| Current
Drug Targets
ISSN: 1389-4501
Current Drug Targets
Volume 7, Number 10, October 2006
Contents
Targeting Arterial Thrombosis - Current Concepts and Future
Developments
Guest Editor: Florian Krötz
Editorial Pp. 1231
Redox Modification of Platelet Glycoproteins
Pp. 1233-1241
D.W. Essex and M. Li
[Abstract]
The Many Antithrombotic Actions of Nitric Oxide
Pp. 1243-1251
C. Tziros and J.E. Freedman
[Abstract]
G-protein Dependent Platelet Signaling –
Perspectives for Therapy Pp. 1253-1263
H. Shankar, B. Kahner and S.P. Kunapuli
[Abstract]
Phosphotyrosine Signaling in Platelets: Lessons
for Vascular Thrombosis Pp. 1265-1273
J.L.K. Wee and D.E. Jackson
[Abstract]
Cyclooxygenase Inhibition and Atherothrombosis
Pp. 1275-1284
H-Y. Sohn and F. Krötz
[Abstract]
Thrombin Inhibitors and Anti-Factor Xa Agents
in the Treatment of Arterial Occlusion Pp. 1285-1290
V. Klauss and M. Spannagl
[Abstract]
Beyond Chemotherapy: Future Directions in Lymphoma
Treatment
Guest Editor: Thomas Decker
Editorial Pp. 1291
Radioimmunotherapy of Non-Hodgkin’s Lymphomas
Pp. 1293-1300
B.D. Cheson
[Abstract]
Immunotoxins in the Treatment of Hematologic Malignancies
Pp. 1301-1311
R.J. Kreitman and I. Pastan
[Abstract]
Genetics, Gene Expression, and Targeted Therapies
in Chronic Lymphocytic Leukemia Pp. 1313-1327
D. Winkler, H. Döhner and S. Stilgenbauer
[Abstract]
Targeting the Oncogenic Tyrosine Kinase NPM-ALK
in Lymphoma: The Role of Murine Models in Defining Pathogenesis
and Treatment Options Pp. 1329-1334
C. Miething, C. Peschel and J. Duyster
[Abstract]
The Bcl10 / Malt1 Signaling Pathway as a Drug
Target in Lymphoma Pp. 1335-1340
P. Jost, C. Peschel and J. Ruland
[Abstract]
Proteasome Inhibition as a New Therapeutic Principle
in Hematological Malignancies Pp. 1341-1347
C.S. Mitsiades, N. Mitsiades, T. Hideshima, P.G. Richardson
and K.C. Anderson
[Abstract]
Cell Cycle Inhibition in Malignant Lymphoma: Disease
Control by Attacking the Cellular Proliferation Machinery
Pp. 1349-1359
I. Ringshausen, C. Peschel and T. Decker
[Abstract]
Therapeutic Targeting of Apoptotic Pathways in
Cancer Pp. 1361-1369
J. Meiler and M. Schuler
[Abstract]
Current status of Immunotherapy in B Cell Malignancies
Pp. 1371-1374
D.M. Kofler, C. Mayr and C.-M. Wendtner
[Abstract]
Abstracts
[Back
to top]
Editorial
Myocardial infarction caused by thrombotic occlusion
of a coronary artery represents the most dreaded complication
of atherosclerotic disease. Conjoined with other forms of
appearance of atherosclerotic vascular disease it represents
one of the most important causes of mortality in the western
civilization and is thus a major socio-economic problem.
The immediate thrombotic occlusion of a diseased vessel represents
a complicated scenario spanning from rupture of an atherosclerotic
plaque to the ultimate necrosis of the depending myocardial
tissue. A sequelae of pathophysiological events take place
within seconds of the development of vascular thrombosis,
which include numerous triggering elicitors and mediators
that support, augment or confine the several steps of primary
and secondary hemostasis. Past years’ scientific advances
have further unraveled and helped to classify the roles of
various agents that support arterial thrombosis and specified
cellular signaling mechanisms, which put these actions into
effect. In addition, it has become clear that the balance
of vascular homeostatic small molecule mediators and the activation
state of the cellular structure that is the crucial mediator
of primary thrombotic occlusion - the anucleate platelet –
may be the decisive determinants of fatal arterial occlusion.
