The American Journal of Surgery 186 (2003) 264 –268

Special article

Targeted therapies for the treatment of cancer

Julian A. Kim, M.D.*
Department of General Surgery and Center for Cancer Drug Discovery and Development, Cleveland Clinic Foundation, Desk A80, 9500 Euclid Ave.,
Cleveland, OH 44195, USA

Manuscript received April 30, 2003

Abstract
Background: In contrast to conventional cytotoxic chemotherapy and radiation therapy, a new method of targeted cancer therapeutics is
being directed towards molecular pathways that underlie the malignant phenotype. These therapies target specific tumor cell receptors or
signaling events that are critical to tumor progression while reducing toxicity to normal cells.
Data sources: The purpose of this review is to highlight several examples of novel targeted therapeutics that are currently approved by the
FDA for treatment of patients with cancer. Rituxan is a humanized monoclonal antibody that binds to the CD20 antigen present on B cell
lymphomas and is currently approved for the treatment of patients with relapsed or refractory low-grade CD20 positive follicular lymphoma.
The humanized anti-HER-2/neu herceptin is approved for use in patients with metastatic breast cancer that demonstrates overexpression of
HER-2/neu. Finally, Gleevec is a tyrosine kinase inhibitor that inhibits abl-specific phosphorylation and is approved for use in select patients
with chronic myelogenous leukemia that is refractory to interferon therapy.
Conclusions: The lessons learned from the use of these therapeutics will add to the growing knowledge of mechanistic approaches to the
treatment of patients with cancer based upon targeted therapies, and herald a bright future that will improve the lives of patients with cancer.
© 2003 Excerpta Medica, Inc. All rights reserved.

Keywords: Targeted therapies; Cancer; HER-2 neu; C-kit; Monoclonal antibodies; Rituxan; Herceptin; Gleevec

Conventional cancer treatments such as cytotoxic chemo-
therapy and radiation therapy have been developed based
upon the observation that malignant cells divide at a more
rapid rate than the normal cells. For example, ionizing
radiation induces DNA damage that, upon multiple cell
divisions, may lead to errors in transcription and translation
resulting in cell death [1]. Similarly, cytotoxic chemother-
apy may interrupt microtubule formation that is essential for
mitotic events that ultimately affect cell survival [2]. It is
without question that conventional therapies have resulted
in significant survival advantages in patients with breast and
colon cancer as examples [3–5].
Despite the benefits derived from the antitumor activity
of conventional cytotoxic therapies, treatment-related tox-
icity can substantially reduce quality of life in cancer pa-
tients. Therapies directed against rapidly dividing cells will
result in death of epithelium (such as the lining of the
gastrointestinal tract) or may affect hematopoietic progeni-
* Corresponding author. Tel.: ⫹1-216-445-3612; fax: ⫹1-216-445-
7653.
E-mail address: kimj@ccf.org
tors resulting in cytopenias. These side effects not only
reduce the quality of life of cancer patients, but also limit
dose intensification and ultimately therapeutic antitumor
activity.
The advent of molecular biology techniques that enable
rapid isolation and analysis of DNA, RNA, and protein has
lead to research efforts that focus on tumor biology at the
cellular and subcellular levels. Identification of pathways
that are unique to cancer cells has lead to development of
cancer drug therapeutics that target specific processes es-
sential to tumor cell survival. The purpose of this review is
to highlight several examples of novel targeted therapeutics
that are currently approved by the FDA for treatment of
patients with cancer.
Targeting tumor cell antigens—Rituxan
Monoclonal antibodies (mAbs) were originally devel-
oped by Milstein and Kohler in 1975 when they success-
fully fused an antibody-producing B-cell with an immortal-
ized myeloma cell line resulting in a hybridoma [6]. These

0002-9610/03/$ – see front matter © 2003 Excerpta Medica, Inc. All rights reserved.
doi:10.1016/S0002-9610(03)00212-5
 J.A. Kim / The American Journal of Surgery 186 (2003) 264 –268 265

