Farnesyltransferase Inhibitor Tipifarnib (Zarnestra) in Refractory Mantle Cell Lymphoma (MCL): A Therapeutic Target Only for Specific Patients Categorized by the 2-Gene Classifier for Predictive Response to Tipifarnib.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1561-1561
Author(s):  
Delphine Rolland ◽  
Vincent Ribrag ◽  
Corinne Haioun ◽  
Herve Ghesquieres ◽  
Fabrice Jardin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Therapeutic Strategies ◽  
Prediction Of Response ◽  
Expression Ratio ◽  
Tumor Biopsy ◽  
Gene Expression Ratio ◽  
Mantle Cell ◽  
Initial Tumor

Abstract Background. Mantle cell lymphoma is one of the most refractory B-cell lymphomas. Despite the recent improvement of novel therapeutic strategies including high dose therapy and the introduction of immunotherapy, MCL patients are not cured by conventional therapeutic strategies. The increasing understanding of the MCL cell biology leads to the development of new drugs targeting to molecular mechanisms of the disease. Among the specific genes found to be overexpressed in MCL by gene expression profiling analysis, farnesyltransferase (FTase) encodes for an enzyme essential in the post- translational modifications of proteins that require prenylation for conversion to mature forms, allowing their participation in various signaling pathways regulating growth and survival. We recently demonstrated that inhibition of FTase by tipifarnib (Zarnestra) is associated in vitro with growth inhibition and apoptosis of MCL cell lines and in vivo with tumor xenograft stability. To determine the efficacy, the safety profile and the toxicity of tipifarnib in MCL, we conducted a phase II trial in patients with refractory MCL, and we evaluated the response considering published molecular predictors. Methods. Primary endpoint was the efficacy measured by the evaluation of the overall response rate (ORR) at 4 cycles, and, in case of response, at 6 cycles. Planned sample size of the study was 27 evaluable patients enrolled for an analysis based on an optimal two-stage design comprising 11 patients for the first stage and 16 for the second stage, under the hypothesis of an ORR of 35% to conclude for an effective drug and an ORR of 10% to conclude for an ineffective drug. Tipifarnib was administered at 300 mg orally twice daily for the first 21 days of each 28-days cycle for 4 to 6 cycles. Prediction of response was retrospectively evaluated in the initial tumor biopsy by the analysis of the 2-gene classifier, the RASGRP1/APTX gene expression ratio, and the AKAP13 expression level. Results. Eleven patients with refractory MCL were included in the analysis. Median number of lines of therapy before tipifarnib was 2.5 (range 1–7). Median age was 71 (range 66–79). All patients presented with stage IV disease and with good performance status. At 4 cycles of tipifarnib, 1 patient presented a complete response and 10 patients were in progressive disease. Two patients progressed during or after the first cycle, three patients after 3 cycles, and five patients after 4 cycles. No grade III-IV hematological toxicities were recorded. One patient presented an unrelated neurological symptom after the first dose administered. Evaluation of the molecular prediction of response to tipifarnib was realized for 3 patients: one responder patient and two non-responder patients. Results showed an increase in the RASGRP1/APTX gene expression ratio and a decrease in AKAP13 expression in the responder patient, and a decrease in the RASGRP1/APTX gene expression ratio and an increase in AKAP13 expression in the non-responder patients. This corresponds to the expected results of the response prediction to tipifarnib. Conclusion. Tipifarnib in refractory MCL was beneficial for only one patient. Response could be exactly predicted by specific molecular predictors of response evaluated in the initial tumor biopsy. These results demonstrate the necessity of categorizing molecularly the patients when targeted therapies are proposed to select those patients that might respond to.