This thematic issue of Current Drug Targets embraces fine
review articles by scientific leaders in the field of platelet
pathophysiology, vascular biology, and antithrombotic pharmacology.
Their contributions comprise insights into new concepts derived
from medicinal chemistry and pharmacology to recent experimental
perceptions with potential clinical relevance. The composition
of this issue is designed to provide the scientifically interested
clinicians with important new information about evolving outstanding
research concepts, and also provide the basic researcher with
up-to-date reviews on emerging topics in vascular pathophysiology.
The first article of this issue by Essex and Li is a brilliant
example of such an emerging scientific topic. Although platelet
glycoprotein receptors like the fibrinogen receptor (GPIIb/IIIa)
have long been known to be the most important mechanical mediators
of platelet-platelet interaction, the molecular regulation
of their redox-sensitive disulfite sites has not been understood
so far. However, Essex and colleague nicely demonstrate, how
redox state may form the basis for functionality of such glycoprotein
receptors.
In close relation to redox state, free reactive oxidant or
nitrogen species are increasingly recognized to dominate vascular
homeostasis not only by regulating endothelial function, but
also by modulating platelet signaling. The article by Tziros
and Freedman explains why this has recently led to the development
of new NO donors that attempt to enhance the antithrombotic
actions of NO as a means to manipulate arterial thrombosis.
The articles by Shankar and colleagues and the review by Wee
and Jackson further underline the integral role of platelets
and their activatory signaling that form the basis for the
development of more specific and highly effective antiplatelet
agents. Based upon the finding that the P2Y12 receptor, the
target of thienopyridine antiplatelet drugs like Clopidogrel,
mediates its actions through G-protein dependent signaling,
Shankar and colleagues have assembled an impressing overview
of how several crucially important agonists like adenosine
diphosphate (ADP), thrombin and thromboxane A2
(TXA2) activate platelets by acting via
G-proteins and demonstrate how many of anti-thrombotic drugs
mediate their beneficial effects by interfering with or preventing
the initiation of the G-protein signaling pathway.
The crucial importance of specific signaling in platelet-dependent
thrombosis is further being highlighted in the article by
Wee and Jackson. For the first time, their contribution reviews
in a most fascinating way, how tyrosine phosphorylation events
regulate key signaling molecules that either stimulate signaling
pathways in platelets, such as the collagen-dependent activation
of glycoprotein GPVI, or are associated with regulatory pathways
that limit the extent of platelet activation.
Lastly, the articles by Sohn and colleagues and the article
by Klauss and Spannagl span a bridge from preclinical physiological
knowledge to either clinical pathophysiology leading to myocardial
infarction or to the development and first clinical experiences
with a promising new antithrombotic class of drugs, which
target at inhibiting the activated factor X or thrombin directly.
The article by Sohn et al. focuses on the reasons
why a specific class of drugs may have an intrinsic risk of
fostering atherothrombosis. First recognized by the appraisal
that selective COX-2 inhibitors degrade intravital levels
of vascular antiplatelet prostanoid prostacyclin, this article
outlines the pathophysiological reasons and summarizes current
clinical knowledge, and how the balance between anti- or prothrombotic
prostanoids released within the vessel may be influenced by
several members of the class of drugs targeting cyclooxygenase,
the so-called non-steroidal antiinflammatory drugs (NSAID).
Finally, Klauss and Spannagl excellently dissect the various
drugs that have recently been developed to target either the
final step of coagulation, activated factor X, or thrombin
directly. This tutorial not only illuminates the underline
physiology, but also focuses on the current clinical experience
with these drugs in treatment of myocardial infarction or
thrombotic disease. Thereby, it also draws attention to the
most important clinical limitation that any drug targeting
arterial thrombosis must overcome, which is the side effect
of a clinically relevant risk of bleeding.
