Mantle cell lymphoma: Therapeutic strategies are different from CLL

Hiddemann, Wolfgang; Dreyling, Martin

doi:10.1007/s11864-003-0023-x

Cited by 13 publications

(11 citation statements)

References 41 publications

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“…MCL counts for about 5% of all cases NHL in the US and Europe with a median survival of 3-4 years and is generally considered incurable. With the fi rst-line chemotherapeutic regimens including cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate, 30-95% of initial overall response rate can be achieved; however, remission durations are short and overall survival remains limited (Hiddemann and Dreyling, 2003;Lenz et al, 2004;Lenz et al, 2005).…”

Section: Bortezomib (Ps-341; Velcadementioning

confidence: 99%

Future Cancer Therapy with Molecularly Targeted Therapeutics: Challenges and Strategies

Kim¹

2011

Biomolecules and Therapeutics

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In a pharmaceutical industry in which nine out of ten attempts to bring a product to market fail, oncology is among the most challenging therapeutic area (Kola and Landis, 2004;Kamb et al., 2007). In the recent article published in the Nature Rev. Drug Discov. (Arrowsmith, 2011), 83 Phase III and submission failures during 2007 to 2010 were divided according to therapeutic area and reason for failure. Largest numbers of failures was in the area of cancer (28%) followed by neurodegeneration (18%). The 66% of the failures across all therapeutic areas were attributed to lack of effi cacy and 21% of the failures were due to safety issues. Therefore, there is a desperate need for new drugs, especially in the cancer treatment.As a rational approach to cancer therapy in the middle of the last century, a new class of drug discoveries emerged to exploit the differential dependence of proliferating cancer cells on vital functions such as DNA metabolism, replication, chromosome segregation and cytokinesis. These efforts ultimately produced range of nucleoside analogues, DNA-modifying chemicals and natural products -the traditional chemotherapeutic (cytotoxic) agents. The mechanism of action of these Invited ReviewBiomol Ther 19(4), 371-389 (2011) www.biomolther.org drugs-inhibition of essential cellular functions-dictates a narrow therapeutic window (Kamb et al., 2007). A new strategy for cancer therapy has emerged during the past decade based on molecular targets that are less likely to be essential in all cells in the body, therefore more apt to confer a wider therapeutic window than traditional cytotoxic drugs (Kamb et al., 2007;Reichert and Wenger, 2008).In this review, some of the strategies and the opportunities in the molecular targeted oncology drug discovery are discussed. EXCEPTIONAL HETEROGENEITY AND ADAPTABIL-ITY OF CANCER: MAJOR CHALLENGES IN ONCOL-OGY DRUG DISCOVERYCancer is an extraordinarily heterogeneous disease with somatic alterations arise as individual cancer develops (Greenman et al., 2007;Kamb et al., 2007;Harris and McCormick, 2010). This exceptional heterogeneity of cancer is refl ected in observed differences in drug responses, and is the probable cause of acquired resistance. It is also presumably related to drug sensitivity and tumor aggressiveness which display a wide range of variation among malignancies.Due to the heterogeneity both among the cells of an individual tumor and among different cancers, the effi cacy predictions made from xenograft animal models often fail (Kamb, 2005), which presents signifi cant challenges in the oncology drug discovery where advancement of compounds largely based on a pharmacological effect in the xenograft models. Even though xenograft represents signifi cant aspects of the tumor from which it was derived, it probably captures only a fraction of the total genetic and epigenetic heterogeneity of a given tumor subtype. Low response rate in phase I oncology trials is refl ective of poor predictability of clinical effi cacy based on these xenograft mo...

