Meeting Report
45th Annual Meeting of
the Italian Cancer Society
Bergamo, 9-12 November, 2003
Raffaella Giavazzi1, Massimo Aglietta2, Annalisa Astolfi3, Anna Falanga4, Alfredo Fusco5, Roberto Labianca6, Pier Luigi Lollini3, Claudio Lombardo7, Pier Giorgio Natali8, Marco A. Pierotti9, Marco Presta10, Massimo Santoro5, Giulia Taraboletti1, Gabriella Zupi8, Giancarlo Vecchio5.
1Dipartimento di Oncologia, Istituto di Ricerche Farmacologiche Mario Negri, Bergamo
2Cattedra
di Oncologia Medica, Università di Torino
3Dipartimento di Patologia Sperimentale, Università di Bologna
4 Divisione
di Ematologia, Ospedali Riuniti, Bergamo
5Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università Federico II, Napoli
6Dipartimento di Oncologia, Ospedali Riuniti, Bergamo
7Ambasciata
Italiana in Belgio, Lussemburgo e NATO, Brussels
8Dipartimento di Oncologia Sperimentale, Istituto Regina Elena, Roma
10Dipartimento di Scienze Biomediche e Biotecnologie, Università di Brescia
The session chaired by G. Vecchio (University Federico II, Napoli), President of the SIC and H. Grunike (University of Innsbruk, Austria), President of the European
Association for Cancer Research (EACR) was opened by S. Garattini (Mario Negri
Institute, Milano) who reviewed the
anti-cancer agents introduced into clinical practice in the last few years. He
pointed out that the recent spectacular advances in molecular biology have
provided a completely new approach to cancer therapy. By knowing many of the
molecular events, which are altered in certain types of cancer, pharmacological
research, can focus on finding inhibitory drugs selective for the altered
molecules and not just targeting proliferating cells. However Garattini
underlined that, surprisingly, in spite of the great advances of cancer
molecular biology only a few drugs, licensed up to the end of the year 2000,
are based on the concept of targeting the products of genes which are
specifically altered in tumour cells. Tumour cell heterogeneity, their
plasticity and the poor blood supply of the solid tumours are probably among
the main problems that have impaired the development of many new drugs.
Although the overall outlook is disappointing, an array of new approaches is
now available in cancer pharmacology to meet the challenge of these obstacles.
C. Lombardo (Italian Embassy, Brussels) discussed the prospective of the
finance research activity in Europe. In the Sixth Framework Programme, under
the specific heading "combating cancer", the total budget allocated is
400 million euros. Certainly, cancer research should also benefit from other
contributions available under Priority 1: "Life sciences, genomics and
biotechnology for health" or under the Priority 2: "Information
Society Technologies". A great effort is mandatory to get to know and to
be able to exploit all of the FP6 possible facets that may otherwise go
unnoticed. The priority 8: “Specific activities covering a wider fields of
research”, the ERA-NET, the research training networks of the Host-driven actions
in the Marie Curie scheme and the possibility to set up integrating activities
among research infrastructures are only few examples of “other possibilities”
that should be investigated. These actions could favour in Italy a process that
will help the Country to look with confidence the objective foreseen by the
Lisbon Council "to becoming the most competitive and dynamic knowledge
based economy in the world by 2010". The European cancer societies should
adapt their mandates to meet the globalisation challenges and should play a
major role in the building process of the European Research Area (ERA).
In a following Round Table J. Meldolesi (Vita Salute San Raffaele, Milano) presented the general atmosphere
in which Academy interfaces with Industry and A. Noseda (Sigma Tau, Roma),
on behalf of the Biotechnology Group of Farmindustria, proposed a more
integrated collaboration between Academy and Industry focusing in translating
laboratory science to clinical intervention and promoting technology transfer.
The discussion was chaired by L. Santi
(ISO, Genova) and S. Dompé (Dompé S.p.A., Milano).
The complete sequencing of the
3-billion base-pair human genome has opened a new era for molecular oncology.
