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 therapyresistant 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.Mantle cell lymphoma (MCL) is one of the most aggressive lymphomas among the B-cell malignancies, with a median survival of only 5-7 years.1 MCL is characterized genetically by the t(11;14)(q13;q32) translocation, which leads to overex pression of cyclin D1.2 Although existing therapies using different combinations of chemotherapeutic agents such as cyclo phosphamide, vincristine, doxorubicin, prednisone (CHOP), cyclophosphamide, vincristine, doxorubicin, dexamethasone (hyper-CVAD), Rituximab and Bortezomib (BTZ) increase disease-free survival, relapse due to residual therapy-resistant MCL is the main roadblock to cure of this disease.3,4 Therefore, an effective treatment strategy is needed to target the biological basis of therapy resistance. Current evidence suggests that single or multiple agents are often inadequate for the treatment of aggressive lymphomas like MCL.3-7 Therefore, effort should be put into developing new approaches such as strategies that sequentially administer targeted agents. 5,8 We have developed an innovative therapeutic strategy that combines CHOP chemotherapy (to reduce the tumor burden) and inhibition of hedgehog signaling or tumor microenvironment (to target therapy-resistant MCL) followed by treatment using transplantation of MCL-specifi...

Novel Treatment for Mantle Cell Lymphoma Including Therapy-Resistant Tumor by NF-κB and mTOR Dual-Targeting Approach

“…We selected GRL for this study because in a previous study, we showed that among the stable therapy-resistant MCL cell lines we developed, GRL is the most aggressive cell line (16, 38). Seven days following tumor transplantation, the mice were randomized and divided into two groups.…”

“…The therapy-resistant MCL cell lines were characterized and established after transplanting the Granta 519 into the NOD-SCID mice following treatment with CHOP chemotherapy and bortezomib as described previously (16, 38). These therapy-resistant tumor cells derived from liver, kidney and lungs were described as Granta 519 resistant from liver (GRL), Granta 519 resistant from kidney (GRK), and Granta 519 resistant from lungs (GRR), respectively, and compared to parental Granta 519 cells (GP).…”

“…These cells have been shown to be resistant to chemotherapy as confirmed both in vitro and in vivo studies. The additional properties of these therapy-resistant cell lines have been recently published (16, 38). …”

Polo-Like Kinase 1: A Novel Target for the Treatment of Therapy-Resistant Mantle Cell Lymphoma

“…The therapy-resistant MCL cell lines were established from the relapsed lymphoma cells from liver, kidney, and lungs from Granta 519 bearing NOD-SCID mice following treatment with CHOP chemotherapy and bortezomib as described previously [11,12]. These therapy-resistant tumor cells derived from liver, kidney, and lungs were described as GRL isolated from liver, GRK isolated from kidney, and GRR isolated from lungs, respectively, and compared to parental Granta 519 cells (GP).…”

“…As previously described, our lab has generated therapyresistant MCL cell lines from the relapsed lymphoma from liver (GRL), kidney (GRK), and lungs (GRR) of CHOP and bortezomib-treated NOD-SCID mice bearing Granta 519 human MCL [11,12]. During the characterization of these therapy-resistant MCL cell lines, gene expression profiling was done in comparison to parental Granta 519 (GP).…”