ARTICLE
Auteur(s) :, Jean-Yves Blay1, Axel
Le Cesne2, Laurent Alberti1, Isabelle
Ray-Coquart3
1Inserm Unit 590, Centre Leon Berard, 28 rue Laennec,
69008 Lyon, France & Hopital Edouard Herriot, Place d’Arsonval,
69003 Lyon, France
2Institut Gustave Roussy, 94805 Villejuif
3Département de Médecin, Centre Léon Bérard
The term “targeted therapies” refers to treatment strategies
directed against molecular targets considered to be involved in the
process of neoplastic transformation. This is not a new concept in
oncology; hormonal manipulations for the treatment of advanced and
local disease (adjuvant) in breast, prostate, thyroid cancer have
long been studied for their potential benefits.In the past 30
years, the genetic alterations characteristic of neoplastic cells,
such as specific translocations, activating mutations, or gene
amplifications, were described. These have brought considerable
changes to the nosological classification of cancers. The molecular
classification of certain cancers recently permitted to develop and
evaluate a new class of drugs that aim to block, more or less
specifically, the activity of these activating proteins. These new,
“modern” targeted therapies can be divided into different
categories:
- 1) therapies that target molecular defects directly
contributing to the initiation of malignant transformation;
- 2) therapies that target later molecular defects
involved in tumor progression but not in the onset of malignant
transformation;
- 3) therapies that target molecular defects with no
direct mediating effect on cell transformation.
The present document examines examples of each category.
Therapies targeted to molecular defects causative of
cancer
This first category comprises treatments targeted to molecular
alterations directly responsible for malignant transformation. This
is the case, for instance, of alterations of the bcr-abl fusion
gene in chronic myeloid leukemias (CML), or the EWS-Fli1 fusion
gene in Ewing sarcomas, or activating mutations of KIT in
gastrointestinal stromal tumors (GIST).
Both leukemias and GIST now benefit from effective antitumor
treatments using imatinib mesylate (also known as
Glivec®), a recently introduced drug that inhibits two
tyrosine kinase enzymes involved in the malignant transformation,
bcr-abl and KIT [1-4]. The example of GIST will be used as an
illustration for this model [5-10].
GIST are rare tumors that may arise anywhere in the
gastrointestinal tract. Their estimated annual incidence is
approximately 2 new cases per 100,000 people. GIST have been
regarded as a specific nosological entity since their relation with
Cajal cells, the pacemakers that regulate gastrointestinal
motility, has been established. Their phenotype is characterized by
the expression of different markers: CD34 that is also present in
Cajal cells, and mutated and/or activated forms of c-kit
tyrosine-kinase receptor (CD117) [10-14]. These activating
mutations are an early event in malignant transformation; they
might well constitute the oncogenic mechanism causative of the
disease [15-22].
The product of the KIT proto-oncogene, KIT protein, is a
transmembrane receptor with tyrosine-kinase activity mediated by
its physiological ligand, SCF (stem cell factor) [16, 21]. The KIT
gene, located on the long arm of chromosome 4 [16, 21], encodes for
a member of the family of type 3 tyrosine-kinase receptors. KIT
shares extensive structural homologies with macrophage colony
stimulating factor 1 (M-CSF) or platelet-derived growth factor
(PDGF) receptors. KIT mutations belong to two categories [12, 16,
21]: 1) mutations occurring in the regulatory regions that affect
extra-cellular domains of the molecule, or juxta-membrane
dimerization domains, 2) mutations in the kinase domain, generally
in parts of the protein encoded by exon 13 or 17 that generally
have limited sensitivity to imatinib.