Although classical genetics has been a powerful tool for dissecting molecular
diseases caused by mutations in single genes, such a strategy proved to be less
fruitful for diseases like cancer that are controlled by many genes whose
alterations comprise both qualitative and/or quantitative changes. Based on the
notion that many of the protein products of the so-called oncogenes or
tumour-suppressor genes are signalling molecules, the systematic analysis of
the differential expression of such genes between normal and tumour tissues
(i.e. the functional genomic approach), has become one of the most widely used
strategies for discovering the molecular circuitry underlying cancer. Several
methods have been developed to study differential gene expression at the mRNA
(genomic) or protein (proteomic) level. We are clearly at a transition point,
moving from empirical to molecular medicine and making “tailored treatment” of
cancer a reasonably close reality. These arguments have been the focus of the
“Oncogenomics and Proteomics” symposium. The Meeting was opened by a
videoconference held by E. C Kohn (NCI, Bethesda, MD) focusing on
fascinating novel approaches to cancer biomarkers discovery. Her approach
starts from the knowledge that degradation and cleavage of proteins in cancer tissues
generate fragments small enough to enter the blood and produce diagnostic
traces. Such low-molecular-weight blood proteome can be studied by analysing
carrier proteins (acting as magnets to accumulate low-abundance biomarkers) by
surface-enhanced laser desorption and ionization time-of-flight (SELDI) mass
spectroscopy. E. Kohn showed proof-of-principle examples, dealing in particular
with ovarian cancer. Indeed, appropriate algorithms can identify blood cluster
patterns that segregated cancer from non-cancer patients, justifying the use of
proteomic pattern technology as a screening tool.
Bioinformatics is
essential for novel unbiased and high-throughput approaches to pinpoint gene
and protein patterns in cancer patients. In his lecture, A. Califano (Columbia University, New York)
introduced a novel pattern-discovery technique for the analysis of microarray
data. His approach proved to be efficacious for the identification of subtle
signatures in microarray data. He showed that restricting the genetic pool only
to specific, functionally related genes, significantly improves patterns
identification.
Examples of gene profiles
determination were then given by the other speakers. C. Sotiriou (Free University,
Brussels) showed how, in the case of breast cancer, expression signatures
discriminated estrogen receptor status, refined cancer prognosis better than
the classical parameters (e.g. St. Gallen criteria), and predicted treatment
response to anthracycline and taxanes. In the same disease context, I. Zucchi
(ITB-CNR, Milano) reported the
identification of genes that are exclusively expressed in the tumoural mammary
epithelium and associated to tumour progression. His group approached the
problem by manual microdissection to obtain cells from invasive ductal
carcinoma (IDC) of the breast and its nodal metastases. From this material they
have prepared SAGE-libraries and by comparing at first IDC SAGE library versus
non-tumoural and non-displastic cell SAGE libraries, they have identified 227
statistically significant differences, now under further analysis. M. Gariboldi (INT and FIRC Institute of
Molecular Oncology, Milano) has shown how microarray-based gene expression
patterns identify sets of genes specific for the different histological types
of sarcomas and, as in the case of synovial sarcoma, this technique discloses
new classes across the tumour subtype (mono or biphasic) and the type of
translocation (Syt with SSX1 or SSX2). A.
Astolfi (University of Bologna) has
exploited a model of mammary carcinogenesis in p185neu-transgenic mice to
identify expression profiles that occur and change during mammary carcinoma
progression and following immune prevention by active vaccination. Novel
genomic approaches are not solely based on gene expression profiling but also
on high-throughput genome screening to identify gene translocations. E. Lualdi (INT, Milano) has shown an elegant multicolour spectral karyotyping
(SKY) approach to identify cytogenetic changes in epithelioid sarcoma, a soft
tissue tumour of uncertain origin occurring in the distal extremities of young
adults. Her findings identified breakpoints pointing to the presence of key
gene/s for the pathogenesis of this sarcoma on the long arm of chromosome 22.
