institut de Recerca Contra la Leucemia Josep Carreras, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Barcelona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Mallo
authors.affiliation: MDS Research Group, Institut de Recerca Contra la Leucemia Josep Carreras, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Sole
authors.affiliation: Division of Hematology and Oncology, UC San Diego Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, CA 92093 USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Bejar
authors.affiliation: Department of Hematology Oncology: 1600 SW Archer Rd. PO box 100278, Gainesville, FL 32610, USA. Electronic address: christopher.cogle@medicine.ufl.edu.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Cogle
mesh_terms: D002869:Chromosome Aberrations; D015331:Cohort Studies; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation / Q000592:standards; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000077269:Lenalidomide; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics*; D060066:Protein Interaction Maps / Q000235:genetics; D012189:Retrospective Studies; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D013792:Thalidomide; D000077269:Lenalidomide
keywords: Computational biology; Hma; Lenalidomide; Mutanome; Myelodysplastic syndromes; Response prediction