I am convinced that the articles in this thematic issue of
Current Drug Targets will be an enrichment for any reader
interested in clinical development of new antithrombotic drug
regimens, and a plentiful source of background information
for the scientists working in the field. Bringing together
clinical and scientific experiences and necessities is one
of the most important tasks in accelerating and thus positively
advancing medical knowledge and practice. It therefore has
been a major goal during the assembly of these articles.
Florian Krötz, MD
Cardiology, Medical Policlinic
Ludwig-Maximilians-University
Ziemssenstr.1, 80336 Munich
Germany
Tel:+49-89-218075-384
Fax:+49-89-218075-378
E-Mail: florian.kroetz@med.uni-muenchen.de
[Back to top]
Redox Modification of Platelet Glycoproteins
D.W. Essex and M. Li
Platelets contain several glycoprotein receptors including
the adhesion receptor glycoprotein Ib and the fibrinogen receptor
glycoprotein IIbIIIa, also know as the αIIbβIIIa
integrin. Both of these receptors contain thiol groups and
vicinal thiols representing redox sensitive sites are present
in αIIbβIIIa.
Disulfide isomerases such as protein disulfide isomerase (PDI)
that are on or recruited to the platelet surface have a role
in platelet aggregation. Dynamic rearrangement of disulfide
bonds in receptor signaling and platelet activation is a developing
concept that requires an attacking thiol. Biochemically, a
role for disulfide isomerization is suggested as the αIIbβIIIa
integrin undergoes major structural changes upon activation
centered around a disulfide knot in the integrin. Additionally,
the P2Y12 ADP receptor is involved in platelet activation
by most platelet agonists and contains extracellular thiols,
making it a possible site for redox modification of platelet
aggregation. Various forms of redox modulation of thiols or
disulfides in platelet glycoproteins exist. These include
modification by low molecular weight thiols such as reduced
glutathione or homocysteine, oxidized glutathione or by nitric
oxide (NO) derived from s-nitrosothiols. Levels of these redox
compounds change in various disease states and in some cases
physiologic concentrations of these compounds have been shown
to modify platelet responsiveness. Additionally, platelets
themselves contain a transplasma membrane redox system capable
of reducing extracellular disulfide bonds. It is likely that
a redox homeostasis exists in blood with the redox environment
being controlled in a way analogous to the control of ionized
calcium levels or the pH of blood. Changes in this homeostasis
induced by disease states or pharmacologic agents that modify
the platelet redox environment will modify platelet function.
[Back to top]
The Many Antithrombotic Actions
of Nitric Oxide
C. Tziros and J.E. Freedman
Vessel occlusion within a coronary artery is the
precipitating event in unstable coronary syndromes and is
primarily due to rupture of atheromatous plaque and subsequent
thrombus formation. In the nondiseased vessel, the intact
endothelium releases the vasodilator and antithrombotic agent
nitric oxide (NO) preventing platelet adherence and activation.
In the diseased vessel and during unstable coronary syndromes,
release of both endothelial and platelet NO is impaired contributing
to thrombus formation. Nitric oxide availability in the vascular
system has been associated with various disease states, genetic
variants, and medication use. Recently, through the development
of new NO donors and by targeting specific signaling pathways,
there has been an attempt to enhance the antithrombotic actions
of NO as a means to manipulate arterial thrombosis.