These mutations potentially involve different intracellular
signaling pathways that deserve to be explored in the near future
[12, 20-23]. The gene is found mutated in 85 to 90% of GIST where
it spontaneously activates KIT in a ligand-independent manner [12,
21]. These mutations are identified in the germ line of the rare
patients with familial GIST and in a majority of early or advanced
stage tumors [17, 19, 21]. In GIST tumors where no mutation of KIT
has been identified, a constitutive activation of the kinase is
observed [12]. Gene mutations and, more generally, gene activation
might play a key oncogenic role in GIST tumorigenesis. GIST are
frequently associated with KIT mutations in exon 11, and
occasionally in exon 9; mutations are exceptionally found in exons
13, 17, and 14 [11-14, 17-21, 23, 24]. A majority of mutations are
located on each side of the trans-membrane domain of the receptor
that mediates kinase dimerisation after binding to its ligand. The
outcome of GIST patients seems to be related to the type of
mutation even before the advent of imatinib [24-26]. The fact that
these mutations are present in small tumors (< 1cm), as well as
in familial forms of the disease, demonstrates that they are an
early, and possibly causative, genetic event in GIST tumorigenesis
[12, 21]. Yet, other genetic alterations may occur downstream of
these mutations, notably allele alterations and losses in
chromosomes 14, 22, and 1 [23, 25, 27, 28-31]. A recent microarray
expression analysis identified several other genes that were
over-expressed, and potentially activated, in vivo in GIST [23].
Their role in tumor progression remains to be elucidated.
Before the introduction of imatinib, surgery was the only
potentially active treatment for patients with GIST; chemotherapy
was globally ineffective and radiotherapy was not an option. In
2001, the first phase I clinical studies evaluating imatinib in
advanced or metastatic GIST was started, soon followed by phase II
and III trials [4-9]. Available data show that imatinib can induce
60 to 70 % objective responses on conventional radiography
(CT-scan / MRI), with disease stabilization in 15 to 20 % of
the patients and 10 to 15 % primary resistant tumors. PET-scan
functional imaging is probably associated with better and earlier
detection of imatinib efficacy in this disease. Secondary
resistance to the treatment (recurrence after initial response) is
now being reported in 10 to 30 % of the patients, a number of
whom will react positively to secondary treatment with more active,
broader spectrum tyrosine kinase inhibitors, such as SU011248 [34],
or downstream modulators of the PI3K/Akt/mTOR survival pathway
[35].
The one-year survival rate of patients with advanced GIST, that
was approximately 35 % before imatinib, is currently close to
90 % [4-9, 36]. Overall survival, progression-free survival
and response to treatment are related to the type of KIT mutations
found in tumor cells: mutations on exon 11, for instance, and are
associated with more favorable prognosis [32, 33]. Contrariwise, no
antitumor activity of imatinib was observed initially in other
non-GIST CD117-negative sarcomas and/or sarcomas that do not
display mutations associated with the activation of a PDGF
autocrine loop [8], although recently tumor control was observed in
sarcomas distinct from GIST.
Two major phase III studies, both elaborated and realized in
less than 2 years, were reported recently. They compared two daily
doses of imatinib, 400 mg and 800 mg, in respectively 946
and 756 patients with advanced GIST. The trial reported by Rankin
et al. [37] demonstrated no difference between the two arms in
terms of response to treatment, progression-free survival and
overall survival, although a trend favoring the high dose imatinib
arm for progression free survival was observed. Contrariwise, the
study of Verweij et al. [9] that included more patients with
slightly longer follow-up, reported a significant progression-free
survival gain in the 800 mg arm. At 24 months of follow up,
progression-free survival was 55 % in the group of patients
receiving 800 mg imatinib, vs. 40 % in the group receiving
400 mg. From the very beginning, the two studies were intended
to be pooled and data used for a programmed meta-analysis. This
analysis has become more necessary than ever. The molecular biology
of KIT mutations remains a crucial element for treatment prognosis
and response to imatinib, as reported by the US and European groups
[32, 33]. Patients bearing mutations of exon 11 appear to have
higher response rate, progression-free survival and overall
survival than patients with mutations located in exon 9 or any
other part of the molecule [32, 33]. It has also been reported that
activating mutations of PDGFRA could be found in 36 % of GIST
patients presenting no detectable mutation of kit. The presence of
PDGFRA exon 18 point mutations, notably mutation D842V, was
associated with no response to imatinib [20].
GIST now serve as a model in solid tumor oncology; they were the
first solid tumors ever treated by drugs specifically targeted to
the molecular cause of tumor development. Only few other tumor
models have benefited from this type of therapy: CML [1-3], chronic
myelomonocyte keukemia (CMML) characterized by a translocation
involving PDGF receptor [38], Darier-Ferrand dermatofibrosarcoma
associated with complex chromosomal rearrangements involving the
beta chain of [39-41], and some hypereosinophilic syndromes
[42].
