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Jürgen C Becker

Publications and source records attributed to Jürgen C Becker.

At least 19 recordsLinked to original sources
PubMed2006

Molecularly targeted therapy for melanoma: current reality and future options.

Effective therapy for melanoma remains an unmet goal, with most traditional therapies representing inadequate trade-offs among the several goals of specificity, efficacy, and toxicity. Targeted molecular therapeutics are tailored to genetic abnormalities that are associated with tumor progression. Modulation of aberrant signaling pathways in cancer cells has the potential to provide more effective and potentially nontoxic therapy for a broad range of cancers, including melanoma. Among the possible targets in melanoma are the Ras-MAPK and PI3K/AKT signal transduction pathways, the proteasome, histone deacetylases, methyltransferases, and melanoma-induced angiogenesis.

Angiogenesis Inhibitors↗
PubMed2006

HLA-A24 and survivin: possibilities in therapeutic vaccination against cancer.

Recently, it was described that an HLA-A24 restricted peptide derived from the survivin splice variant survivin-2B can be recognized by CD8+ cytotoxic T-cells. The identification of an HLA-A24 epitope is critical for survivin-based immunotherapy as HLA-24 is the most frequent HLA allele in Asia. Consequently, this survivin-2B epitope is already a target in a clinical study in patients with advanced or recurrent colorectal cancer expressing survivin. However, the splice variant survivin-2B has been described to be pro-apoptotic, and is only expressed at low levels in most malignant tissues. Furthermore, survivin-2B expression are significantly decreased in later tumor stages and inversely correlated with tumor differentiation and invasion. Consequently, survivin is a more general vaccination candidate than the splice variant survivin-2B. Here, we on the basis of spontaneous immune responses in HLA-A24+ cancer patients describes that a HLA-A24-restricted survivin epitopes does indeed exist. Consequently, this epitope is an attractive target for the ongoing survivin-based peptide immunotherapy against cancer.

Editorial↗
PubMed2006

Tumor infiltrating lymphocytes in seminoma lesions comprise clonally expanded cytotoxic T cells.

Seminoma lesions are characterized by a brisk inflammatory infiltrate containing both CD4 and CD8 T cells, which is of prognostic significance. However, whether seminoma cells express the HLA molecules required for classical T-cell recognition remains controversial. In the present study, we conducted a molecular, phenotypical and functional characterization of tumor infiltrating lymphocytes (TILs) from seminoma lesions. T-cell receptor clonotype mapping demonstrated the presence of clonally expanded T cells in the majority of the lesions. The cytotoxic capacity of TILs was indicated by expression of CD107a, which is a recently described surrogate marker for cytolytic activity. Indeed, the frequency of CD107a positive cells was substantially higher in TILs when compared to peripheral blood mononuclear cells. Moreover, fluorescence activated cell sorting of CD107a positive TILs allowed comparison of the clonotypic T-cell receptor fingerprint and demonstrated the ability of expanded clones to express this cytotoxic marker, suggesting cytotoxic activity at the tumor site. The cytotoxicity was confirmed by in situ granzyme B expression. Furthermore, by staining with multimeric HLA-peptide complexes, we could demonstrate the presence of Mage-3 specific T cells among TILs. In summary, specific and functional T-cell responses are operative in seminoma, indicating that the inflammatory infiltrate is indeed involved in the immunological control of the tumor.

Adult↗
PubMed2006

HLA-B8 association with late-stage melanoma--an immunological lesson?

BACKGROUND: Differences in HLA allele frequencies between the diseased and healthy populations may signify efficient immune responses, a notion that has been successfully tested for infectious diseases or for association with genetic elements involved in a distinct type of immunity. This retrospective study is intended to detect differences in MHC class I carrier frequencies of advanced melanoma patients compared to healthy bone marrow donors. METHODS: The HLA-A and -B carrier frequencies of 748 stage IV melanoma patients retrieved from serotyping at 6 different centers in Germany were compared using a chi-square test to 13,386 fully HLA typed bone marrow donors registered in the German national bone marrow donor registry. RESULTS: The comparison of HLA carrier frequencies in advanced cancer patients with healthy bone marrow donors revealed a significant decrease in HLA-B8 carrier frequencies, which was also apparent in patients with advanced disease compared to patients with loco-regional disease. CONCLUSION: The data suggest that protective immune responses restricted to distinct MHC class I molecules may be operational in a subset of melanoma patients, which is the prerequisite for a large scale screen for the corresponding epitopes. Alternatively, the known association of the ancestral haplotype HLA-A1, -B8 and -DR3 with genetic elements such as distinct TNF-alpha alleles might have a protective effect on disease progression. In any case, identification of the cause of protection within this patient subset might lead to a significant improvement in the efficacy of current immunotherapeutic approaches.