[Back to top]
G-protein Dependent Platelet Signaling –
Perspectives for Therapy
H. Shankar, B. Kahner and S.P. Kunapuli
Platelet activation and aggregation is an integral component
of the pathophysiology that leads to thrombotic and ischemic
diseases such as cerebral stroke, peripheral vascular disease
and myocardial infarction. Anti-platelet agents (such as aspirin,
ADP receptor antagonists, and GPIIb/IIIa antagonists), phosphodiesterase
inhibitors and anti-coagulants are major part of the current
treatment towards treating ischemic diseases. However, their
limited efficacy in the setting of arterial thrombosis, unfavorable
side effect profile and cost-to-benefit issues substantiate
the need for the development of newer and more efficacious
antithrombotic drugs. Various platelet agonists like adenosine
diphosphate (ADP), thrombin and thromboxane A2
(TXA2) activate platelets by acting via
their respective surface receptors, which couple to one or
more distinct G-proteins belonging to either the Gi,
Gq, G12-13 or Gs families.
Upon activation, each of these G-proteins trigger a series
of intracellular signaling cascades, causing the platelets
to undergo shape change, secrete their granular contents,
generate positive feedback mediators and form stable platelet
aggregates. In addition, various G-protein-mediated signaling
cascades act in synergy with one another to amplify the magnitude
of the platelet responses. The significance of G-proteins
as key mediators of the platelet function and normal hemostasis
is further corroborated by extensive gene knockout studies.
In this review we will limit our discussion to understanding
the role of G-proteins in the process of platelet activation
and discuss some of the anti-thrombotic drugs that mediate
their beneficial effects by interfering with or preventing
the initiation of the G-protein signaling pathway.
[Back to top]
Phosphotyrosine Signaling in Platelets: Lessons
for Vascular Thrombosis
J.L.K. Wee and D.E. Jackson
Platelet activation is crucial for normal hemostasis
to arrest bleeding following vascular injury. However, excessive
platelet activation in narrowed atherosclerotic blood vessels
that are subject to high shear forces may initiate the onset
of arterial thrombosis. When platelets come into contact with,
and adhere to collagen exposed by damaged endothelium, they
undergo morphological and functional changes necessary to
generate a platelet-rich thrombus. This process is complex
and involves precise co-ordination of various signaling pathways
which lead to firm platelet adhesion to sites of tissue damage,
release of granule contents from activated platelets, platelet
shape change, platelet aggregation and subsequent thrombus
formation and consolidation. Induction of tyrosine phosphorylation
of key signaling molecules has emerged as a critical event
central to stimulatory signaling pathways that generate platelet
activation, but is an essential component associated with
regulatory pathways that limit the extent of platelet activation.
Understanding mechanisms that regulate platelet activation
may contribute to the development of novel therapeutics that
control common vascular diseases such as myocardial infarction
and ischaemic stroke.
[Back to top]
Cyclooxygenase Inhibition and Atherothrombosis
H-Y. Sohn and F. Krötz
Cyclooxygenases represent a major target of pharmaceutical
therapy. Cyclooxygenase inhibitors are applied in order to
reduce inflammation, to relieve from pain, or to prevent atherothrombotic
complications in cardiovascular disease. Inhibition of platelet
aggregation by aspirin, which is due to inhibition of platelet
cyclooxygenase-dependent formation of thromboxane A2, is a
cheap, safe and effective strategy to prevent myocardial infarction
or stroke and is thus the most established strategy of secondary
prevention of atherothrombotic disease. However, the existence
of several isoforms of the cyclooxygenase enzyme, their tissue-specific
expression patterns, their spatial and functional association
with enzymes that further degrade the major cyclooxygenase
products and the specific pharmacological properties of substances
that have the potential of inhibiting cyclooxygenase make
the ultimate physiological effects of a specific cyclooxygenase
inhibitor a highly sophisticated pharmacological question.
Specific inhibitors of the cyclooxygenase-2 isoform (COX-2)
have at first promised to represent a major improvement of
pharmaceutical therapy, but later have been suggested to enhance
the risk of atherothrombotic events in vivo. This
has led to the withdrawal of some of these substances from
global markets and also initiated a discussion as to whether
some non-selective cyclooxygenase inhibitors (non-steroidal
anti-inflammatory drugs, NSAID), such as naproxen would also
have an antithrombotic effect in vivo.