These reports are consistently point out the fact that, when the
molecular alteration is involved in tumor formation, targeted
oncogene therapy used alone has strong antitumor activity.
Targeted therapies against “late” molecular events
Although not involved in tumor cell transformation, some molecular
alterations may contribute to tumor progression at later stages.
These alterations, that occur only in a subgroup of tumors with a
given histologic type (eg HER2 amplification in breast carcinoma),
often add prognostic information, generally predictive of poor
prognosis. In the following, we will describe three examples.
Trastuzumab in HER2 amplified breast cancer: the first
example
The amplification of HER2 gene is found in 15 to 20 % of all
breast adenocarcinomas, where it is associated with unfavorable
prognosis and impaired response to antineoplastic treatment [43].
Trastuzumab is a humanized antibody that targets the extracellular
domain of HER2 proto-oncogene. Weekly administration of the drug
given alone results in 10 %-20 % response rates [44].
Yet, when given in combination with paclitaxel, trastuzumab
significantly increases response to chemotherapy and survival in
patients with Her2 gene amplification [44, 45]. In the particular
context of treatments targeted to late molecular events,
monotherapy generally yields poor results, with limited response
and no, or few, cases of long progression-free survival. Yet, when
used in combination with conventional chemotherapy, targeted
therapy increases response to treatment, progression-free survival
and overall survival.
Other examples of similar situations can now be described.
Antiangiogenic therapy
Anti-angiogenic drugs are another interesting example of targeted
treatments directed at late molecular events [46]. The production
of neovessels (angiogenesis) is a crucial step of tumor progression
when the volume of the tumor exceeds 2mm3. The density
of neovessels, measured by immunohistochemical analysis of factor
VIII or CD31 expression, has prognostic value for recurrence and
survival in a number of malignant diseases, notably in breast,
colon, lung, and prostate adenocarcinomas or in sarcomas [46].
Neoangiogenesis is also involved in the dissemination of tumor
cells to distant sites, resulting in the production of metastases.
This phenomenon is regulated by tumor cells themselves; in response
to hypoxia or to other accumulating molecular defects (p53), tumor
cells produce angiogenic growth factors that induce the sprouting
of blood vessels from the existing vasculature, their maturation
and growth into the tumor, then stimulate endothelial cell survival
[46]. VEGF (vascular endothelial growth factor) is the first factor
involved in the development of neovessels; it increases vessel
permeability, stimulates the mitogenesis and dissemination of
endothelial cells and, when neovascularization is underway,
promotes the survival of endothelial cells in the vessels. PDGF,
FGFb, and angiopoietins are also crucial for the development,
maturation and maintenance of neovessels. Until recently, drugs
directed against angiogenic growth, mostly inhibitors of growth
factor tyrosine kinase receptors, had not shown significant
clinical efficacy in the tumor models tested. However, two studies
recently reported encouraging therapeutic results with VEGF
inhibitors [47, 48].
The first one, reported by Yang et al in the New England Journal
of Medicine, was a randomized phase II study comparing two doses of
anti-VEGF bevacizumab to placebo in 114 patients with metastatic
renal cancer [47]. Patients receiving 10 mg bevacizumab per
kilogram of body weight, given every 2 weeks, had a significantly
improved progression-free survival compared to patients of the
placebo group or patients receiving only 3 mg: 30 %
progression-free survival at 8 months vs. 14 % and 5 % in
the other two arms, respectively. This study demonstrated that
tumor growth is inhibited by neutralizing antibodies to
angiogenesis, and that bevacizumab can increase time to progression
in tumors where VEGF production has established prognostic
value.