CD10-positive mantle cell lymphoma: biologically distinct entity or an aberrant immunophenotype? Insight, through gene expression profile in a unique case series

2015 ◽  
Vol 68 (10) ◽  
pp. 844-848 ◽  
Author(s):  
Ariz Akhter ◽  
Etienne Mahe ◽  
Lesley Street ◽  
Payam Pournazari ◽  
Marco Perizzolo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mantle Cell Lymphoma ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
Case Series ◽  
Convincing Evidence ◽  
Minimal Impact ◽  
Mantle Cell

BackgroundMantle cell lymphoma (MCL) is an aggressive disease with genetic heterogeneity and discrete clinical subtypes. MCL is rarely CD10 positive. These cases raise the question whether a subset of MCL may be germinal centre (GC) derived, and have distinct clinicopathological characteristics.Aims and methodsA series of nine CD10-positive MCL cases is described herein. The clinicopathological and immunophenotypic features, immunoglobulin somatic hypermutation (SHM) status and gene expression profile (GEP) data are detailed. These features were compared with two independent sets (n=20, each) of CD10-negative MCL cases (controls), which were randomly selected from our institutional registry.ResultsGEP showed distinct expression of a GC signature in CD10-positive MCL cases with minimal impact on downstream signalling pathways. There were no significant differences in the clinicopathological features or clinical outcome between our CD10-positive and CD10-negative MCL cases. The frequency of SHM was comparable with established data.ConclusionsThis study provides convincing evidence that CD10 expression is related to a distinct GC signature in MCL cases, but without clinical or biological implications.

Biology and Treatment of Mantle Cell Lymphoma in the Genomic Era.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-28-SCI-28
Author(s):  
Adrian Wiestner
Keyword(s):  
Gene Expression ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
Genetic Alterations ◽  
Diagnostic Methods ◽  
Genetic Changes ◽  
Mantle Cell

Abstract Abstract SCI-28 The t11;14 translocation, the genetic hallmark of MCL, drives cyclin D1 expression in the tumor cells and historically facilitated the separation of MCL into a distinct entity. FISH cytogenetics are part of the workup and can be particularly helpful to separate leukemic MCL from CLL. Morphology and clinical course of MCL are heterogeneous and might have suggested the presence of different entities. Gene expression profiling answered this concern and provided several important insights: 1. despite the clinical heterogeneity, MCL has a characteristic gene expression profile supporting the accuracy of current diagnostic methods; 2. cyclin D1 negative MCL has the same diagnostic pathologic and gene expression features as cyclin D1 positive MCL, and 3. a gene expression based measure of tumor proliferation is a potent predictor of outcome and identifies patients with survival probabilities ranging from less than 1 year (highly proliferative tumors) to more than 6 years (low proliferation).1 Biologically, the gene expression based proliferation score integrates several acquired genetic changes in the tumor that include deletions of the INK4a/ARF locus encoding the tumor suppressors p14 and p16, amplification of BMI1, and secondary changes in the cyclin D1 locus. Mutations and deletions that alter the structure of the 3'UTR can enhance cyclin D1 mRNA stability,2 and the loss of miR binding sites in this region can enhance protein translation.3 These changes increase cyclin D1 protein resulting in increased proliferation. Additional genetic lesions such as deletions of ATM and p53 affect DNA damage responses pathways. The high frequency of secondary genetic changes in MCL cells may indicate genomic instability and the presence of additional chromosomal aberrations and certain genetic alterations hold prognostic information.4 With the continued refinement of whole genome genetic approaches the goal of identifying crucial pathways and possible driver genes in the pathogenesis of MCL may be within reach. MCL characterized by an antiapoptotic phenotype combined with features of aggressive lymphomas remains an incurable disease and having the worst outcome among all B-cell lymphomas. Biologic markers that predict treatment response and that could give way to targeted therapy have remained elusive. Several new drugs could help overcome treatment resistance and new analytic tools when incorporated into clinical trials may help dissect mechanisms of drug action and resistance. Our approach has been to incorporate gene expression profiling into a clinical trial of bortezomib to directly monitor the effects of the treatment on tumor biology in vivo. We identified an integrated stress response to bortezomib in sensitive tumors that may yield clinically usefully predictors of sensitivity and that could guide the development of improved therapies. 1. Rosenwald A, Wright G, Wiestner A, et al. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell. 2003;3:185-197. 2. Wiestner A, Tehrani M, Chiorazzi M, et al. Point mutations and genomic deletions in Cyclin D1 create stable truncated mRNAs that are associated with increased proliferation rate and shorter survival in mantle cell lymphoma. Blood. 2007. 3. Chen RW, Bemis LT, Amato CM, et al. Truncation in CCND1 mRNA alters miR-16-1 regulation in mantle cell lymphoma. Blood. 2008;112:822-829. 4. Salaverria I, Espinet B, Carrio A, et al. Multiple recurrent chromosomal breakpoints in mantle cell lymphoma revealed by a combination of molecular cytogenetic techniques. Genes Chromosomes Cancer. 2008;47:1086-1097. Disclosures Off Label Use: Bortezomib in previously untreated patients with MCL.