This review summarizes current pathophysiological and clinical
knowledge about the effects on atherothrombosis of drugs that
target cyclooxygenases either as specific inhibitors of a
cyclooxygenase isoform, or as non-specific cyclooxygenase
inhibitors. It specifically discusses the question, whether
all selective COX-2 inhibitors may have an intrinsic risk
of enhancing the risk of atherothrombosis.
[Back to top]
Thrombin Inhibitors and Anti-Factor Xa Agents
in the Treatment of Arterial Occlusion
V. Klauss and M. Spannagl
Cardiovascular disease is the leading cause for mortality
and morbidity in the western world. Arterial thrombosis has
multiple origins and may present with different clinical presentations
such as acute coronary syndromes, stroke, and peripheral embolization.
Furthermore, thrombotic complications may occur during percutaneous
interventions. The underlying causes range from atherosclerosis
with plaque rupture or erosion, embolization, stasis and hypercoagulable
states. Thrombotic complications lead to activation of the
intrinsic coagulation system and to platelet aggregation.
Despite the development of effective platelet inhibitors,
there is still the need for an optimal anticoagulation regimen.
While unfractionated heparin is the most commonly used antithrombotic
agent, which has major inherent limitations. Direct thrombin
inhibitors and anti factor Xa agents are agents which may
overcome the limitation of unfractionated heparin. The potential
advantages of these new compounds are discussed on the basis
of available clinical data in patients with coronary artery
disease.
[Back to top]
Editorial
These are exciting days for physicians treating patients
with Lymphoma. The introduction of chemotherapy has resulted
in dramatic improvement of outcome in the early 1970s, when
the diagnosis of leukaemia or lymphoma meant a death warrant
in the vast majority of cases. However, variation of chemotherapeutic
components and increasing the dose during the following decades
of research has only resulted in small additional benefits
– a notable exception is Hodgkin’s disease which
can be cured by aggressive polychemotherapy regimens in most
cases. Therefore, chemotherapy regimens of the early days
like CHOP still remained the gold standard for lymphoma therapy
at the beginning of this century. The same was true for many
other haematological diseases with very view improvements,
if any, in terms of survival for most patients.
Beginning with the success story of the tyrosine kinase inhibitor
Imatinib in CML, strong efforts have been made to treat haematological
malignancies with more specific drugs which are directed against
cell surface molecules, signal transduction pathways or the
cell cycle. This special issue of current drug targets, entitled
“Beyond chemotherapy: future directions in lymphoma
treatment” contains reviews dealing with very
exciting fields of clinical and preclinical research in the
field of targeted therapy in malignant lymphoma.
The issue starts with a review in which the current status
of radioimmunotherapy is presented by Bruce Cheson. Another
approach to enhance cytotoxic activity of monoclonal antibodies
is to add a plant or bacteria toxin – available data
are summarized in the following paper by Kreitman and Pastan.
The next review by Winkler et al, nicely illustrates the interplay
of genetics, gene expression and targeted therapy using B-CLL
as a prototype disease.
Like BCR-ABL in CML, NPM-ALK is an oncogenic tyrosine kinase
which is involved in lymphomagenesis. The review of Miething
and colleagues describes the efforts to better understand
and finally target this oncogenic event. The BCL-10/MALT-1
pathway is another signal transduction pathway which is involved
in lymphomagenesis and might be a promising drug target as
reviewed by Jost and coworkers. A real success story of targeted
therapy is described by Mitsiades et al. Proteasome inhibition
has already been shown to be a very effective treatment approach
in multiple myeloma and is just being tested in lymphoma treatment
as well. In contrast to cytotoxic chemotherapy, drugs targeting
the cell cycle might be able to stop disease progression or
maintain remissions for prolonged periods of time. Ringshausen
and coworkers present preclinical and clinical data currently
available. Another promising approach is to modulate pro-
and antiapoptotic mechanisms in cancer and lymphoma as reviewed
by Meiler and Schuler. Last but not least, considerable progress
has been made in bringing immnotherapeutic approaches from
bench to bedside. Different strategies including active and
passive immunotherapy are reviewed by Kofler and colleagues
at the end of this issue.