Gene Frequency↗
PubMed2006

The carcinogenic potential of tacrolimus ointment beyond immune suppression: a hypothesis creating case report.

BACKGROUND: Since tacrolimus ointment was approved by the U.S. Food and Drug Administration (FDA) as a promising treatment for atopic dermatitis, it has been approved in more than 30 additional countries, including numerous European Union member nations. Moreover, in the current clinical routine the use of this drug is no longer restricted to the approved indication, but has been extended to a wide variety of inflammatory skin diseases including some with the potential of malignant transformation. So far, the side-effects reported from the topical use of tacrolimus have been relatively minor (e.g. burning, pruritus, erythema). Recently, however, the FDA reviewed the safety of topical tacrolimus, which resulted in a warning that the use of calcineurin inhibitors may be associated with an increased risk of cancer. CASE PRESENTATION: Oral lichen planus (OLP) was diagnosed in a 56-year-old women in February 1999. After several ineffective local and systemic therapeutic measures an off-label treatment of this recalcitrant condition using Tacrolimus 0.1% ointment was initiated in May 2002. After a few weeks of treatment most of the lesions ameliorated, with the exception of the plaques on the sides of the tongue. Nevertheless, the patient became free of symptoms which, however, reoccurred once tacrolimus was weaned, as a consequence treatment was maintained. In April 2005, the plaques on the left side of the tongue appeared increasingly compact and a biopsy specimen confirmed the suspected diagnosis of an oral squamous cell carcinoma. CONCLUSION: The suspected causal relationship between topical use of tacrolimus and the development of a squamous cell carcinoma prompted us to test the notion that the carcinogenicity of tacrolimus may go beyond mere immune suppression. To this end, tacrolimus has been shown to have an impact on cancer signalling pathways such as the MAPK and the p53 pathway. In the given case, we were able to demonstrate that these pathways had also been altered subsequent to tacrolimus therapy.

Administration, Topical↗
PubMed2006

Expression of the NKG2D ligand UL16 binding protein-1 (ULBP-1) on dendritic cells.

Innate and adaptive immunity have not evolved separately. In this regard, the NKG2D molecule first identified on NK cells and classified as an activating NK cell receptor is also an important receptor for CD8(+) T cells. Functional analyses of human NKG2D and its ligands, i.e. UL16 binding proteins (ULBP) and MHC class I chain-related (MIC), have so far focused on immune cell-target cell situations because of the expression of NKG2D ligands on infected, stressed or transformed cells. Here, however, we address a possible function of NKG2D/ULBP-1 during the initiation of T cell responses. ULBP-1 can be detected on mature dendritic cells both in situ in the T cell areas of lymph nodes as well as in vitro after artificial maturation. FCM analysis further demonstrated that although NKG2D is expressed to some degree on all analyzed T cell subsets from peripheral blood, in vitro stimulation of T cells results in up-regulation of NKG2D on proliferating T cells. Using the sentinel lymph nodes of primary melanoma as a model for induction of defined T cell responses in vivo, we were able to demonstrate the expression of NKG2D on melanoma-associated antigen-specific T cells. Thus, our results suggest a role for NGK2D-ULBP-1 in the induction or reactivation of T cell responses.

CD8-Positive T-Lymphocytes↗
PubMed2006

Antibody targeted drugs as cancer therapeutics.

Treatment of cancer is a double-edged sword: it should be as aggressive as possible to completely destroy the tumour, but it is precisely this aggressiveness which often causes severe side effects - a reason why some promising therapeutics can not be applied systemically. In addition, therapeutics such as cytokines that physiologically function in a para- or autocrine fashion require a locally enhanced level to exert their effect appropriately. An elegant way to accumulate therapeutic agents at the tumour site is their conjugation/fusion to tumour-specific antibodies. Here, we discuss recent preclinical and clinical data for antibody-drug conjugates and fusion proteins with a special focus on drug components that exert their antitumour effects through normal biological processes.

Animals↗
PubMed2006

Cytotoxic T cells.