Back to proteomic approaches, M. Simmaco (University La Sapienza, Roma) has shown how combined 2D
electrophoresis and matrix-assisted laser desorption/ionization (MALDI-TOF)
mass spectrometry identifies specific patterns for nodular hyperplasia of the
thyroid and for chronic liver disease in HCV-infected patients. L. De Monte (San Raffaele, Milano)
showed the identification of specific colon tumour associated antigens (TAAs)
in serum by SERPA (SERological Proteome Analysis), that combines serology with
2D-electrophoresis and mass spectrometry. Finally, R. Sgarra (University of Trieste) presented a notable example of
how new technologies can be used, not solely to generate patterns and gene
lists, but also to address the molecular function of cancer-relevant proteins.
High levels of HMGA proteins characterise the chromatin of cancer cells. He
showed a systematic approach based on yeast 2-hybrid, affinity chromatography,
2D-gel electrophoresis and mass spectrometry to identify HMGA partners and
elucidate the role of these proteins in cell transformation.
A general take-home message emerging
from this interesting symposium is that it is the right time now to move beyond
gene listing and get down to the biology by
using sophisticated algorithms to focus on specific
gene networks and by designing experiments to address the function and the
interaction of relevant cancer proteins.
Round Table SIC-AIOM: Chemoprevention from the
bench to the clinic
The session dedicated to
chemoprevention was opened by A. Albini
(IST, Genova) who emphasised the relevance
of the microenvironment in tumour development and progression. She and her
collaborators have analysed the effects of chemopreventive drugs on endothelial
cells (EC), a major constituent of growing
tumours. The effects of anti-oxidant N-acetyl cysteine (NAC), the green tea
flavonoid/epigallocatechin gallate (EGCG) and the synthetic retinoid
4-Hydroxyphenyl-retinamide (4HPR) were determined on ECs and tumour cells and
on xenografts in nude mice. The study has led to the conclusion that angiogenesis
is one of the key targets of chemopreventive drugs. In order to understand the
molecular mechanism by which different drugs yield the same functional outcome,
Dr. Albini and co-workers analysed the drug response of ECs by microarray gene
expression profiling. They showed that 4HPR affects endothelial cell growth and
migration and the invasion of Kaposi’s sarcoma derived cells (KS). This finding
was associated with decreased release of MMP-2 and rapid reduction of VEGF
expression by KS cells and of the VEGF receptor 2 by endothelial cells. They
extended the study to a-lipoic acid, an endogenous liver derived
thiolic anti-oxidant that also showed strong anti-angiogenic activity by a
distinct pathways.
P. Ricchi (University Federico II, Napoli) focused
on the molecular based rationale for the treatment of tumours with
cyclooxygenase (COX) inhibitors. Several in
vivo studies indicate that non-steroid anti-inflammatory drugs (NSAIDs) and
COX-inhibitors inhibit the development of colon cancer. This depends on cell
growth inhibition and induction of apoptosis. It is becoming evident that both
prostaglandin dependent and independent pathways may play a role in the
generation of these effects. Dr. Ricchi and his co-workers evaluated the
effects of aspirin and NS-398 (a COX-2 selective inhibitor) as single agent on
proliferation and survival of the colon adenocarcinoma Caco-2 line.
Subsequently they have evaluated the effects of these treatments on the
responsiveness to topoisomerase inhibitors VP-16 and CPT-11.The data presented
indicate that aspirin, but not NS-398 could increase or reduce the toxicity of
both anticancer drugs. They found also that aspirin protects Caco-2 cells from
apoptosis through the activation of a phosphatidylinositol 3-Kinase/AKT/p21
pathway. Finally, they verified in an in
vivo model the ability of aspirin to induce the activation of AKT protein
in the colonic mucosa.
G. Biasco (Policlinico S. Orsola-Malpighi, Bologna) focused
his talk on the role of COX-2 inhibitors in the chemoprevention of colorectal
cancer. He reminded that animal studies conducted with COX-2 inhibitors
(celecoxib and rofecoxib, originally addressed to the treatment of rheumatic
disease) showed their protective effects against cancer development, in
particular colon cancer. Clinical studies carried out on patients affected by
Familial Adenomatous Polyposis (FAP) showed that the administration of high
dose of celecoxib induces a reduction in the number of adenomas in both colon
and duodenum. Data from three ongoing multicentric international studies should
assess the safety-profile of long-term administration of these agents.
