As a New Challenge for Tumour Pathology

Kreipe, Reinhard von Wasielewski Recent Results in Cancer Research, Vol. 176 Springer-Verlag Berlin Heidelberg 2007 In order to bring about its beneficial effects in oncology, targeted therapy depends on accurate target analysis. Whether cells of a tumour will be sensitive to a specific treatment is predicted by the detection of appropriate targets in cancer tissue by immunohistochemistry or molecular methods. In most instances this is performed by histopathologists. Reliability and...

VEGFR2 Inhibition

VEGF signaling is mediated by several tyrosine kinase receptors, among them VEGFR1 and VEGFR2 (Shinkaruk et al. 2003). VEGFR2, but not VEGFR1, is overexpressed in human untreated AML bone marrow samples and the expression correlates with the bone marrow microvessel density (Padro et al. 2002). Upon induction of a CR, VEGFR2 levels decreased to normal range. Stimulation of primary leukemic cells by VEGF led to an activation of growth and migration, and this activation was mediated through VEGFR2...

Abstract

With increasing knowledge of tumor-associated antigens and T cell epitopes, and the mechanisms of induction and regulation of T-cellular immune responses, therapeutic vaccination is increasingly being explored as a treatment option for cancer. Several clinical cancer vaccination trials, the majority of them with melanoma patients, have demonstrated efficient induction of tumor-specific cellular immune responses in patients. However, these immune responses, in most cases, do not translate into...

Role of Immunological Vaccine Adjuvants

Following intradermal injection, TAA-derived peptides are thought to bind to empty MHC class I molecules on dendritic cells, which then migrate to the draining lymph nodes where specific T cell activation occurs. Vaccination with TAA-derived peptides alone may be suboptimal to charge and activate dendritic cells, and elicit specific T cell responses it thus requires simultaneous administration of adjuvants. GM-CSF has been used in various vaccine protocols, as it promotes local recruitment and...

History and Epidemiology of GIST

GIST was first described in 1941 by Golden and Stout as leiomyomatosal neoplasia with unusual histological features (Golden and Stout 1941). During the following years GIST changed its name, being called leiomyoblastoma or epithe-loid leiomyoma. In 1984 an additional neurogenic origin of GIST was discovered by electronic microscopy (Knapp et al. 1984) and immune histology (Saul et al. 1987), and in 1995 an overexpression of CD34 (Miettinen et al. 1995) and a gain-of-function mutation in the...

Biological Activities of VEGF

Angiogenesis is a highly complex and well-coordinated process that has many modulators from natural sources (as shown in Table 16.2). The process is arranged by the sequential activation of receptors and ligands. VEGF, also know as VEGF-A, and its receptors is of very high importance since the activation of the corresponding signal pathways is a critical and limiting step in physiological angiogenesis. VEGF belongs to a gene family that comprises placental growth factor (PLGF) as well as...

Designs of Therapeutic Cancer Vaccines

T cell vaccines have to fulfill the following conditions for induction of CD8+ T cell (Stuhler and Walden 1993, 1994, 2002). First, CD8+ T cell induction is dependent on T cell help. Second, the collaboration of cytotoxic precursor T cells and helper T cells has to be organized by antigen-presenting cells, most efficiently by dendritic cells (Schuler et al. 2003), that present epitopes for both T cell types on the respective MHC molecules, MHC class I for the CD8+ and MHC class II for the CD4+...

Defining a Cancer Metastasis

The NIH Metastatic Working Group defines cancer metastasis as follows The dissemination of neoplastic cells to discontiguous nearby or distant secondary (or higher order) sites where they proliferate to form an extravascular mass. This definition is based on the following principles of metastasis Metastasis is distinct from tumori-genicity metastatic potential varies between people, by tumor type, and within a given tumor metastases are clonal in origin, but heterogeneity can redevelop during...

Platinum Containing Drugs Used for Treatment of Ovarian Carcinoma

In the last few years, the platinum-containing drug cisplatin was replaced in the treatment of ovarian carcinoma by its analogue carboplatin. Carboplatin differs from cisplatin in a closed cyclobutane dicarboxylate moiety on its leaving arm instead of the chloride ligands of cisplatin. The result is an altered DNA binding kinetics, though carboplatin forms the same reaction products at equivalent doses. After the entry of the neutral square-planar platinum (II) complex cisplatin or carboplatin...