Fig. 1. Possible mechanism of action of monoclonal antibodies (Mabs). (A) The antibody has activity by virtue of its specific binding region (Fv) and the
constant region (Fc). (B) Mabs may bind extracellular tumor cell surface receptors resulting in signals that induce caspases and tumor cell apoptosis. (C)
Binding of Mabs to a growth factor receptor may sterically inhibit the binding of the growth factor ligand, resulting in blockade of intracellular signalling.
(D) Recognition of the Fc portion of a Mab bound to a tumor-associated antigen may result in phagocytosis by macrophages that have an Fc receptor. (E)
Finally, the Fc portion of Mab bound to the tumor cell surface may activate the complement cascade, resulting in lysis of the tumor cell.

hybridoma cells could then be cloned and screened for
large-scale production of mAb, a discovery that was
awarded the Noble Prize in 1984. Monoclonal antibodies
bind specifically to short peptide sequences or antigens with
remarkable specificity and affinity by virtue of their variable
(Fv) regions. Rapid development of mAbs lead to the avail-
ability of reagents that could be used to define cell surface
markers that were expressed on subclasses of cells from
similar hematopoietic lineage. The resulting cluster desig-
nation (CD) represented a simple yet robust method of
determining the characteristics or phenotype of cells for
diagnostic purposes [7].
B-cell non-Hodgkin’s lymphoma (NHL) is highly cur-
able by combined multimodal therapies including chemo-
therapy, radiation therapy, and in rare cases surgery. How-
ever, up to 25% of patients either relapsed or were
refractory to therapy, with many progressing to death. Re-
search of the biology of B-cell lymphomas defined a com-
mon receptor expressed on the cell surface termed CD20.
Despite the fact that CD20 was expressed on normal mature
B-cells, efforts were aimed at developing mAbs that would
specifically bind to CD20 as therapeutics for B cell NHL.
Testing of these anti-CD20 mAbs in vitro and in vivo
demonstrated high-affinity binding to B-cell lymphoma
cells but not other hematopoietic cells such as T cells. These
observations lead to the idea that CD20 could be a suitable
target for design of therapies for patients with B-cell lym-
phoma.
Rituxan mechanism of action
Binding of a mAb to a cell surface receptor can result in
several possible antitumor effects (Fig. 1). The mAb may
bind a portion of the extracellular domain of that receptor
that may block ligand-receptor interactions, which in the
case of growth factor receptors, may result in cell death.
Alternatively, mAbs may induce cell signaling by virtue of
binding a specific region of the receptor, with downstream
events leading to programmed cell death or apoptosis. Ex-
perimental evidence suggests that the anti-CD20 mAb Rit-
uxan provide pro-apoptotic signals to B-cell lymphomas as
one mechanism of its antitumor activity in vivo [8].
Binding of anti-CD20 mAbs to the cell surface exposes
the constant region (Fc) of the immunoglobulin, which can
initiate immunologic mechanisms of antitumor activity. The
Fc can be recognized and bound by phagocytic cells such as
macrophages and engulfed in a process known as antibody-
dependent cellular cytotoxicity (ADCC). Alternatively, the
Fc region of the immunoglobulin can also activate the
complement cascade resulting in cell lysis, a process termed
complement-dependent cytotoxicity (CDC). Recent studies
have suggested that although B-cell lymphoma cells ap-
pear to be uniformly susceptible to ADCC, there appears to
be differences in sensitivity of the cells to CDC that corre-
lated with clinical antitumor responses after Rituxan therapy
[9].
266 J.A. Kim / The American Journal of Surgery 186 (2003) 264 –268
Development and approval of Rituxan
A major factor limiting repeated dosing of mAbs in
humans was that the Fc region of the immunoglobulin
structure was murine in origin. After intravenous adminis-
tration of these mAbs, patients developed human-antimouse
antibodies (HAMAs) that were shown to complex with
murine mAbs upon repeat administration and in some cases
lead to acute anaphylactic or chronic serum sickness-like