The second report by Hurwitz et al is a multicentric trial which
included 815 patients with metastatic colorectal cancer randomized
to first-line standard chemotherapy (Saltz regimen) with irinotecan
(CPT11), 5-FU and leucovorin, or to chemotherapy combined with
bevacizumab [48]. The experimental arm showed a statistically
significant increase over standard treatment for response
(45 % vs. 35 %, p=0.0029) as well as for survival (median
survival 20.3 vs. 15.6 months, p=0.00003) and progression–free
survival (10.6 vs. 6.24 months, p<0.00001). Hypertension was
more frequent under bevacizumab. The study by Hurwitz et al. was
the first to demonstrate survival improvement with antiangiogenesis
strategy, thus validating this approach for the treatment of human
solid tumors [49]. In view of this study, bevacizumab in
combination with standard chemotherapy regimen in colon cancer,
could be considered the reference treatment. Importantly, these
results demonstrate the significant antitumor efficacy of
antiangiogenic drugs. This is second example of targeted therapy
directed against late molecular events provides significant
survival benefit in both tumors.
Other trials also reported at ASCO 2004 confirmed this
therapeutic benefit of antiangiogenesis treatments. Indeed three
groups reported on the results of the broad spectrum tyrosine
kinase inhibitors SU011248 (targeting VEGFR, KIT, PDGFR), BAY
43-9006 (targeting VEGFR as well as Raf kinases), and a combination
of erlotinib and bevacizumab,for the treatment of renal cell
carcinomas and other refractory carcinomas [49-51]. The SU011248
phase II trial in advanced renal cell carcinoma reported a
33 % response rate in 65 patients, with 37 % stable
disease and 65 % overall survival at 1 year in patients
failing immunotherapy [49], Using the BAY43-9006 raf and VEGF
kinase inhibitor, high response rates and prolonged PFS survival
was also observed in RCC and other carcinomas [50]. Interestingly,
using a combination of EGFR inhibitor erlotinib and VEGF Ab
bevacizumab in a series of 58 patients with renal cell carcinoma, a
21% response rate with an overall survival of 80 % at 1 year
was reported in a phase II study in ASCO this year [51]. It is
noteworthy that each of the compound alone yield no or minimal
response rates in previous phase II trials in RCC, suggesting that
combined targeted therapy may have synergistic activity.
Future clinical trial will have to demonstrate whether a
combination of targeted therapy focusing on a single target, ie
“combined single-target-therapy”, or targeted treatment inhibiting
multiple targets (such as SU11248, or BAY 43 9006) may yield
additive or synergistic results when the molecule targeted plays a
late role in tumor progression.
Gefitinib, erlotinib and other HER1 targeting therapies: a
rapidly evolving field
The third example of therapy targeted to late molecular events is
gefitinib and erlotinib for advanced non-small cell lung cancers
[52-56]. Gefitinib (250 or 500 mg/day) given in second or
third line after failure of conventional treatment elicits almost
10 % response and significantly improves quality of life in
certain patients [52-54]. Contrariwise, two large phase III trials
testing gefitinib in combination with first-line standard
chemotherapy failed to produce significant improvements regarding
survival or response to treatment. Similar observations were made
using erlotinib, an other HER1 inhibitor [55, 56]. Recently
erlotinib single agent therapy was reported to improve overall
survival in patients with NSCLC failing first or second line
chemotherapy with CDDP.
In view of these results, the determination of the molecular
predictors of response to HER1 inhibitor had become the subject of
intensive translational research. A key finding of 2004 is the
discovery made by several groups that several mutations within the
EGFR gene, eg tyrosine kinase domain mutations, may predict the
sensitivity of tumor cells to erlotinib or gefitinib. In most
reports, these mutations were either small, in-frame deletions or
amino acid substitutions clustered around the ATP-binding pocket of
the tyrosine kinase domain Interestingly, these mutations are
observed most often in epidemiological subgroups in which higher
response rates were observed, ie female, non smokers, with
adenocarcinomas [57-60]. Mutations in HER2 have also been reported
suggesting that HER2 inhibitors may as well be evaluated in subsets
of patients [57, 61].