Conclusion

The differential function of genes affecting drug metabolism, interactions with cellular targets, or transport can cause a dramatic shift in the toxicity profile and efficacy of drugs. Analyses with a high predictive value for drug response should include not only the individual's genetic background, but also gene-gene interactions, somatic mutations of the tumor cell, and dynamic characteristics such as variations of RNA expression. Nonetheless, the individualization of chemotherapy based on...

Thalidomide

Besides other mechanisms of action, antiangio-genic effects have been shown for thalidomide in a mouse model (Kenyon et al. 1997 D'Amato et al. 1994). This antiangiogenic effect is probably mediated by an inhibition of endothelial cell proliferation (Moreira et al. 1999). We conducted a phase I II-study with thalidomide in 20 patients with refractory AML or patients not eligible for intensive induction chemotherapy (Steins et al. 2002). Out of these 20 patients, 4 reached a partial remission...

Structure and Function of the Proteasome

The 26S proteasomes are highly conserved, multicatalytic protease complexes that are responsible for protein degradation and maintenance of protein homeostasis. They are localized in cytoplasm and the nucleus of eukaryotic cells and are predominantly involved in the regulation of turnover of short-living proteins that regulate cell-cycle progression, apoptosis, signal transduction, antigen presentation, and inflammatory processes (Adams 2003 Kloetzel 2001). Proteins that are targeted for...

Case Report

A 61-year-old male patient was admitted to our hospital in October 2001 due to a large intraabdominal mass that was discovered during a routine check up (Fig. 12.1A and B). The patient underwent explorative laparotomy, and a tumor at the urine bladder with infiltration of the small bowl and multiple knots of the peritoneum was found. R2 resection was performed revealing a CD117-positive extragastrointestinal stromal tumor of the gastrointestinal type. At the end of November 2001, therapy with...

The Nuclear FactorKB Transcription Factors

The nuclear factor-KB proteins are a small group of closely related transcription factors which Fig.15.4 In a mantle cell lymphoma with the t(11 14) translocation, the neoplastic cells show a strong nuclear expression of the cyclinDl protein. (Immunohisto-chemical detection was performed with an anti-cyclin D1 monoclonal antibody and the APAAP technique) consist of five members Rel (also known as c-Rel), RelA (also known as p65 and NF-kB3), RelB, NF-kB1 (also known as p50) and NF-kB2 (also...

Colorectal Cancer Metastasis The Major Cause of Death

Approximately 90 of all cancer deaths arise from the metastatic dissemination of primary tumors (Christofori 2006). Although about 50 of the tumors can be treated curatively by surgery alone, metastatic growth is the major factor that compromises the successful treatment and outcome of colorectal cancer. Today, patient prognosis is mainly defined by histopathological staging, a static description of the anatomical extent of tumor spread within a surgical specimen. Tumor infiltration depth (T),...

Preface

Over the past 50 years, the efficacy of cancer chemotherapy has improved considerably. Nonetheless, particularly in the metastatic situation, clinical outcome parameters, such as overall survival, have changed only modestly. This fact continues to represent a tremendous obligation for the scientific community and the pharmaceutical industry to develop new approaches in the fight against cancer. The enormous progress in the knowledge of functional tumor cell biology, in particular of the...

Targeted Therapies in Cancer

Manfred Dietel Institut f r Pathologie Charit Humboldt-Universit t zu Berlin Schumanstr. 20-21 10117 Berlin Germany Library of Congress Control Number 200693901 ISSN 0080-0015 ISBN 978-3-540-46090-9 Springer Berlin Heidelberg New York This work is subject to copyright. All rights reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any...

Proteasome Inhibitors

The first compound with documented effects on proteasomal function was identified as the non-peptidic Streptomyces metabolite lactacystin. Its intermediate clasto-lactacystin -lactone interferes with the p5-subunit (chymotrypsin-like activity) irreversibly by selective modification of amino-terminal threonine residues and revers-ibly with the p1-subunit (peptidylglutamyl-like activity) and p2-subunit (trypsin-like activity) (Fenteany et al. 1995 Dick et al. 1997). In the course of further...

Inhibition of Angiogenesis 2121 Introduction

The role of increased angiogenesis in AML has been elucidated since the beginning of this century (Hussong et al. 2000 Aguayo et al. 2000 Pa-dro et al. 2000). Bone marrow infiltrated by AML blasts exhibits an increased microvessel density compared to normal bone marrow (Hussong et al. 2000 Padro et al. 2000) and microvessel density decreased in response to induction che-mo therapy (Padro et al. 2000). Hypothetically, growth factors expressed by AML blasts stimulate the growth of vascular...