illness. Molecular techniques allowed for replacement of
murine Fc with human sequences, thus making them “hu-
manized” and less immunogenic [10].
Initial clinical trials using Rituxan demonstrated an ap-
proximate 36% objective response rate (complete and par-
tial response) in patients with chemotherapy refractory low-
grade NHL [11]. Interestingly, although Rituxan therapy did
result in B-cell lymphopenia due to CD20 expression on
mature B-cells, this side effect was reversible with discon-
tinuation of treatment and did not result in significant im-
munosuppression. A pivotal trial in 166 patients reported an
objective response rate of 48% (6% complete response and
42% partial response) with a median duration of response of
11.2 months [12]. These data resulted in Food and Drug
Administration approval of Rituxan for the treatment of
patients with relapsed or refractory low-grade CD20 posi-
tive follicular lymphoma. The FDA approval of Rituxan in
November 1997 represented the first mAb therapy approved
for the treatment of human malignancy, and ushered the
modern era of targeted therapeutics for cancer.
Targeting tumor cell growth factor
receptors—Herceptin
Molecular analysis of the pathways that underlie tumor
growth has resulted in defining tumor-associated growth
factor receptors as potential targets for therapeutic interven-
tion. The epidermal growth factor receptor (EGFR) family
consists of immunoglobulin-like receptors that, upon bind-
ing with the respective growth factor ligand, result in intra-
cellular phosphorylation of transcription factors and in-
creased DNA synthesis [13]. One of the EGFR family that
was overexpressed on approximately 25% of human breast
carcinomas was HER-2/neu, encoded by the gene c-erb B2.
In the late 1980s, Dennis Salmon and William McGuire
authored a series of papers published in Science demonstrat-
ing that overexpression of the HER-2/neu proto-oncogene
was associated with poor clinical outcome in patients with
breast carcinoma [14,15]. These findings were supported by
in vitro analysis of human breast carcinoma cell lines, which
lead to a working hypothesis that HER-2/neu played a
critical role in the biologic behavior of breast cancer. It has
more recently been shown that HER-2/neu overexpression
is a predictive marker of response to adjuvant cytotoxic
chemotherapy or hormonal therapy or both, and is also
predictive of poor prognosis in early stage, node negative
patients [16,17].
Herceptin mechanism of action
There appear to be several possible mechanisms by
which Herceptin exerts its antitumor therapeutic effects
against tumor cells that overexpress HER-2/neu. Since the
mAb is binding a tumor cell-associated receptor, it may
render the tumor cell susceptible to ADCC and/or CDC in a
manner similar to Rituxan (Fig. 1). Additionally, herceptin
may prevent ligation of HER-2/neu with its ligand, a pro-
cess that may induce apoptosis. Finally, there is experimen-
tal evidence that herceptin may affect the regulation of
genes related to angiogenesis such as vascular endothelial
growth factor (VEGF) and angiopoietin-1 [18].
A critical observation of herceptin activity observed both
in preclinical experimental animal models and human clin-
ical trials is the synergistic antitumor effects when used in
combination with cytotoxic chemotherapy [19,20]. Combi-
nations of herceptin and anthracyclines such as doxorubicin
resulted in synergistic antitumor effects against human
breast cancer xenografts in vivo; similar effects were ob-
served when used in combination with cisplatin against
human ovarian carcinoma xenografts. Herceptin appears to
block DNA repair mechanisms, rendering tumor cells more
susceptible to various cytotoxic agents. The effects of com-
binations of herceptin and anthracyclines may also result in
increased toxicity to normal cells, as evidenced in the hu-
man clinical trial results where cardiac toxicity has been
observed [21].
Development and approval of Herceptin
A humanized anti-HER-2/neu mAb was developed by
Slamon in collaboration with Genentech and tested in hu-
man clinical trials of patients with metastatic breast cancer.
Several Phase I and II trials demonstrated objective clinical