Bortezomib Induces an Antioxidant and ER-Stress Response Gene Expression Signature in Mantle Cell Lymphoma: Implications for Response Prediction and Optimized Chemotherapy Regimens.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 830-830
Author(s):  
Edgar G. Rizzatti ◽  
Helena Mora-Jensen ◽  
Raymond Lai ◽  
Masanori Daibata ◽  
Therese White ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stress Response ◽  
Er Stress ◽  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Er Stress Response ◽  
Mantle Cell ◽  
Sensitive Group ◽  
Resistant Cells

Abstract Mantle cell lymphoma (MCL) is an aggressive and incurable B-cell lymphoma for which new treatment options are needed. Recent phase II clinical trials reported response to the proteasome inhibitor bortezomib (BZM) in up to 50% of pre-treated patients. Despite the successful use of BZM in the clinic, the precise molecular mechanisms underlying sensitivity or resistance to BZM in MCL remain largely unknown. To address this issue, we used U133A 2.0 microarrays to analyze gene expression in MCL cells from peripheral blood of 5 patients with previously untreated leukemic MCL. Samples were collected immediately before (0h) and at 3, 6, 24, and 72 hours after administration of BZM (1.5 mg/m2). After the blood collection at 72 hours, a second dose of BZM was given, and cells were collected 24 hours later. Two patients had major reductions in peripheral ALC already at 24h from dose 2 and normalized their blood counts by day 21 (sensitive), 1 patient had no change over a full course of 4 injections (resistant), and 2 patients had some decrease in ALC (intermediate). Genes differentially expressed with treatment were ranked according to the degree of correlation with time (Pearson). We used gene set enrichment analysis (GSEA) to detect distinct functional gene expression signatures; the most consistently up-regulated of which was a signature composed by proteasome and chaperone genes. To confirm and expand these findings, we exposed 10 MCL cell lines (7 sensitive, IC50<10nM; 3 resistant IC50>10nM) to 10nM of BZM and analyzed gene expression at 1, 3, 6 and 24 hours. The proteasome signature was again dominant, and the majority of the up-regulated genes in both clinical and cell line samples shared binding motifs for the NRF, MAF, ATF and HSF families of transcription factors (TF). Thus genes up-regulated by BZM in vivo and in cell lines predominantly belonged to a functional response to oxidative and/or endoplasmic reticulum (ER) stress. Under physiologic conditions, this is thought to help restore homeostasis and protect from apoptosis. This response could therefore contribute to drug resistance or be a marker of an overwhelming insult before the cells undergo apoptosis. To address this issue, we investigated differences in response to BZM between sensitive and resistant cell lines. The proteasome signature was more strongly up-regulated in sensitive cells than in resistant cells, and the ER-stress response as measured by genes controlled by the NRF and MAF family of TFs was also more highly expressed in the sensitive group. Consistently, expression of HMOX1, which encodes a key enzyme in the antioxidant response, was increased by 32× at 24h in the sensitive group, but only by 4× in the resistant group; the expression of DDIT3, a transcription factor implicated in a pro-apoptotic response to ER-stress was 5.5-fold up-regulated in the sensitive cells but only 1.4-fold in the resistant cells. We conclude that in sensitive cells BZM induces an overwhelming ER-stress response with high expression of proteasome components and chaperone proteins that could serve as a predictor of response to BZM.