Angiogenesis Inhibitors in Clinical Trials

A compilation of antiangiogenetic agents now being tested in clinical trials can be found in Table 16.3 (Tandle et al. 2004). One has to differentiate between modified monoclonal antibod ies, named abs, and synthesized inhibitors, named ibs, the latter representing so-called smart small drugs that inhibit growth factors or their receptor kinases by binding to essential structural domains. Most the antiangiogenetic agents aim at VEGF or its receptors.

Vascular Endothelial Growth FactorC

In contrast to VEGF-A and VEGF-B, different forms of VEGF-C and VEGF-D are not built by alternative splicing but by proteolytic processing. VEGF-C is subjected to an intracellular conversion by PC5 and PC7 as well as to an extracellular proteolysis by plasmin. The final 21-kDa homodimeric protein binds to VEGF-R2 and VEGF-R3 with high affinity. It induces mito-genesis, migration, and survival of endothelial cells and is mainly expressed in regions in which lymph vessels are built. Expression...

Info

AA AO, anaplastic astrocytoma (anaplastic oligodendroglioma) GBM, glioblastoma PFS, progression-free survival RR, response rate TMZ, temozolomide TTP, time to progression AA AO, anaplastic astrocytoma (anaplastic oligodendroglioma) GBM, glioblastoma PFS, progression-free survival RR, response rate TMZ, temozolomide TTP, time to progression TGF-P regulates key mechanisms of tumor development, such as immunosuppression, metastasis, angiogenesis, and proliferation. In a phase I II study with the...

References

Alizadeh AA, Eisen MB, Davis RE, et al (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403 503-511 Argatoff LH, Connors JM, Klasa RJ, Horsman DE, Gas-coyne RD (1997) Mantle cell lymphoma a clinico-pathologic study of 80 cases. Blood 89 2067-2078 Baldwin AS (2001) Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest 107 241-246 Bargou RC, Leng C, Krappmann D, et al (1996) Highlevel nuclear...

Conclusions

Proteasome inhibitors represent a novel class of antitumor agents. Bortezomib, the first pro-teasome inhibitor introduced in clinical use, abrogates chemotherapy-induced resistance mechanisms and may act synergistically with a broad range of cytostatic agents. Results of clinical studies revealed high activity in multiple myeloma and certain subtypes of NHL, e.g., mantle cell lymphoma and follicular lymphoma. The response rates of single-agent use in solid tumors are much lower, and appropriate...

Antibody Based Antiangiogenesis Therapy

Bevacizumab (Avastin) is a humanized antibody against VEGF. Inhibition of tumor growth was shown in preclinical and early clinical trials. Tolerance was good. In the first decisive phase III study, Bevacizumab was administered as first-line therapy to 925 patients with metasta-sized colorectal carcinoma. They were randomized into two groups, one getting Avastin, the other a placebo in combination with irinotecan, 5-FU, and folinic acid (Hurwitz et al. 2004). Be-vacizumab showed better data...

Resistance to Chemotherapy in Ovarian Carcinoma

Recent Results in Cancer Research, Vol. 176 Springer-Verlag Berlin Heidelberg 2007 Resistance to cytotoxic chemotherapy is the main cause of therapeutic failure and death in women suffering from ovarian carcinoma. The standard first-line chemotherapy of ovarian cancer consists of a combination of a taxane and a platinum-containing drug. Thus, the cellular and molecular mechanisms involved in resistance against these compounds are of vital importance in the context of chemotherapy of ovarian...

DNA Synthesis

Troxacitabine is a novel cytosine analog with an L-conformation it was initially designed as an antiretroviral drug (Kim et al. 1992). Troxacitabine exhibits strong antitumoral activity in a variety of tumors (Grove et al. 1995). Troxacitabine had clinical activity as a single dose in a dose-escalation study with complete responses in 3 out of 30 evaluable patients with advanced AML (Giles et al. 2001). This compound, in contrast to established D-nucleosides, cannot be inactivated by cytidine...

Proteomic Approaches

The term proteome was coined in 1994 and is defined as the entire protein complement expressed by a cell line, tissue or organism. Pro-teomics, in analogy to genomics, is the study of the proteome, i.e. of all proteins including their relative abundance, distribution, post-transla-tional modifications, functions and interactions with other macromolecules in a given cell or organism within a given environment at a specific stage in the cell cycle (Wasinger et al. 1995 Cai et al. 2004)....