and radiographic responses to herceptin therapy, particu-
larly when used in combination with cytotoxic chemother-
apy [22,23]. These trials results led to FDA approval of
herceptin for use in combination with paclitaxel in patients
with metastatic breast cancer in 1998. Herceptin was indi-
cated in patients who had breast cancer with overexpression
of HER-2/neu and had not previously received chemother-
apy for metastatic disease. The mAb was administered
weekly as an intravenous infusion of a loading dose of 4
mg/kg and subsequent doses of 2 mg/kg. The results of a
Phase III trial published in the New England Journal of
Medicine in 2001 extended the utility of herceptin in pa-
tients with metastatic disease [24]. In it, 469 women with
metastatic breast cancer that overexpressed HER-2/neu
were randomly assigned to receive either standard chemo-
therapy alone or standard chemotherapy in combination
with herceptin. Patients who had not previously received
anthracyclines in the adjuvant setting were treated with
either standard chemotherapy consisting of doxorubicin or
epirubicin in combination with cyclophosphamide. Those
 J.A. Kim / The American Journal of Surgery 186 (2003) 264 –268
patients who had been previously treated with anthracy-
clines were given paclitaxel as standard chemotherapy. The
addition of herceptin to standard chemotherapy was associ-
ated with a significant increase in time to disease progres-
sion (median 7.4 months versus 4.6 months), and objective
response (50% overall response rate versus 32%). Herceptin
in combination with standard chemotherapy was associated
with a lower rate of death at 1 year (22% versus 33%) and
increased overall survival (median 25.1 months versus 20.3
months, P ⫽ 0.01). More recent data suggest that herceptin
monotherapy may result in a 26% objective response rate as
a first-line treatment in patients with metastatic breast car-
cinoma that overexpresses HER-2/neu [25]. These encour-
aging results have led to current studies of herceptin as a
first-line agent in combination with chemotherapy or hor-
monal therapy, or both, in the adjuvant and neoadjuvant
treatment of patients with primary breast cancer.
Targeting tumor cell intracellular signaling
pathways—Gleevec
Rational drug design based upon knowledge of intracel-
lular signaling pathways that are essential for tumor cell
growth has been the focus of intense study. The advent of
rapid and efficient methods of isolation, amplification and
analysis of RNA, DNA and protein have allowed for accel-
erated research into the mechanisms critical to tumor cell
progression and metastasis.
Chronic myelogenous leukemia (CML) is a malignancy
that provided the paradigm by which future efforts of ratio-
nal drug design will be compared. Cytogenetic studies per-
formed decades ago correlated the presence of the Philadel-
phia chromosome, an abnormal chromosome developed
from a translocation of chromosomes 9 and 22, with devel-
opment of CML [26]. Molecular studies demonstrated that
this translocation resulted in the juxtaposition of the genes
bcr-abl, which appeared to be central regulators of CML
progression into a chronic phase [27]. Subsequent studies
revealed that bcr-abl resulted in a cytoplasmic fusion pro-
tein (p210) with significant tyrosine kinase activity, a phe-
nomenon that was essentially a switch that was continu-
ously “on” in that it was phosphorylating intracellular signal
transduction molecules leading to increased DNA synthesis
and mitogenic processes [28].
Purification of the bcr-abl protein and x-ray crystallog-
raphy of the tyrosine kinase domain led to the design of
small molecules that could bind and block the phosphory-
lation of kinase activity [29]. These small molecules, termed
tyrosine kinase inhibitors or TKIs, are designed to inhibit
tyrosine kinase activity associated with specific receptors or
proto-oncogenes based upon the crystal structure of the
kinase domain. The signal transduction inhibitor (STI) 571
of Gleevec was developed by Novartis initially as an inhib-
itor of platelet-derived growth factor receptor (PDGF-R) but
was subsequently discovered to exhibit potent inhibition of
abl-specific tyrosine kinase activity [30].