Taken together, these nine reviews present current research
dealing with new drug targets in lymphoma treatment. Some
of the therapeutic approaches presented in this issue will
likely alter the way we treat lymphoma in the future.
Thomas Decker
TU München
IIIrd Departement of Medicine
Ismaninger Str.22
81675 München Germany
and
Schwerpunktpraxis für Tumortherapie
88250 Weingarten
[Back to top]
Radioimmunotherapy of Non-Hodgkin’s Lymphomas
B.D. Cheson
The availability of active monoclonal antibodies has
altered the treatment paradigms for patients with non-Hodgkin’s
lymphomas (NHL). Nevertheless, some patients do not respond,
while almost all of the others eventually relapse and require
additional treatment. Thus, more effective alternatives are
needed. Radioimmunotherapy (RIT) is an attractive option because
of the inherent radiosensitivity of most NHL. Yttrium-90 ibritumomab
tiuxetan and iodine-131 tositumomab are the first two radioimmunoconjugates
currently available for clinical use. These agents appear
comparably active in patients with follicular and low-grade
NHL after failure following chemotherapy and/or rituximab.
Activity has also been demonstrated against other histologies,
including diffuse large B-cell NHL, mantle cell NHL, and transformed
NHL. Toxicities primarily include myelosuppression, with a
potential risk of treatment-associated myelodysplastic syndrome
and acute myelogenous leukemia. Current clinical trials are
attempting to optimize the use of these agents by evaluating
them earlier in the course of the disease, and sequenced with
a variety of chemotherapy regimens. Hopefully, the rational
development of RIT will lead to a prolongation of survival
for patients with NHL.
[Back to top]
Immunotoxins in the Treatment of Hematologic
Malignancies
R.J. Kreitman and I. Pastan
Immunotoxins, composed of protein toxins connected to
cell binding ligands including monoclonal antibodies and growth
factors, have been developed for several decades to target
hematologic malignancies. Protein toxins from either plants
or bacteria are extremely potent based on their enzymatic
inhibition of protein synthesis and induction of apoptosis.
Plant toxins, particularly ricin, are useful for chemically
conjugating to monoclonal antibodies, and have shown clinical
activity in several types of lymphoma and leukemia. Their
dose is generally limited by vascular leak syndrome. Bacterial
toxins have been used to produce single chain fusions with
either growth factors or recombinant antibody fragments. These
agents are smaller in size (55-65 kDa) and exit the bloodstream
much more rapidly than the chemical conjugates, and generally
do not cause severe vascular leak syndrome. The only approved
drug containing a protein toxin is denileukin diftitox, a
fusion of human interleukin 2 with truncated diphtheria toxin.
Denileukin diftitox has shown efficacy in cutaneous T-cell
lymphoma, chronic lymphocytic leukemia, and non-Hodgkin's
lymphoma. Recombinant immunotoxin BL22 is an anti-CD22 Fv
fragment fused to truncated Pseudomonas exotoxin; it induces
complete remissions in a high percentage of patients with
chemoresistant hairy cell leukemia. The anti-CD25 recombinant
immunotoxin LMB-2 is active in several CD25+ hematologic malignancies.
Several other recombinant immunotoxins are undergoing preclinical
development for other target antigens expressed on hematologic
malignancies.