G. Bernardo (Fondazione Maugeri, Pavia) reminded
that presently, Tamoxifen (a selective oestrogen receptor modulator) is the
gold standard in breast cancer chemoprevention and represents the only drug
approved for cancer risk reduction in healthy women at increased risk. In order
to develop other endocrine therapies for breast cancer (BC) with lower rate of
toxicity many studies have been designed such as the MORE study (with
Raloxifene) and the ongoing STAR trial (which directly compares Tamoxifen and
Raloxifene). Another ongoing trial is the comparison of Tamoxifen and
Anastrozole for the treatment of oestrogen-positive ductal carcinoma in situ
(NSABP B-35 trial). Among the most promising chemopreventive agents, Retinoids
(i.e. Fenretinide) have been shown to reduce the incidence of second breast
carcinoma in premenopausal women. A suggested mechanism of action is the
reduction of insulin-like growth factor (IGF)-1, a known risk factor for
premenopausal BC. A large number of new agents, including COX-2 inhibitors are
attractive as potential prevention agents and some of them are already in clinical
testing (new selective SERMs which lack uterine oestrogen agonist activity,
isoflavones and aromatase inhibitors for postmenopausal women;
gonadotropin-releasing hormones for premenopausal women; retinoids and
deltanoids in ER+/tamoxifen-resistant BC). Thousands of patients and several
years are needed to test a single agent; thus, there is a need to develop
clinical trial models to validate surrogate endpoint biomarkers as indicators
of efficacy.
Symposium: Epigenetics and cancer
The session was opened by P. Sassone Corsi (CNRS-IGBMC,
Strasburgo) who highlighted that the histone phosphorylation represents a
direct link between chromatin remodelling and intracellular signalling
pathways. Specific, conserved serine residues are present on the N-terminal
tails of each histone. These are phosphoacceptor sites for a number of kinases,
whose identification is essential to decipher the transduction routes leading
to various physiological responses. The chromosomal passengers aurora-B kinase,
INCENP and survivin, are essential proteins that have been implicated in the
regulation of metaphase chromosome alignment, spindle checkpoint function and
cytokinesis; they form one complex. He showed
that phosphorylation of survivin at threonine117 by aurora-B may regulate targeting of survivin, and
possibly the entire passenger complex, in mammals.
P. G. Pelicci (IEO, Milano) discussed
the possibility of an innovative therapy of the acute promyeloctic leukemias
carrying the PML-RAR translocation, based on the recent acquisition on the
function of the PML-RAR, that would be able to recruit aberrant quantities of
histone deacetylase complexes. Therefore the use of inhibitor(s) of HDAC is
proposed as a new therapeutic approach.
M. Negrini (University of Ferrara) showed that hypermethylation can be used as
a diagnostic tool. Methylation specific PCR allows the detection of aberrant
hypermethylation not only in tumour specimen, but also in body fluids with high
sensitivity and specificity. Since hypermethylation is an early event in tumour
genesis, it may allow early tumour detection. DNA hypermethylation is also a
potential target for tumour therapy. Subsequently he has shown the example of
KvDMR1 located on 11p15.5 chromosomal region. In human tumours, demethylation
leads to reactivation of the maternal KvDMR1 allele, which in turn represses
various maternally inherited genes.
M. Maio (University of Siena) reported that
deregulated methylation of CpG dinucleotides and aberrant histone acetylation,
may impair the immunogenic potential of cancer cells; in fact, DNA
hypermethylation and/or histone deacetylation contribute to the absent or
down-regulated expression of different components of the “tumour recognition
complex” (i.e. HLA class I antigens, Cancer/Testis Antigens and
accessory/co-stimulatory molecules) in solid and hematopoietic human
malignancies. Pharmacological agents inducing DNA hypomethylation or inhibiting
histone deacetylation can modify these epigenetic phenomena, restoring the
defective expression of selected components of the “tumour recognition complex”
in cancer cells. These antigenic modifications positively modulate the
immunogenicity and the immune recognition of cancer cells, making epigenetic
drugs attractive agents to design new combined chemo-immunotherapeutic
strategies for the treatment of cancer patients.