Clinical-Biological Characterization of Variant B Chronic Lymphocytic Leukemia, Characterized by a Mantle Cell Lymphoma-Like Immunophenotype, t(11;14)(q13;q32) Negative.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1259-1259
Author(s):  
Andrea Ferrario ◽  
Lilla Cro ◽  
Nadia Zucal ◽  
Marta Lionetti ◽  
Francesco Bertoni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
Mantle Cell Lymphoma ◽  
Statistical Difference ◽  
Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Fish Analysis ◽  
Mutational Status ◽  
Mantle Cell ◽  
Igvh Mutational Status

Abstract Abstract 1259 Poster Board I-282 We describe the clinical-biological features of 63 cases of variant B chronic lymphocytic leukemia (v-B-CLL), characterized by a mantle cell lymphoma-like immunophenotype, atypical cytomorphology in absence of t(11;14)(q13;q32) in FISH analysis. A historical series of 130 B-CLL was used as comparison. The v-B-CLL were significantly different from the B-CLL in terms of the following clinico-hematological variables: age <70 yrs (p <.001), lymphocytosis <20 × 109/ (p <.001), lymphocyte doubling time < 12 months (p = .02), high serum β2-microglobulin levels (p <.001), and splenomegaly (p = .002). Considering immunophenotipic features, CD38 and CD49d expression were significantly more expressed in v-B-CLL than B-CLL (p <.001); whereas, no statistical difference was observed for ZAP-70 reactivity. Considering the IgVH mutation status, there were more patients mutated in the v-B-CLL group than in the B-CLL group (p = .001). Other significant differences were found about the frequency of the recurrent chromosome alterations, evaluated by means of FISH analysis: trisomy 12 was more frequent in v-B-CLL ( p<.001), while del13q14, considered as a single alteration, was more frequent in B-CLL (p=.008). Gene expression profiling of a panel of 9 v-B-CLL compared with 60 B-CLL samples indicated that the variant group is characterized by a specific molecular pattern of gene expression. In particular we observed the upregulation of tumor protein D52 (TPD52), and that of 6 genes (AFF1, GMPS, PICALM, JUN, REL, RAC2) known to be protooncogenes. Furthermore, we found that upregulated genes with apoptosis related functions (IL-7, HSP90B1, NOTCH2, BECN1, ANXA4, MCL1) are all negative regulators of apoptosis. Microarray analysis revealed that various genes (TRIM38, EEF1D, CASP1, MALT1, RHOH0) involved in the I-kB kinase/NF-kB cascade of the canonical NF-kB signaling pathway, are furtherly upregulated in v-B-CLL. Furthermore, among the genes found differentially expressed in SAM analysis, we observed also the upregulation of CD1c (according to the surface expression of this antigen), OSBPL3 and ITGA4. After a median follow-up of 55 months (range 4-196) and 60 months (range 6-180), 25/42 (59%) v-CLL and 55/93 (59 %) CLL pts were treated. TTT was significant different between 2 groups when the IgVH mutational status was considered (p= .006). Median OS of v-CLL subset was 112 months vs 171 months of CLL subset. When the IgVH mutational status was considered, mutated cases showed a worse OS even if a statistical difference was not observed (p= 0.062). In conclusion, our study identifies, on the basis of a defined CFM-FISH diagnostic approach, a variant form of B-CLL that shows peculiar biological and clinical features that should be considered in the future clinical and prognostic studies. The inclusion of this form in B-CLL study could alter the interpretation of results, especially related to biological markers. Disclosures No relevant conflicts of interest to declare.

