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The New Generation of Targeted Therapies for Breast Cancer

The New Generation of Targeted Therapies for Breast Cancer

ABSTRACT: Traditional therapies for breast cancer have generally relied upon the targeting of rapidly proliferating cells by inhibiting DNA replication or cell division. Although this strategy has been effective, its innate lack of selectivity for tumor cells has resulted in diminishing returns, approaching the limits of acceptable toxicity. A growing understanding of the molecular events that mediate tumor growth and metastases has led to the development of rationally designed targeted therapeutics that offer the dual hope of maximizing efficacy and minimizing toxicity to normal tissue. Promising strategies include the inhibition of growth factor receptor and signal transduction pathways, prevention of tumor angiogenesis, modulation of apoptosis, and inhibition of histone deacetylation. This article reviews the development of several novel targeted therapies that may be efficacious in the treatment of patients with breast cancer and highlights the challenges and opportunities associated with these agents.

In recent years, the strategy in cancer
therapy in general and breast
cancer in particular has shifted
from the use of high doses of toxic,
nonspecific agents to a range of novel
agents that target specific molecular
lesions found in tumor cells. Advances
in molecular biology have allowed
the isolation of novel interactions and
downstream targets, driving the development
of rationally designed
targeted therapies. The success of
trastuzumab (Herceptin) in breast cancer
and imatinib mesylate (Gleevec)
in chronic myelogenous leukemia and
gastrointestinal stromal tumors provides
proof of principle that such an
approach can have a marked impact
when the mechanism of growth of a
particular cancer is understood and
specifically interrupted.

This article will focus on new,
molecular-targeted approaches to the
treatment of breast cancer. Of particular
interest are classes of drugs that
target the tyrosine kinase signal transduction
pathways, block tumor angiogenesis,
modulate apoptosis, and
inhibit histone deacetylation.

Targeting the erbB1 Receptor

The erbB family consists of four
closely related transmembrane receptors:
erbB1 (also termed epidermal
growth factor receptor [EGFR] or
HER1), erbB2 (also termed HER2 or
neu), erbB3 (HER3), and erbB4
(HER4). All four erbB receptors share
a common molecular architecture
composed of three distinct regions:
an extracellular ligand-binding domain,
a transmembrane region, and
an intracellular tyrosine kinase-containing
domain that is responsible for
the generation and regulation of intracellular
signaling (Figure 1). The
formation of erbB homodimers and
heterodimers following ligand binding
and receptor aggregation activates
the intrinsic receptor kinase activity
via intramolecular phosphorylation
and generates a cascade of downstream
chemical reactions that
transmit a wide variety of cellular
effects.[1]

The rationale for and development
of therapeutics targeting erbB2, particularly
trastuzumab, have been reviewed
elsewhere,[1] and this section
will be limited to a discussion of therapeutics
targeting erbB1. The erbB1
receptor is overexpressed in about
40% of breast cancers.[2,3] The frequency
of overexpression varies
depending on the evaluation method
used and whether the truncated
EGFRvIII form-a constitutively activated
erbB1 variant expressed in a
large proportion of breast cancers-is
included.[3]

The overexpression of erbB1 has
been associated with increased proliferation,
disease progression, and a
poor prognosis in breast cancer.[3,4]
ErbB1 expression has also been correlated
with decreased estrogen-receptor
expression and increased resistance
to endocrine therapy.[2,3,5,6] ErbB2
and erbB1 are commonly (10%-36%)
coexpressed, and such coexpression
has been correlated with a less favorable
prognosis.[7,8] Given the wide
expression of erbB1 in breast cancer
and the important role this receptor
plays in signal transduction, the use
of erbB1 inhibitors in the treatment of
breast cancer has generated considerable
interest.

The aberrant signaling that occurs
through the erbB1 pathway can be
caused by high expression of erbB1,
mutation of erbB1 (eg, EGFRvIII),
decreased phosphatase levels, or
heterodimerization of erbB1 with
other members of the erbB receptor
family (such as HER2).[3] Several
different strategies have been used to
downregulate signaling through this
pathway (Table 1). These include
monoclonal antibodies directed
against erbB1 such as cetuximab
(IMC-C225, Erbitux) and ABX-EGF,
and small-molecule inhibitors of
erbB1 tyrosine kinase such as gefitinib
(ZD1839, Iressa) and erlotinib
(OSI 774, Tarceva).