M. Zanon (INT, Milano)
investigated Apaf-1
levels in malignant melanomas and melanocytic lesions. Western blot and
immunofluorescence analysis in primary and metastatic melanoma cell lines, in comparison
to adult melanocytes, showed a heterogeneous expression of Apaf-1 and the
absence of correlation between loss of Apaf-1 expression and tumour
progression. Interestingly, these changes in Apaf-1 expression do not modify
the cell susceptibility to apoptosis.
A. Catalano (University
Politecnica delle Marche, Ancona) showed results that delineate a novel role of Sema-3A in VEGF function mediated
by p38 MAPK, and suggested that the abrogation of regulated Sema-3A expression
is responsible for VEGF-driven growth of tumour cells.
M. Rusnati (University of Brescia) demonstrated
that Tat/avb3 interaction occurs with high affinity. This
interaction leads to endothelial cell adhesion to immobilised Tat and to the
assembly of focal adhesion contacts with the recruitment of Tat receptors,
cytoskeleton components, and second messengers. Linear and cyclic
RGD-containing peptides and the RGD-peptidomimetic compound SCH221153
effectively block endothelial cell adhesion to immobilised Tat. These results
identify Tat/avb3 interaction as a potential target for the
development of Tat antagonists with possible therapeutical implications.
Poster Discussion: Invasion, metastasis
& angiogenesis
The discussion on “Invasion,
metastasis & angiogenesis” chaired by G.
Taraboletti (Mario Negri Institute,
Bergamo) and M. Presta (University of Brescia), allowed young
scientists to present and discuss their most recent findings. Selected topics
on “tumour angiogenesis” and “metastatic process” were chosen on the basis of
the 50 scientific communications displayed on the poster boards.
Data were presented concerning gene
expression profile in endothelial cells when stimulated by pro-angiogenic
factors or when inhibited by angiostatic molecules, several of them being
natural compounds with putative chemopreventive action. The hypothesis that
metronomic therapy may inhibit angiogenesis via thrombospondin-1 upregulation
was raised. Novel modulators of the angiogenic process, including pentraxin-3
and PDGF-BB, were shown to interact with the pro-angiogenic FGF2, thus
affecting its biological activity in
vitro and in vivo. Interesting
observations were reported describing functional and morphological alterations
of tumour vasculature following angiogenic growth factor expression or silencing
in novel models of tumour angiogenesis. The discussion focused also on possible
functional differences in tumour vasculature among different tumour regions,
including the invasive front. The heterogeneity of tumour endothelium in
response to angiostatic and/or vascular targeting therapies was addressed.
The relationship between tumour
angiogenesis and metastatic spread was introduced by studies aimed at
characterising the interaction of tumour cells with endothelium, its effects on
tumour cell behaviour, and the identification of possible inhibitors, including
heparin.
The mechanisms modulating tumour
cell movement and invasive potential were the focus of several studies. To this
end, modulation of microtubule dynamics by stathmin, the role of laminin
receptor, integrins, and proteases in cell invasion and movement represented
the basis for discussion. Finally, the molecular mechanisms of tumour
progression and acquisition of the metastatic phenotype were addressed by
different groups. In particular, the characterisation of a truncated tyrosine
kinase Ron receptor and the role of the transcriptional repressor PLZF in
tumour progression were described.
The whole section was characterised
by the quality of the communications and by the enthusiasm of the young
participants, an indication of the high scientific standards of basic and translational research
at SIC.