The immune system is a complex arrangement of cells and molecules that preserve the integrity of the organism by elimination of all elements judged dangerous. Within the immune system, a humoral and a cellular as well as an innate and an adaptive arm can be differentiated. The key players of adaptive cellular immune responses are T lymphocytes in general and, for the effector function, cytotoxic T lymphocytes (CTLs) in particular. T lymphocytes arise in the bone marrow and migrate to the thymus for maturation. During this process, T cells somatically rearrange gene segments, eventually leading to the expression of a unique antigen-binding molecule, the T-cell receptor (TCR). This receptor allows them to monitor all cells of the body, ready to destroy any cell posing a threat to the organism. Cytotoxicity is exerted directly through the Fas or perforin pathway and/or indirectly by the release of cytokines. Obviously, the activity of such a potent cell is tightly regulated. Indeed, a predominance of stimulatory over inhibitory signals is required for effective immune responses to pathogens, and a predominance of inhibitory over stimulatory signals is required for maintenance of self-tolerance. Still, several situations occur in which an inappropriate CTL response leads to either autoimmune disease or persistence of pathogens.

Autoimmune Diseases↗
PubMed2006

[New therapeutic approaches for solid tumors: histone deacetylase, methyltransferase and proteasome inhibitors].

Recent results from basic and translational research on tumor genesis and progression establish the basis for future therapeutic approaches. Targeted therapeutics are tailored toward the molecular abnormalities that cause tumor progression and could potentially provide an effective, non-toxic therapeutic approach in a broad range of cancers including melanoma. Cancer is as much a (cyto)genetic disease as it is an epigenetic disease. Indeed, the fate of the cell depends on a delicate balance between expression and repression of genes. The notion that drastic changes in DNA methylation and histone modifications are present in a variety of human tumors has prompted the development and characterization of epigenetic drugs. Inhibitors of histone deacetylases and methyltransferases as well as of the proteasome are covered in this review.

Antineoplastic Agents↗
PubMed2006

New insights into the molecular biology and targeted therapy of cutaneous T-cell lymphomas.

Cutaneous T-cell lymphoma is an extra-nodal non-Hodgkin lymphoma of mature T cells. These tumor cells home to and persist in the skin,producing a broad spectrum of clinical entities. Recent results of basic research on tumor biology and tumor immunology as well as molecular genetics of cutaneous T-cell lymphoma have fostered the development of new therapeutic approaches. Several clinical trials testing these targeted therapies have shown encouraging results. This article provides an overview of recent research developments and therapeutic strategies for cutaneous T-cell lymphoma.

Animals↗
PubMed2006

[Immunotherapy of malignant melanoma--basic principles and novel therapeutic approaches].

Immunotherapy has assumed increasing importance in the therapy of malignant melanoma. The main reason is the high immunogenicity of the tumor itself, so that an immune response against the tumor often exists even without immune stimulation. The goal of modern immunotherapeutic approaches is to augment these anti-tumoral immune reactions to fight the tumor. Despite multiple successes, the ultimate breakthrough in the therapy of malignant melanoma has not yet been achieved. This overview summarizes the reasons for this lack of success and highlights future strategies for more successful therapy of malignant melanoma.

Cancer Vaccines↗
PubMed2005

Absence of mutations in the coding sequence of the potential tumor suppressor 3pK in metastatic melanoma.

BACKGROUND: Activation of Ras or Raf contributes to tumorigenesis of melanoma. However, constitutive Raf activation is also a characteristic of the majority of benign melanocytic nevi and high intensity signaling of either Ras or Raf was found to induce growth inhibition and senescence rather than transformation. Since the chromosome 3p kinase (3pK)) is a target of the Ras/Raf/Mek/Erk signaling pathway which antagonizes the function of the oncogene and anti-differentiation factor Bmi-1, 3pK may function as a tumor suppressor in tumors with constitutive Ras/Raf activation. Consequently, we tested whether inactivating 3pK mutations are present in melanoma. METHODS: 30 metastatic melanoma samples, which were positive for activating mutations of either BRaf or NRas, were analyzed for possible mutations in the 3pk gene. The 10 coding exons and their flanking intron sequences were amplified by PCR and direct sequencing of the PCR products was performed. RESULTS: This analysis revealed that besides the presence of some single nucleotide polymorphisms in the 3pk gene, we could not detect any possible loss of function mutation in any of these 30 metastatic melanoma samples selected for the presence of activating mutations within the Ras/Raf/Mek/Erk signaling pathway. CONCLUSION: Hence, in melanoma with constitutively active Ras/Raf inactivating mutations within the 3pk gene do not contribute to the oncogenic phenotype of this highly malignant tumor.