List of Contributors

Medizinische Klinik A Universit tsklinikum M nster Albert-Schweitzer-Str. 33 48149 M nster Germany Medizinische Klinik A Universit tsklinikum M nster Albert-Schweitzer-Str. 33 48149 M nster Germany ProteoSys AG Carl-Zeiss-Str. 51 55129 Mainz Germany Christian de Duve Institute of Cellular Pathology Universit catholique de Louvain 1200 Brussels Belgium Charit Centrum f r Tumormedizin Medizinische Klinik mit Schwerpunkt H matologie und Onkologie Charit Campus Virchow-Klinikum 13344 Berlin Germany...

Tyrosine Kinase Inhibitors

Semaxanib (Su5416) was the first specific synthesized inhibitor of VEGF-RTK activity and showed a growth inhibition in mouse xenotrans-plants of human tumors. In several phase II trials, results were disappointing, albeit providing a good security profile. Table 16.3 Angiogenesis inhibitors in clinical trials (adapted from Tandle et al. 2004)

Interactions Between HLAA1 MAGEA1 and Hyb3

The most remarkable feature regarding HLA-A1 MAGE-A1 recognition by Hyb3 is the unequal use of its CDR loops by the rAb. While nearly all TCR employ all of their six CDR for this purpose, only the CDR loops of the heavy chain and the CDR-L3 of Hyb3 contact the pMHC directly, through hydrogen bonds or van der Waals' contacts of less than 3.5 A (Fig. 20.2). CDR-H1 recognizes exclusively residues of the a1-helix, and CDR-L3 interacts with both a-helices of the HLA-A1 MAGE-A1 molecule, whereas...

Materials and Methods

All materials and experimental procedures have already been described (Hulsmeyer et al. 2005). Briefly, the HLA-A1 heavy chain and -microglobulin were separately expressed as inclusion bodies in Escherichia coli, and the solubilized proteins were then mixed with the MAGE-A1 peptide (obtained by solid phase synthesis), followed by refolding of the ternary complex and its purification by size-exclusion chromatography. Hyb3 was also expressed in E. coli and purified as described for Fab-G8 (Chames...

And Classification of Angiogenesis Inhibitors

Antiangiogenesis as a potential therapy option for tumors dates back to the works of Judah Folkman et al. who, in 1971, isolated for the first time a tumor factor for which they could prove an angiogenetic effect. Together with the naming TAF (tumor angiogenesis factor), the authors hypothesized, It is suggested that blockade of this factor (inhibition of angiogenesis) might arrest solid tumors at a tiny diameter of a few millimeters (Folkman et al. 1971a). TAF could be characterized...

Progesterone Receptors

In view of the substantial fraction of ER+ patients failing to respond to hormone therapy, the tumoral expression of PR has always been an attractive candidate in the quest for the improved prediction of endocrine responsiveness. Assuming that PR is primarily regulated by ER, immu-nohistologically detectable PR should indicate a functionally intact estrogen response pathway. As expected, several studies have demonstrated a more pronounced response to adjuvant endocrine therapy hormonal...

Protein Degradation

Degradation of the majority of cellular proteins is mainly regulated by the proteasome. Cellular proteins designated for destruction are tagged with the small peptide ubiquitin and directed to degradation by the proteasome complex. Inhibition of the proteasome leads to an undirected accumulation of proteins with profound effects on the cells, resulting in apoptotic cell death in a dose-dependent manner. Malignant hemato-poietic cells show a more profound sensitivity to proteasome inhibitors...

Pharmacological Mechanisms of Drug Resistance

Chemotherapy should be given at the maximum tolerated dose (MTD) to achieve maximum tumour cell killing. A tumour is deemed clinically resistant to the MTD if the effective drug dosage in the tumour, given as the area under the curve (AUC drug concentrationxtime of drug exposure), is not efficient at achieving a cytostatic or cytotoxic effect within the neoplastic cells. This therapeutically insufficient drug dosage may be due to different physiological mechanisms that can be summarized as...

Cellular Mechanisms of Drug Resistance

In addition to these pharmacological mechanisms of drug resistance, various cellular mechanisms taking place directly within the tumour cell have been described. In the last four decades dramatic progress has been made in the understanding of cellular drug resistance-associated genes, proteins and their mechanisms of action (Gottesman 2002). Due to the inherent difficulties of investigation drug resistance directly in the patient, a large number of in vitro models have been developed and...