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Section: Bortezomib (Ps-341; Velcadementioning

confidence: 99%

Future Cancer Therapy with Molecularly Targeted Therapeutics: Challenges and Strategies

Kim¹

2011

Biomolecules and Therapeutics

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“…There is no defined standard treatment for MCL. The most commonly used regimen is CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), usually in combination with immunotherapy, such as rituximab [32][33][34]. Recent results show increased response to this combined therapy, but it does not improve the long-term outcome of MCL patients [35].…”

Section: Mantle Cell Lymphoma -Historical Per-spectivesmentioning

confidence: 99%

“…However, in 10 15% of MCL patients, limited stage (I/II) disease is diagnosed. Since these patients only have a few localized tumors, regional radiation therapy has been shown to be a potentially curative treatment [34].Thus, MCL is far from a homologous entity and even though the tumors share many characteristics, they can potentially be divided into sub-groups. Novel technologies, including various microarrays, can be used to identify the molecular differences involved in morphological heterogeneity, clinical behavior and mutational status.…”

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confidence: 99%

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Parallel Gene Expression Profiling of Mantle Cell Lymphoma – How Do We Transform ´Omics Data into Clinical Practice

Ek¹,

Borrebaeck

2007

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DNA microarray technology has been a valuable tool to provide a global view of the changes in gene expression that characterize different types of B cell lymphomas, both in relation to clinical parameters but also in comparison with the non-malignant counterparts. The number of transcripts that can be analyzed on an array has dramatically increased, and now most commercially available arrays cover the whole genome, enabling overall analysis of the transcriptome. The backside of collecting this massive amount of information is that even after strict data filtering, it is impossible to do follow-up studies on all findings. Down-stream analysis is time-consuming and when performing confirmatory experiments on the protein level, the experiments are in most cases restricted to proteins recognized by commercially available reagents. Furthermore, since gene expression data is a comparative method not only are the experimental set-up but also the characteristics of both the sample and reference crucial for our ability to answer the questions posed. Thus, initial care must be taken in the design of the experiment and the preparation of the samples.The aim of this review is to discuss the progress in mantle cell lymphoma research enabled by gene expression analysis and to pinpoint the difficulties in making efficient use of the generated data to provide a fast and accurate clinical diagnosis, efficient stratification of patients into disease sub-groups and improved therapy. MANTLE CELL LYMPHOMA -HISTORICAL PER-SPECTIVESB cell lymphomas are the malignant counterparts of different developmental stages of normal B lymphocytes and are divided into precursor B cell neoplasms and mature/ peripheral B cell neoplasms, according to the WHO classification [1]. B cell differentiation is strictly regulated by homeostatic controls but even so, malignant transformation occasionally proceeds unimpeded [2]. The main groups of B cell neoplasms are precursor B-lymphoblastic leukaemia/lymphoma, Chronic lymphocytic leukaemia/lymphoma (CLL), plasma cell myeloma, extranodal marginal zone (MZ) B cell lymphoma of mucosa-associated lymphoid tissue (MALT) type, follicular lymphoma (FL), mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma [1].MCL was originally considered to be derived from naïve B cells and most tumors show unmutated variable heavy chain (V H) genes. However, several studies have shown that 10 20% of MCLs have somatically mutated immunoglobulin (Ig) genes, indicating that a sub-group has passed through a differentiation stage involving somatic hypermutation of V H genes [3][4][5][6][7][8]. Recently, it has been shown that using an alternative method up to 60% of the MCL were shown to have <98% homology with the germline sequence and were thus considered to carry somatically mutated Ig genes [9]. In the same study it was further shown that patients with somatically hypermutated V H genes had a better survival *Address correspondence to this author at the Department of Immunotechnology, ...

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“…5 Consequently, treatment should be administered immediately after diagnosis, although conventional chemotherapy is not curative. 6 Recently, the progression-free survival (PFS) of patients with MCL was found to be significantly improved by high-dose therapy followed by autologous stem cell transplantation. 7 Similarly, very encouraging results have been obtained using aggressive regimens (e.g., hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) as induction chemotherapy or for patients for whom autologous stem cell transplantation is not possible.…”

Section: Introductionmentioning

confidence: 99%