[Back to top]
Genetics, Gene Expression, and Targeted Therapies
in Chronic Lymphocytic Leukemia
D. Winkler, H. Döhner and S. Stilgenbauer
Chronic lymphocytic leukemia (CLL) represents the most
common leukemia among adults in the Western countries. CLL
is a remarkably diverse disorder following an extremely variable
clinical course. Some patients have an indolent disease that
may never require treatment. In others a progressive clinical
course is rapidly fatal. CLL affects mainly elderly individuals,
but about a third of patients are less than 60 years of age
at diagnosis. Traditionally, the therapeutic procedures were
aimed at palliation, but over the recent years highly effective
and potentially curative approaches such as combined antibody-chemotherapy
and autologous or allogeneic stem cell transplantation have
been developed. In parallel there has been progress in the
understanding of pathogenesis and outcome prediction. The
cornerstones to estimate prognosis are the clinical staging
systems of Rai and Binet. To refine outcome prediction for
individual patients there has been intensive work on biological
factors of potential prognostic relevance. Among these, the
genetic characteristics of the CLL cells that can be divided
into genomic aberrations and the mutation status of the variable
segments of immunoglobulin-heavy chain genes (VH) have attained
considerable importance. In addition, data on gene expression
of CLL cells are accumulating which further characterize the
CLL subgroups. In this context, the expression of ZAP-70 has
been recognized a useful surrogate marker to predict the VH
mutation status and outcome of CLL patients. At present, targeted
therapies are focused on humanized antibodies that bind proteins
expressed on the surface of CLL cells. The most prominent
agents of these are the anti-CD52 antibody alemtuzumab and
the anti-CD20 antibody rituximab, which are currently being
tested in clinical trials. To identify CLL-specific gene expression
products as candidates for targeted therapies will be an important
part of CLL research in the next years.
[Back to top]
Targeting the Oncogenic Tyrosine Kinase NPM-ALK
in Lymphoma: The Role of Murine Models in Defining Pathogenesis
and Treatment Options
C. Miething, C. Peschel and J. Duyster
Oncogenic tyrosine kinases play a ever growing role in
the pathogenesis of human malignancies. In human non-hodgkin
lymphomas, the NPM-ALK oncogene arising from the t(2;5) chromosomal
translocation represents the most important oncogenic tyrosine
kinase identified so far. The ALK-kinase is constitutively
activated by NPM-induced dimerization and signals through
a multitude of growth promoting and antiapoptotic pathways.
Murine models have made a significant impact on the elucidation
of the molecular pathogenesis and new treatment options of
malignant diseases. Here, the latest developments in the analysis
of NPM-ALK induced lymphomagenesis by murine models is reviewed.
[Back to top]
The Bcl10 / Malt1 Signaling Pathway as a Drug
Target in Lymphoma
P. Jost, C. Peschel and J. Ruland
The development of lymphomas and leukemias is frequently
caused by chromosomal translocations that deregulate cellular
pathways of differentiation, proliferation or survival. The
molecules that are involved in these aberrations provide rational
targets for selective drug therapies. Recently, several disease
specific translocations have been identified in human MALT
lymphoma. These aberrations either upregulate the expression
of BCL10 or MALT1 or induce the formation of API2-MALT1 fusion
proteins. Genetic and biochemical experiments identified BCL10
and MALT1 as central components of an oligomerization –
ubiquitinylation – phosphorylation cascade that activates
the transcription factor NF-κB
in response to antigen receptor ligation. Deregulation of
the signaling cascade is directly associated with antigen
independent MALT lymphoma growth. Here we provide an overview
of the physiological and pathological functions of BCL10 /
MALT1 signal transduction and discuss the potential of this
pathway as a drug target.
[Back to top]
Proteasome Inhibition as a New Therapeutic Principle
in Hematological Malignancies
C.S. Mitsiades, N. Mitsiades, T. Hideshima, P.G. Richardson
and K.C. Anderson
The intracellular concentration of proteins in both normal
and tumor cells are regulated by the balance between the rates
of protein synthesis vs. degradation. The ubiquitin-proteasome
pathway is the main intracellular cascade for controlled degradation
of proteins and has attracted in recent years major interest
not only because of its biochemical complexity and the intricate
regulation of its function, but also because diverse cell
cycle regulators and modulators of apoptosis are subject to
regulation by proteasome function, and can therefore be significantly
affected by small molecule inhibitors of the proteolytic activity
of the proteasome. In fact, bortezomib, the prototypic member
of this class of agents, was recently approved by the U.S.
