title: Novel therapy for therapy-resistant mantle cell lymphoma: multipronged approach with targeting of hedgehog signaling.
abstract: Mantle cell lymphoma (MCL) is one of the most aggressive B-cell lymphomas with a median patient survival of only 5-7 years. The failure of existing therapies is mainly due to disease relapse when therapy-resistant tumor cells remain after chemotherapy. Therefore, development and testing of novel therapeutic strategies to target these therapy-resistant MCL are needed. Here, we developed an in vivo model of therapy-resistant MCL by transplanting a patient-derived MCL cell line (Granta 519) into NOD/SCID mice followed by treatment with combination chemotherapy. Cytomorphologic, immunophenotypic, in vitro and in vivo growth analyses of these therapy-resistant MCL cells confirm their MCL origin and resistance to chemotherapy. Moreover, quantitative real-time PCR revealed the upregulation of GLI transcription factors, which are mediators of the hedgehog signaling pathway, in these therapy-resistant MCL cells. Therefore, we developed an effective therapeutic strategy for resistant MCL by treating the NOD/SCID mice bearing Granta 519 MCL with CHOP chemotherapy to reduce tumor burden combined with GLI-antisense oligonucleotides or bortezomib, a proteosome inhibitor, to target therapy-resistant MCL cells that remained after chemotherapy. This regimen was followed by treatment with MCL-specific cytotoxic T lymphocytes to eliminate all detectable leftover minimal residual disease. Mice treated with this strategy showed a significantly increased survival and decreased tumor burden compared to the mice in all other groups. Such therapeutic strategies that combine chemotherapy with targeted therapy followed by tumor-specific immunotherapy are effective and have excellent potential for clinical application to provide long-term, disease-free survival in MCL patients.
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198-6395, USA.
authors.forename: Ganapati V
authors.initials: GV
authors.lastname: Hegde
authors.forename: Tara M
authors.initials: TM
authors.lastname: Nordgren
authors.forename: Corey M
authors.initials: CM
authors.lastname: Munger
authors.forename: Amit K
authors.initials: AK
authors.lastname: Mittal
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Bierman
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Weisenburger
authors.forename: Julie M
authors.initials: JM
authors.lastname: Vose
authors.forename: J Graham
authors.initials: JG
authors.lastname: Sharp
authors.forename: Shantaram S
authors.initials: SS
authors.lastname: Joshi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D053823:Hedgehog Proteins