Symposium: Inflammation and cancer
The first lecture by A. Sica (Mario Negri Institute, Milano) dealt with the phenotype of tumour infiltrating
macrophages (TAM). It is known that helper T cells give rise to dichotomic
responses that are classified as “type I”, mainly based on the production of g-interferon (IFN-g), or as “type II”, based on the
production of interleukin 4 (IL-4), IL-13 and other cytokines. It is now known
that macrophages, like helper T cells, come in two flavours, a type I (or M1)
cell, following exposure to IFN-g, and a type II (or M2, or
“alternatively activated”) cell, following exposure to IL-4. The work of Sica and
co-workers with immunological and microarray technologies showed that
macrophages and dendritic cells associated to the tumour microenvironment (TAM
and TADC, respectively) are mainly characterised by a type II phenotype that
entails a poor antigen presenting capacity, low IL-12 release, and the
production of prostaglandins, IL-10 and TGF-b that suppress T cell activation. In
conclusion the type II phenotype of TAM favours tumour growth and promotes
tumour progression and metastasis. A review on this subject can be found in the
September-October 2003 issue of Tumori
(Mantovani et al., Tumori, 89: 459,
2003).
T. A. Dragani
(INT, Milano) examined the
relationships between the pulmonary adenoma susceptibility locus 1 (Pas1) and
inflammation using two lines of outbred mice selected for differential acute
inflammatory responses (AIR). AIRmin mice have a low acute inflammatory
response, but develop persistent subacute inflammation, and have a higher
incidence of lung tumours than AIRmax mice that in turn have a high, but
transient inflammatory response. AIRmin mice have the Pas1s allele, while
AIRmax have the Pas1r allele, thus suggesting that Pas1 controls lung
carcinogenesis through the generation of inflammatory responses. Candidate
genes in the Pas1 region include Kras2 and four other genes.
V. Bronte (University of Padova) described a
different cell type endowed with suppressive activity on antitumour responses.
The expansion of a myeloid subpopulation of cells expressing CD11b and Gr-1 is
frequently observed in mice bearing the TS/A mammary carcinoma and other poorly
immunogenic tumours. The in vitro
isolation and characterisation of Cd11b+ Gr-1+ cells
showed that, in response to signals from activated T cells, they upregulate
arginase 1 and nitric oxide synthase 2, two enzymes involved in the degradation
of arginine and in the production of nitric oxide. Treatment with specific
enzyme inhibitors abolished their suppressive function, resulting in the
restoration of T cell cytolytic activity.
L. Rivoltini
(INT, Milano) dealt with methods to
optimally activate and differentiate dendritic cells (DC) in vitro in view of therapeutic protocols based on the
administration of autologous, antigen-primed DC to cancer patients. Rivoltini
showed that adherent peripheral blood monocytes are a better starting
population than CD14+ sorted monocytes because a proportion of CD16+
NK cells is retained with monocytes. Exposure of maturing DC and NK cells to
IFN-a
promotes a cellular cross-talk and results in an “intermediate” degree of
maturation of DC that coincides with an optimal ability to present tumour
antigens to T cells.
A. Naldini (University of Siena) discussed in
detail the role of a-thrombin in the regulation of inflammatory
responses. In addition to its central role in coagulation, a-thrombin inhibits the release of
IL-12 and IFN-g by
peripheral blood mononuclear cells. Analogous results were obtained with
agonists of the thrombin-activated receptor PAR-1, whereas anticoagulants promoted
the release of IL-12. The inhibition of IL-12 and IFN-g release were mediated, at least in
part, by IL-10.
A novel way to target tumour
necrosis factor a (TNF-a) to neovasculature in
tumour-bearing mice was shown by L.
Borsi (INT, Genova). A fusion
protein (L19mTNFa) was
constructed between mouse TNF-a and a high affinity antibody fragment (L19) to
the extra-domain B (ED-B) of fibronectin that is highly expressed by tumour
neovasculature. L19mTNFa administration to tumour bearing mice resulted
in the accumulation of therapeutic doses of TNF-a at the tumour site and
significantly delayed tumour growth in preclinical tumour models. As TNF-a in humans is used for cancer
therapy in isolated limb perfusion in combination with melphalan, Borsi showed
that, preclinical models, the association of melphalan with L19mTNFa is more effective in than
recombinant TNF-a plus
melphalan.