267
Gleevec mechanism of action
STI571 was initially tested in vitro and found to have
TKI activity against abl, PDGF-R, and the c-kit proto-
oncogene. By virtue of its TKI activity against abl, STI571
was effective in inhibiting the proliferation of Ph⫹ cells in
vitro that were derived from a number of patients with
CML. Preclinical animal studies demonstrated a dose-de-
pendent reduction in human tumor xenografts that contained
the bcr-abl gene, again confirming antitumor therapeutic
effects.
Development and approval of Gleevec
Clinical trials of STI571 were initially performed in
patients with Ph⫹ CML. A phase I study in 83 patients who
had failed conventional interferon therapy were treated with
daily oral doses and a maximum tolerated dose was not
reached [31]. Amazingly, for patients treated with 300 mg
or more there was a 98% complete response rate, and these
responses were durable for up to 300 days. Phase II clinical
trials confirmed the striking response rate and confirmed the
lack of serious toxicity, making STI571 arguably the first
small molecule targeted therapeutic for cancer that demon-
strated specific and potent elimination of tumor cells. Based
upon these data, Gleevec received accelerated FDA ap-
proval in May 2001 for the treatment of patients with Ph⫹
CML who have failed interferon therapy.
The remarkable potency and selectivity of STI571 lead
to additional studies in patients with other tumor histolo-
gies. Gastrointestinal stromal tumors (GIST) are relatively
rare malignancies that have been largely refractory to con-
ventional cytotoxic chemotherapy regimens. However, ba-
sic studies demonstrated that a significant percentage of
GIST contained a c-kit proto-oncogene mutation that re-
sulted in tyrosine kinase activity. Based upon the observa-
tion that STI571 was an inhibitor of c-kit kinase activity,
early phase clinical trials were initiated in patients with
unresected or metastatic GIST [32]. Again, in the subset of
patients whose GIST was associated with a c-kit mutation,
oral STI571 resulted in dramatic tumor regression in a
significant percentage of patients with a tumor histology
that previously had been considered refractory. Gleevec is
rapidly being evaluated as a first-line therapy in patients
with GIST and other tumors that demonstrate activating
c-kit mutations.
Targeted therapies—potential limitations and future
targets
Despite the promising clinical results from the agents
that have been highlighted, there are still significant limita-
tions to the concept of “pathway-specific” targeted thera-
pies. The first limitation is that these agents are only effec-
268 J.A. Kim / The American Journal of Surgery 186 (2003) 264 –268
tive in tumor types that are dependent upon the pathways
that are being inhibited. It is readily apparent that most solid
tumors are the result of numerous genetic mutations, and
thus inhibiting a single cellular pathway may not result in
significant therapeutic activity. Design of agents that target
a number of pathways will possibly increase the therapeutic
effect, but also increase the risk of treatment-related toxic-
ities.
The challenges of discovering novel targets for therapeu-
tic intervention and designing specific and potent agents
remains an area of intense research. It is the early success of
the agents reviewed in this article that have built the foun-
dation for development of newer generations of targeted
therapies in the future. Intracellular pathways are currently
being targeted by drugs that inhibit ras, c-myc, NF-␬B, and
MAPK activity. Growth factor pathways that are currently
being targeted by mAbs and kinase inhibitors include
EGFR, PDGFR, and vascular endothelial growth factor
(VEGF) receptor. Many of these agents are in phase I and II
testing in patients with a variety of malignancies that in-
clude breast, lung, pancreatic and colon cancers. The les-
sons learned from these studies will add to the growing
knowledge of mechanistic approaches to the treatment of
patients with cancer based upon targeted therapies, and
herald a bright future that will improve the lives of patients
with cancer.
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