Combined Targeting of Chromatin Modifying Enzymes LSD1, EZH2 and Histone Deacetylases (HDACs) Has Superior Efficacy Against Human Mantle Cell Lymphoma Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2429-2429
Author(s):  
Warren Fiskus ◽  
Sunil Sharma ◽  
Rekha Rao ◽  
Ramesh Balusu ◽  
Sreedhar Venkannagari ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Core Protein ◽  
Cell Lymphoma ◽  
Amine Oxidase ◽  
Combined Treatment ◽  
Reversible Inhibitor ◽  
Mantle Cell

Abstract Abstract 2429 PRC (polycomb repressive complex) 2 contains three core protein components, i.e., EZH2, SUZ12 and EED, of which EZH2 has the SET domain with its intrinsic histone methyltransferase activity that mediates the trimethylation (Me3) of lysine (K) 27 on histone (H) 3-a repressive chromatin mark for gene expression. We have previously reported that treatment with the S-adenosylhomocysteine hydrolase and EZH2 inhibitor, DZNep as well as treatment with the pan-histone deacetylase inhibitor panobinostat (PS, Novartis Pharma) deplete PRC2 complex proteins. LSD1 (KDM1A) is a demethylase of H3K4Me2, and inhibiton of LSD1 leads to increase in H3K4Me3-a permissive mark for gene expression. In the present studies, we determined the chromatin-modifying and cytotoxic effects of LSD1 inhibition alone and in combination with PS or DZNep in cultured (JeKo-1 and Z138C) and primary human Mantle Cell Lymphoma (MCL) cells. Treatment with the non-amine oxidase reversible inhibitor of LSD1 CIT0665 (250 to 1000 nM), or the more potent analogue HCI2509 (20 to 250 nM), dose-dependently increased the levels of H3K4Me2 & Me3, p21 and p27, while decreasing the levels of cyclin D1, which was associated with inhibition of cell proliferation and accumulation of the MCL cells in the G1 phase of the cell cycle. Abrogation of LSD1 by a specific shRNA treatment also induced similar chromatin, cell cycle and growth inhibitory effects. Exposure to CIT0665 or HCI2509 disrupted the binding of LSD1 with the co-repressor CoREST and HDAC1, without affecting the levels of these proteins. As noted above, treatment with PS (10 to 50 nM) dose-dependently depleted the levels of not only EZH2, SUZ12 and the PRC1 complex protein BMI1, but also of LSD1 in MCL cells. PS treatment alone also depleted the levels of AKT, cRAF, CDK4 and cyclin D1, as well as induced cell cycle growth inhibition and apoptosis of MCL cells. Co-treatment with PS enhanced the chromatin modifying effects of CIT0665 or HCI2509. The combination synergistically induced apoptosis of the cultured MCL cells (combination indices, CI <1.0). This was associated with greater induction of p27 and depletion of cyclin D1. Treatment with PS and HCI2509 also synergistically induced loss of viability of primary MCL cells (CI <1.0). We have previously reported that DZNep dose-dependently depleted EZH2, SUZ12 and BMI1 expression, inhibited H3K27Me3 levels, induced p21, p27 and FBXO32 (muscle atrophy F-box protein, also called atrogin-1) levels in cultured and primary MCL cells. Here, we determined the effects of co-treatment with HCI2509 and DZNep in MCL cells. Combined treatment with HCI2509, although not synergistic, enhanced the apoptosis of MCL cells induced by DZNep. Taken together these findings indicate that combined targeted depletion of the level and activity of LSD1 by PS and CIT0665 or HCI2509 along with PS-mediated depletion of PRC2 proteins, BMI and HDACs exerts superior activity against MCL cells. These studies also support the in vivo testing of combined epigenetic therapies in the treatment of MCL. Disclosures: Sharma: Novartis: Research Funding.