The session was concluded by a
lecture by F. Balkwill (Queen Mary’s School of Medicine, London) on the role of
inflammatory cytokines in tumour progression. TNF-a is usually considered an antitumour
cytokine, however many human tumours produce TNF-a, and its production may be
associated with a poor prognosis. In fact TNF-a may induce growth and angiogenic
factors, promote tumour invasiveness and trigger the release of proteases like
MMP-9 by TAM. TNF-a and
TNF receptor knockout mice are resistant to diphasic DMBA/TPA-induced skin
carcinogenesis, and TNF-a acts as an endogenous tumour promoter.
Treatment of normal mice with anti-TNF antibodies inhibited skin
carcinogenesis. In the second part of her talk Balkwill focused on the role of
chemokines and chemokine receptors in tumour growth and metastasis. The
recruitment of leukocyte infiltrate by tumours is regulated by the chemokine CCL5/RANTES,
and the treatment of mice with CCL5 antagonists slowed tumour growth, decreased
the percentage of TAM and slightly increased that of CD8 cells, induced tumour
necrosis and increased the area occupied by stromal cells. Chemokine receptors
are also expressed by malignant tumour cells, and the respective ligands
attract metastatic tumour cells to common sites of dissemination. The chemokine
receptor CXCR4 is frequently expressed in human tumours. Transfection of
ovarian tumour cells with CXCR4 resulted in increased invasion and metastatic
spread in nude mice. Such findings suggest that agents that modulate either
inflammation or chemokine activity on tumour cells could be a novel class of
antitumour drugs.
Symposium: Multiple approaches in cancer therapy
Novel retinoids are being
synthesised with the purpose of exploiting the powerful anticancer properties
of natural retinoids; resistance and toxicity are issues that currently limit
their clinical application. E. Garattini
(Mario Negri Institute, Milano) presented preclinical data on
bis-indols, a novel class of compounds that sensitise leukemia cells to the
cyto-differentiating activity of ATRA, and on ST1926, a novel retinoid-related
molecule endowed with powerful pro-apoptotic activity mediated by its ability
to transactivate RARa, activate the p38 and JNK/MAPK modules, and
inhibit the mitochondrial calcium uptake. M. Milella (IRE, Roma)
presented evidence that the MEK/ERK module is a promising therapeutic target in
AML. Indeed, MEK inhibitors, which are currently being tested in a clinical
setting, selectively exert growth-inhibitory and pro-apoptotic effects on AML
cells, but not on normal hematopoietic progenitors. Most interestingly, these
compounds efficiently and selectively sensitise leukaemia cells to suboptimal
doses of other apoptotic stimuli, including classical cytotoxics (nucleoside
analogs, microtubule-targeted drugs, CDDP, g-irradiation), biologicals
(retinoids, interferons, arsenic trioxide) and other signal
transduction/apoptosis modulators (Bcl-2 antagonists, UCN-01, imatinib). In
most instances, these MEK inhibition-based combinations result in a striking
pro-apoptotic synergism in preclinical models.
The EGFR family is also being very
actively pursued as a molecular therapeutic target in many different solid
tumours. N. Normanno (Fondazione Pascale, Napoli) reviewed the field of
preclinical and clinical EGFR targeting, highlighting the promise and pitfalls
emerged from early clinical trials of these agents. In particular, constitutive
activation of cytoplasmic kinase-based signalling pathways is emerging as a
possible way for tumours to escape EGFR inhibitor-mediated cell growth
inhibition and apoptosis. Normanno presented original data identifying the
activation of the PI3K/AKT and MEK/MAPK pathways as mediators of resistance to
EGFR-targeted agents in preclinical models. Along these lines, G. Valabrega (University of Torino) presented data indicating that clinical
resistance to Trastuzumab in breast cancer may be related to the activation of
a TGF-a
autocrine loop, rather than to intrinsic defects in the HER-2 degradation
machinery. Finally, A. Azzariti (INT, Bari) presented interesting
preclinical data on the scheduling-dependent synergistic pro-apoptotic interaction
between the EGFR inhibitor ZD1839 and SN-38, the active metabolite of CPT-11.