Food and Drug Administration for the treatment of advanced
multiple myeloma patients. This review article focuses on
the exciting recent progress in the use of proteasome inhibitors,
with emphasis on the bench-to-bedside research effort which
provided the foundation for clinical development of bortezomib
for the treatment of multiple myeloma, as well as other hematologic
malignancies, such as mantle cell lymphoma.
[Back to top]
Cell Cycle Inhibition in Malignant Lymphoma:
Disease Control by Attacking the Cellular Proliferation Machinery
I. Ringshausen, C. Peschel and T. Decker
Disruption of a proper regulation of cell proliferation
can ultimately cause cancer. Most human B cell malignancies
are driven by chromosomal translocations or other genetic
alterations which directly affect the function of critical
cell cycle proteins, such as cyclins and cyclin-dependent
kinases. In addition, the transformation of indolent lymphomas
into aggressive malignancies is often accompanied by a loss
of tumor suppressors controlling important cell cycle checkpoints.
A better understanding of cell cycle deregulations in human
tumors has promoted the introduction of a new class of antiproliferative
drugs into cancer therapies. These drugs exert their function
by specifically blocking important cell cycle proteins. In
the present review we discuss how alterations in the cell
cycle control contribute to the malignant transformation of
B cells. Furthermore, we provide an overview of novel direct
and indirect cell cycle inhibitors and their impact on the
treatment of patients with B cell lymphomas.
[Back to top]
Therapeutic Targeting of Apoptotic Pathways in
Cancer
J. Meiler and M. Schuler
Programmed cell death (apoptosis) is a key tumor suppressor
mechanism. Consequently, most if not all cancers develop mechanisms
to abolish or circumvent this genetic program. Besides enabling
malignant transformation and tumor progression, defects in
apoptosis can result in resistance to cytotoxic cancer therapies.
Much progress has been made in the delineation of the molecular
pathways leading to apoptosis. This allows the identification
of target molecules and lead compounds to develop novel therapies,
which make use of this intrinsic death program for the treatment
of cancer. Here, we review the current understanding of apoptotic
signal transduction pathways, and strategies of their therapeutic
modulation in relation to lymphoma and other cancers.
[Back to top]
Current status of Immunotherapy in B Cell Malignancies
D.M. Kofler, C. Mayr and C.-M. Wendtner
Conventional treatment of hematologic malignancies mainly
consists of chemotherapeutic agents or a combination of both,
chemotherapy and monoclonal antibodies. Despite recent advances,
chemotherapeutic treatments often remain unsatisfying due
to severe side effects and incomplete long-term remission.
Therefore the evaluation of novel therapeutic options is of
great interest. B cell malignancies, in particularly follicular
lymphomas, chronic lymphocytic leukemia and multiple myeloma,
represent the most immune-responsive types of all human cancer.
Several immunotherapeutic strategies are presently employed
to combat these B-cell malignancies. Active immunotherapies
include vaccination strategies with dendritic cells (DCs)
and genetically-modified tumor cell preparations as well as
DNA and protein vaccination. Most of these vaccines target
the tumor-specific immunoglobulin idiotype and have already
demonstrated some anti-lymphoma activity in early phase clinical
trials while their definitive impact is evaluated in ongoing
phase III randomized trials. In contrast to these active immunizations,
T cells transduced with chimeric antigen receptors and donor
leukocyte infusions (DLI) represent adoptive (passive) immunotherapies.
Recent advances of gene transduction technologies enabled
improvement of immunotherapeutic strategies based on genetic
modification of malignant cells or adoptive T cells. Current
early phase clinical trials are investigating the potential
of these innovative approaches. At the moment it remains unclear
if the novel immunotherapeutic strategies will be able to
play a similar role in the treatment of B cell malignancies
than the already established antibody-based immunotherapy.
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