title: Preclinical pharmacologic evaluation of pralatrexate and romidepsin confirms potent synergy of the combination in a murine model of human T-cell lymphoma.
abstract: OBJECTIVE
  T-cell lymphomas (TCL) are aggressive diseases, which carry a poor prognosis. The emergence of new drugs for TCL has created a need to survey these agents in a rapid and reproducible fashion, to prioritize combinations which should be prioritized for clinical study. Mouse models of TCL that can be used for screening novel agents and their combinations are lacking. Developments in noninvasive imaging modalities, such as surface bioluminescence (SBL) and three-dimensional ultrasound (3D-US), are challenging conventional approaches in xenograft modeling relying on caliper measurements. The recent approval of pralatrexate and romidepsin creates an obvious combination that could produce meaningful activity in TCL, which is yet to be studied in combination.
  
  
  METHODS
  High-throughput screening and multimodality imaging approach of SBL and 3D-US in a xenograft NOG mouse model of TCL were used to explore the in vitro and in vivo activity of pralatrexate and romidepsin in combination. Corresponding mass spectrometry-based pharmacokinetic and immunohistochemistry-based pharmacodynamic analyses of xenograft tumors were performed to better understand a mechanistic basis for the drug:drug interaction.
  
  
  RESULTS
  In vitro, pralatrexate and romidepsin exhibited concentration-dependent synergism in combination against a panel of TCL cell lines. In a NOG murine model of TCL, the combination of pralatrexate and romidepsin exhibited enhanced efficacy compared with either drug alone across a spectrum of tumors using complementary imaging modalities, such as SBL and 3D-US.
  
  
  CONCLUSIONS
  Collectively, these data strongly suggest that the combination of pralatrexate and romidepsin merits clinical study in patients with TCLs.
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors: Salvia
authors: S
authors: Jain
authors: Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York. Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
authors: Xavier
authors: X
authors: Jirau-Serrano
authors: Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York. Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
authors: Kelly M
authors: KM
authors: Zullo
authors: Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York. Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
authors: Luigi
authors: L
authors: Scotto
authors: Department of Pathology and Cell Biology, Columbia University Medical Center, and Irving Institute for Clinical and Translational Research, New York, New York. Department of Medicine, Columbia University Medical Center, New York, New York. Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
authors: Carmine F
authors: CF
authors: Palermo
authors: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. Department of Pathology and Cell Biology, Columbia University Medical Center, and Irving Institute for Clinical and Translational Research, New York, New York. Department of Medicine, Columbia University Medical Center, New York, New York. Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
authors: Stephen A
authors: SA
authors: Sastra
authors: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. Department of Pathology and Cell Biology, Columbia University Medical Center, and Irving Institute for Clinical and Translational Research, New York, New York. Department of Medicine, Columbia University Medical Center, New York, New York. Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
authors: Kenneth P
authors: KP
authors: Olive
authors: Department of Pathology and Cell Biology, Columbia University Medical Center, and Irving Institute for Clinical and Translational Research, New York, New York. Department of Medicine, Columbia University Medical Center, New York, New York. Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
authors: Serge
authors: S
authors: Cremers
authors: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
authors: Tiffany
authors: T
authors: Thomas
authors: Department of Biostatistics, Columbia University Medical Center, New York, New York.
authors: Ying
authors: Y
authors: Wei
authors: Department of Biostatistics, Columbia University Medical Center, New York, New York.
authors: Yuan
authors: Y
authors: Zhang
authors: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
authors: Govind
authors: G
authors: Bhagat
authors: Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York. Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. Department of Medicine, Columbia University Medical Center, New York, New York.
authors: Jennifer E
authors: JE
authors: Amengual
authors: Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York. Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. Department of Medicine, Columbia University Medical Center, New York, New York.
authors: Changchun
authors: C
authors: Deng
authors: Department of Systems Biology High-Throughput Screening Facility, Columbia University Medical Center, New York, New York.
authors: Charles
authors: C
authors: Karan
authors: Department of Systems Biology High-Throughput Screening Facility, Columbia University Medical Center, New York, New York.
authors: Ronald
authors: R
authors: Realubit
authors: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors: Susan E
authors: SE
authors: Bates
authors: Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York. Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. Department of Medicine, Columbia University Medical Center, New York, New York. oo2130@columbia.edu.
authors: Owen A
authors: OA
authors: O'Connor
mesh_terms: D000630:Aminopterin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000008:administration & dosage; D004195:Disease Models, Animal; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D008163:Luminescent Measurements; D016399:Lymphoma, T-Cell / Q000188:drug therapy*; D051379:Mice; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C418863:10-propargyl-10-deazaaminopterin; D047630:Depsipeptides; C087123:romidepsin; D000630:Aminopterin