scholarly journals Pathway discovery in mantle cell lymphoma by integrated analysis of high-resolution gene expression and copy number profiling

Blood ◽  
2010 ◽  
Vol 116 (6) ◽  
pp. 953-961 ◽  
Author(s):  
Elena M. Hartmann ◽  
Elias Campo ◽  
George Wright ◽  
Georg Lenz ◽  
Itziar Salaverria ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Resolution ◽  
Mantle Cell Lymphoma ◽  
Copy Number ◽  
Cell Lymphoma ◽  
Neutral Loss ◽  
Integrated Analysis ◽  
Survival Times ◽  
Novel Genes ◽  
Mantle Cell

Abstract The genome of mantle cell lymphoma (MCL) is, in addition to the translocation t(11;14), characterized by a high number of secondary chromosomal gains and losses that probably account for the various survival times of MCL patients. We investigated 77 primary MCL tumors with available clinical information using high-resolution RNA expression and genomic profiling and applied our recently developed gene expression and dosage integrator algorithm to identify novel genes and pathways that may be of relevance for the pathobiology of MCL. We show that copy number neutral loss of heterozygosity is common in MCL and targets regions that are frequently affected by deletions. The molecular consequences of genomic copy number changes appear complex, even in genomic loci with identified tumor suppressors, such as the region 9p21 containing the CDKN2A locus. Moreover, the deregulation of novel genes, such as CUL4A, ING1, and MCPH1, may affect the 2 crucial pathogenetic mechanisms in MCL, the disturbance of the proliferation, and DNA damage response pathways. Deregulation of the Hippo pathway may have a pathogenetic role in MCL because decreased expression of its members MOBKL2A, MOBKL2B, and LATS2 was associated with inferior outcome, including an independent validation series of 32 MCLs.

Pathogenesis of Mantle-Cell Lymphoma: All Oncogenic Roads Lead to Dysregulation of Cell Cycle and DNA Damage Response Pathways

2005 ◽  
Vol 23 (26) ◽  
pp. 6364-6369 ◽  
Author(s):  
Veronica Fernàndez ◽  
Elena Hartmann ◽  
German Ott ◽  
Elias Campo ◽  
Andreas Rosenwald
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Dna Damage ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Dna Damage Response ◽  
Cell Lymphoma ◽  
Mantle Cell ◽  
Damage Response ◽  
Cell Cycle Machinery

Mantle-cell lymphoma (MCL) is a well-defined subtype of B-cell non-Hodgkin's lymphomas (B-NHL), accounts for approximately 6% of all lymphoid neoplasms, and has a median survival of 3 to 4 years. The genetic hallmark of MCL is the chromosomal translocation t(11;14)(q13;q32) that leads to deregulation and upregulation of Cyclin D1, an important regulator of the G1 phase of the cell cycle. This genetic event is present in virtually all cases of MCL, whereas additional genetic alterations that occur in subsets of MCL have been described. Most of these alterations appear to disturb the cell cycle machinery/interfere with the cellular response to DNA damage, thus making MCL a paradigm for cell cycle and DNA damage response dysregulation in cancer in general. In particular, Cyclin D1 upregulation, genomic amplification of the cyclin-dependent kinase (CDK) -4, deletions of the CDK inhibitor p16INK4a and overexpression of BMI-1, a transcriptional repressor of the p16INK4a locus, are associated with dysregulation of the cell cycle machinery in MCL. The DNA damage response pathway is affected by frequent alterations of the ataxia-telangiectasia mutated (ATM) kinase as well as occasional inactivation of checkpoint kinase (CHK)-1 and CHK2 that are kinases that act downstream of ATM in response to detection of DNA damage. Moreover, p53 is frequently targeted by alterations in MCL. A recent gene expression profiling study defined the proliferation signature, a quantitative measure of gene expression of proliferation-associated genes as the strongest survival predictor available to date allowing the definition of prognostic MCL subgroups that differ in median survival by more than 5 years.

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