Among EGF inhibitors, monoclonal antibodies directed against
EGFR have also produced interesting results in EGFR expressing
malignancies such as lung cancer and head and neck cancers. Using
the anti-EGFR monoclonal antibody cetuximab. Cunningham et al. [62]
reported the results of a randomized multicentric phase III trial
comparing irinotecan + cetuximab vs. cetuximab alone in 329
patients with EGFR+ irinotecan-refractory colorectal cancer. The
combination arm exhibited a significantly increased response rate
compared to cetuximab single agent (22.9 % vs. 10.8 %,
p=0.0074), as well as more prolonged progression-free survival (4.1
months vs. 1.5 month, p<0.0001), though with more episodes of
diarrhea and grade 3-4 neutropenia. Side-effects of cetuximab (skin
rash or acneiform eruptions) are predictive of treatment benefit
for response and progression-free survival. Cetuximab is also
developed in head and neck carcinomas [63]. Other anti-HER1 and/or
HER2 monoclonal antibodies are currently under investigation
(EM72000, GW572016, ABX).
Despite the breakthrough of the discovery of EGFR mutations in
gefitinib, erlotinib sensitive lung carcinomas, the analysis of the
different models showed that the anti-tumor activity of targeted
therapy is not uniformly distributed in all the patients.
Therefore, the essential objective of the coming years remains to
identify molecular parameters correlated to treatment response.
This would help select patients for treatment and, also, highlight
the mechanisms of action of these drugs, thus permitting to improve
their therapeutic index.
Targeted therapies against molecular targets not directly
involved in cell transformation
There are two different possibilities:
- 1. When the targeted therapy is directed to an enzyme
that is not crucial to cell survival, treatment is usually
ineffective. This accounts, for instance, for the negative results
obtained with imatinib in KIT+ or PDGF-R+ tumors, except for
sporadic clinical case reports. This was particularly well reported
in the EORTC trial 62001 testing imatinib 800 mg/day in GIST
and other soft tissue sarcoma patients. Although PDGF receptor (a
target of imatinib) was constantly expressed in the epithelial
cells of the patients, no response was obtained in non-GIST tumors
[9]. Therefore, the physical presence of the specific molecular
target is not enough; targeted therapy only proves effective when
the targeted molecule is directly involved in cell transformation.
Of note, the recent observation made by Chugh et al reporting
prolonged time to progression in some patients with sarcoma
subtypes distinct from GIST (liposarcoma, leiomyosarcomas…)
suggests that, in the field of non GIST sarcoma, targets of
imatinib may be activated and contribute to tumor progression;
These observations deserve further investigations [64].
- 2. On the other hand, adoptive immunotherapy with
monoclonal antibodies may be directed to specific antigens,
generally surface antigens, that are not necessarily involved in
tumor cell survival. Among the targets currently in use or under
evaluation are CD20 and mucins expressed at the surface of
epithelial cells. Combination of rituximab, an antibody directed at
CD20 antigen, and CHOP chemotherapy regimen significantly improved
the survival of patients with CD20+ large-cell B lymphomas. The
combination was thus approved as standard treatment in this
disease. Antibodies trigger tumor cell apoptosis via effectors of
the immune system, such as complement or ADCC effector cells [65,
66], or via associated cytotoxic or radioactive molecules.
Anti-CD22, CD30, CD33, CD52 and CD80 antibodies are under
development for the treatment of hematological diseases, whereas
anti-C125, mucin, PSA and G250 are under evaluation in solid
tumors. The observation that the activation of the immune system
through a single injection of an anti CTLA4 Ab promotes tumor
responses in a phase I trial recently reported at ASCO supports
this notion, that passive immunotherapy, using recombinant Ab, is
still a very attractive approach for the treatment of human
malignancies, and may well represent the future of immunotherapy
[67].
Conclusion
Targeted oncogene therapies have become the standard treatments for
a number of neoplastic diseases (CML, GIST, breast adenocarcinoma,
lymphoma). Several drugs have already been approved for marketing,
and more (targeting other proteins) are under evaluation.
Inhibitors of tyrosine kinase receptors and ligands should
obviously have a fundamental role for the treatment of solid tumors
in the years to come. Biological parameters correlated to treatment
response and efficacy remain to be identified. They will help
improve the selection of patients and further optimize the
therapeutic ratio. High-throughput molecular assays, such as gene
expression micro-arrays or proteomics, will probably be of major
interest in this context, to identify specific nosological
entities, and possibly to identify new targets.
Acknowledgements
We thank MD Reynaud for her commitment and expert editorial
assistance.
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