Data Banking

While tumour banking has been recognized for over a decade as a needed tool to advance the molecular science of oncogenesis and tumour progression (Naber et al. 1992 Naber 1996), only in the last 4-5 years has the linkage to clinical outcomes been regarded as crucial for achieving this goal (Qualman et al. 2004). Therefore, the development of databases represents an independent scientific field, which is separated from molecular and clinical research and demands high logistic and financial...

NFkB and Diffuse Large B Cell Lymphoma

DLBCL is the most common lymphoid malignancy in adults, accounting for nearly 40 of all non-Hodgkin's lymphomas. DLBCL is so named because the malignant lymphocytes diffusely efface the normal architecture of the lymph node or extranodal site. The cells are large transformed lymphocytes, and they have been further divided into morphologic variants centroblastic, immu-noblastic, T cell histiocyte-rich and anaplastic. Though DLBCL has proved to be one of he most chemotherapy-responsive human...

To Chromosomal Translocations

15.4.1 BCL-2 and B Cell Non-Hodgkin Lymphoma Bcl-2 is an anti-apoptotic member of a large family of genes involved in the regulation of pro grammed cell death (Reed 1997 Yang and Korsmeyer 1996). Pro-apoptotic (BAX and BCL-Xs) and anti-apoptotic (BCL-2 and BCL-Xl) molecules reside within the inner mitochondrial membrane and can homo- and heterodimerize upon appropriate stimulus. These interactions control the release of substances such as cytochrome C from the mitochondria into the cytosol....

Fusion Petspect

Fig. 10.5 Penetration of ulIn ibritumomab tiuxetan through the blood-brain (-tumor) barrier in PCNSL. PET with increased uptake of F FDG (upperpanel), corresponding SPECT slices (middlepanel) with increased uptake of min ibritumomab tiuxetan, and image fusion of both modalities (lower panel) therapy with conventional therapy also hold promise for the treatment of malignant gliomas. The results of the first studies with combination regimens are promising (Table 10.4). The median progression-free...

NFkB and Classical Hodgkin Lymphoma

Most evidence for the role of NF-kB in human malignancies came from an analysis of cHL. Classical HL is characterized by the fact that the neoplastic cells Hodgkin and Reed-Sternberg (HRS) cells represent only a small fraction (2 ) of the neoplastic lesions that are populated by eosinophils, neutrophils, T and B cells, plasma cells, histiocytes and others. These reactive cells are attracted by cytokines and chemokines abundantly produced by the HRS cells. While the cellular origin of the HRS...

The Adenoma Carcinoma Sequence and Metastasis

Adenoma Carcinoma Sequence

Tumor progression and metastasis are results of sequential genetic alterations leading to accumulation of mutations in different genes and modulated downstream events. Single molecular events are meanwhile attributed to specific steps during the so-called adenoma-carcinoma sequence of tumor progression for colorectal cancer, first described as the Fearon-Vogelstein model (Fearon and Vogelstein 1990 Fig. 7.3). This adenoma-carcinoma sequence represents the stepwise progression from early lesions...

Cetuximab as an Adjunct to Radiotherapy

Preclinical data and the persuading clinical results obtained in patients with squamous cell head and neck cancer in principle underline that cetuximab is not only effective as a combination partner for cytostatic drugs, but also markedly enhances the antineoplastic properties of radiotherapy Baselga 2001 Bonner et al. 2006 . In the pivotal trial on head and neck cancer, the addition of cetuximab to radiother-apy which was applied according three different optional schedules up to cumulative...

Imatinib and GIST

In 2001 Joensuu et al. published a case report in the New England Journal of Medicine Joensuu et al. 2001 . It reports on a 51-year-old female patient from Finland who suffered from a multiple metastasized GIST. Several resections, different polychemotherapies and treatment with inter-feron-a and thalidomide had been unsuccessful. Within an international phase I study, imatinib at a dose of 400 mg per day was started in March 2000. Already 4 weeks later a complete metabolic remission was...

Recombinant Antibodies Against pMHC

Recombinant antibodies rAb produced in vitro offer a possible solution to these difficulties. They are available in different formats, e.g. as Fab VH, CH1 combined with VL, CL or scFv VH covalently linked to VL and are originally part of large libraries with more than 108 different species of rAb that are mostly displayed either on the surface of bacteriophage Smith 1985 or ribosomes Hanes et al. 2000 . There are various ways in which these libraries can be constructed, but they are usually...