Journal Article↗
PubMed2005

Temozolomide in combination with interferon-alfa versus temozolomide alone in patients with advanced metastatic melanoma: a randomized, phase III, multicenter study from the Dermatologic Cooperative Oncology Group.

PURPOSE: Temozolomide (TMZ) has shown efficacy in metastatic melanoma equal to that of dacarbazine (DTIC), the standard chemotherapeutic agent for melanoma. As the combination with interferon-alfa (IFN-alpha) appears superior to single-agent DTIC regarding response rates, the purpose of this study was to compare TMZ alone and TMZ plus IFN-alpha in terms of objective response (OR), overall survival, and safety in a prospective, randomized, multicenter trial. PATIENTS AND METHODS: Two hundred ninety-four patients with untreated stage IV metastatic melanoma (American Joint Committee on Cancer staging system) were randomly assigned to receive either oral TMZ alone (200 mg/m2/day; days 1 through 5 every 28 days) or in combination with subcutaneous IFN-alpha (5 MU/m2; days 1, 3, and 5 every week). RESULTS: Two hundred eighty-two patients were eligible for an intent-to-treat analysis, 271 patients were treated per protocol. In the TMZ + IFN-alpha arm, 33 (24.1%) of 137 patients responded to therapy (partial or complete remission) whereas in the monotherapy arm, in 18 (13.4%) of 134 patients, a response was evident. Thus, the response rate was significantly higher in the combination arm (P = .036). Median survival time was 8.4 months for patients treated with TMZ (95% CI, 7.07 to 9.27) and 9.7 months for those treated with the combination (95% CI, 8.26 to 11.18; P = .16). Dose modifications and interval prolongations due to hematologic toxicity were significantly more frequent in the TMZ + IFN-alpha arm (P < .001). CONCLUSION: In metastatic melanoma treatment with TMZ + IFN-alpha leads to a significantly superior OR rate compared to treatment with TMZ alone, which did not translate into prolonged survival in our study population.

Adult↗
PubMed2005

Stromal cells as the major source for matrix metalloproteinase-2 in cutaneous melanoma.

Matrix metalloproteinases (MMPs) are essential for tumor progression, invasion and metastases formation. Expression of these proteinases is not only restricted to the tumor cells themselves, but also is found in normal stromal cells. Moreover, immunohistochemistry suggests stromal cells as the major source. To scrutinize this hypothesis we established a slowly growing, syngeneic tumor model using the B16-melanoma cell line B78D14. In vitro analysis demonstrated that B78D14 cells secreted MMP-2, MT1-MMP, and to a lesser degree MMP-9; in addition they expressed both MT1-MMP and EMMPRIN on their surface. In subcutaneous (s.c.) tumors of these cells MMP-2 expression was predominantly present at the tumor-stroma border indicating stromal cells as primary source for this protease in vivo. Indeed, double staining experiments and in situ zymography confirmed that tumor adjacent stromal cells at the invasive front expressed MMP-2 and only at this site activated MMP-2 was detectable. Notably, in an experimental pulmonary metastases model neither tumor nor stromal cells expressed MMP-2, suggesting that the capacity of stromal cells is largely dependent on the surrounding microenvironment.

Animals↗
PubMed2005

Tumor stroma-associated antigens for anti-cancer immunotherapy.

Immunotherapy has been widely investigated for its potential use in cancer therapy and it becomes more and more apparent that the selection of target antigens is essential for its efficacy. Indeed, limited clinical efficacy is partly due to immune evasion mechanisms of neoplastic cells, e.g. downregulation of expression or presentation of the respective antigens. Consequently, antigens contributing to tumor cell survival seem to be more suitable therapeutic targets. However, even such antigens may be subject to immune evasion due to impaired processing and cell surface expression. Since development and progression of tumors is not only dependent on cancer cells themselves but also on the active contribution of the stromal cells, e.g. by secreting growth supporting factors, enzymes degrading the extracellular matrix or angiogenic factors, the tumor stroma may also serve as a target for immune intervention. To this end several antigens have been identified which are induced or upregulated on the tumor stroma. Tumor stroma-associated antigens are characterized by an otherwise restricted expression pattern, particularly with respect to differentiated tissues, and they have been successfully targeted by passive and active immunotherapy in preclinical models. Moreover, some of these strategies have already been translated into clinical trials.

Animals↗