These data, indeed, indicate that SN-38 followed by ZD1839 is the optimal
sequence to achieve synergistic cancer cell killing, while the opposite
sequence would have antagonistic effects, with obvious implications for the
clinical application of such combinations.
In the second part of the symposium,
S.C. Righetti (INT, Milano) reported on the characterisation of the BBR3464 (a
novel trinuclear platinum complex)-resistant A2780 ovarian cancer cell line and
described the role of MARCKS, PKCa, Bax, MLH1, and PMS2 in the
resistance mechanism. P. Zancai (CRO, Aviano, Pordenone) demonstrated
the cell cycle-inhibitory and pro-apoptotic activity of the carotenoid
mofarotene (Ro 40-8757) against Burkitt’s lymphoma cells. In particular, the
pro-apoptotic activity appears mediated by interference with the mitochondrial
respiratory chain, which leads to ROS accumulation and it is potentiated by
inhibitors of the scavenger enzymes superoxide dismutases, such as
2-methoxyestradiol. A.C. Maggi (University of Milano) described the
latest acquisitions in the biology of estrogen receptor (ER) transcriptional
activation, made possible by the transgenic reporter mouse model ERE-LUC established
by her group. Using this model, she demonstrated that peptide growth factors,
in particular IGF-1, might efficiently induce ER transcriptional activation in
non-reproductive organs in diestrus, when the circulating estrogen levels are
low, as well as in ovariectomized mice, shedding light on the mechanisms of
estrogen-independent ER activation.
Finally, E. Sausville, (NCI, Bethesda,
MD) lectured on the possibility to identify multiple therapeutic targets in
the tumour cells, in the stroma surrounding the tumour, as well as in the
immune system of the host. Simultaneous modulation of multiple targets in each
of these areas is now being made possible by the sequencing of the entire human
genome, by the deeper understanding of the relationships between the tumour
cells and the host microenvironment, and by technical developments in
anticancer drug discovery. E. Sausville, indeed, showed examples of the
combination approaches being pursued at NCI, including combination of
Hsp-90-interacting drugs (such as 17-DMAG) with the PDK-1/AKT inhibitor UCN-01,
combination of CDK inhibitors (such as flavopiridol) and histone deacetylase
inhibitors, novel inhibitors of gene methylation (such as zebularine),
regulators of collagen I elaboration (such as halofuginone), novel immunotoxins
based on RNAses that do not provoke a human immune response to the toxin
conjugate, as well as small molecule regulators of the immune response (such as
5-methyltryptophan).
Overall, the symposium showed very
interesting examples of how the thoughtful and continuing collaboration between
laboratory and clinical scientists is generating novel combined approaches to
cancer therapy that hold great promise for the successful treatment of cancer
patients.
The key lecture in memory of
“Giorgio Prodi” was delivered by P.
Comoglio (University of Torino) who underlined that the invasive growth is a genetic program in which
the Scatter Factor and its receptor (the oncogene encoded Met tyrosine kinase)
are the key players in the control of invasive growth. He then showed that
hypoxia promotes tumour progression towards the malignant phenotype by
triggering the Met-driven invasive program.
Congratulations to the winners of
the SIC award (generously offered by the Fabbrocini family from Naples), M. Sacco (CNR, Milano) and G. Baldassarre (CRO, Aviano, Pordenone), and to the
winners, I. Panzini (Ospedale Infermi,
Rimini) and G. Trecate (INT, Milano), of the “ Tumori” award for the best article
published in 2002. The “Prof. Piero Trivella” award to the best posters
(generously offered by the “Pisana Oncology Association”, from Pisa) was
assigned to F. Andriani, (INT, Milano) and D.
Melisi (University Federico II, Napoli).