Small Molecules Targeting
erbB1 Tyrosine Kinase

Small-molecule inhibitors of erbB1
receptor tyrosine kinase prevent receptor
dimerization, autophosphorylation,
and the resulting downstream
signaling. Hypothetically, this approach
could inhibit signaling mediated
by ligands as well as signaling
that is independent of growth factors.
In contrast to monoclonal antibodies,
such agents may also inhibit ligandindependent
signaling due to constitutively
active mutant receptors (eg,
EGFRvIII). Several erbB1 tyrosine
kinase inhibitors are under evaluation,
but the anilinoquinazolines, gefitinib
and erlotinib, are in the most advanced
stages of development.

  • Gefitinib-In preclinical studies,
    gefitinib has demonstrated broad antitumor
    activity in lung, breast,
    ovarian, and other tumors.[9] Cell
    lines that overexpress erbB2 appear
    to be particularly sensitive to gefitinib,
    and preclinical data suggest a
    synergistic inhibitory effect when the
    agent is combined with trastuzumab
    in cell lines that coexpress erbB1 and
    erbB2.[10,11] These observations
    support the use of erbB1 inhibitors
    such as gefitinib in combination with
    therapies that target erbB2. In addition,
    preclinical data suggest that resistance
    to endocrine therapy in
    estrogen-dependent tumors may be
    modulated through erbB1, which may
    be thwarted by gefitinib.[6,12]

    This phenomenon was examined
    in a recent study in which nude mice
    bearing erbB2-expressing breast cancer
    cells (MCF-7/HER2-18) were
    treated with estrogen, tamoxifen, or
    estrogen-deprivation alone or together
    with gefitinib.[12] In this study,
    erbB2 overexpression increased the
    agonist properties of tamoxifen, resulting
    in stimulated growth. However,
    tamoxifen-stimulated MCF-7/HER2-18
    tumor growth was completely blocked
    in mice treated with gefitinib. In mice
    treated with gefitinib and estrogen
    deprivation, the erbB1 tyrosine kinase
    inhibitor delayed the development
    of acquired resistance to estrogen
    deprivation.

    These observations support the
    concept that crosstalk between estrogen
    receptor and erbB1/erbB2-related
    pathways can modulate resistance to
    endocrine therapies and suggest that
    combination therapy may be useful in
    maintaining estrogen sensitivity following
    the development of hormone
    resistance. Additional potential benefits
    of gefitinib and other therapeutic
    agents targeting erbB1 stem from their
    favorable interaction with cytotoxic
    drugs (eg, paclitaxel, docetaxel [Taxotere],
    carboplatin [Paraplatin], cisplatin,
    topotecan [Hycamtin], and
    raltitrexed) in human tumor xenograft
    models and restoration of taxane
    sensitivity in multidrug-resistant cell
    lines.[1,13]

    In phase I trials conducted in patients
    with advanced breast cancer,
    gefitinib has demonstrated a favorable
    tolerability and predictable pharmacokinetic
    profile when given
    orally.[14] The clinical benefit and
    safety profiles of gefitinib were evaluated
    in a recently reported multicenter
    phase II study in patients with
    metastatic breast cancer.[15] Gefitinib
    was administered at a dose of 500 mg
    once daily until disease progression,
    intolerable toxicity, or consent withdrawal.
    Notably, there were no previous
    treatment restrictions, and study
    participants were not screened for the
    target or target aberrations. The study
    end point was the clinical benefit rate,
    defined as the sum of the response
    rate and the rate of stable disease for
    6 months. Of the 63 patients in the
    trial, 27 (43%) had tumors that were
    estrogen-dependent, and 17 (27%) had
    tumors that demonstrated erbB2 over-

    expression
    by immunohistochemistry
    staining.

    Treatment was discontinued in 5%
    of patients because of treatmentrelated
    side effects, and four patients
    were able to continue treatment after
    a dose reduction to 250 mg daily.
    Grade 3/4 toxicity, mainly grade 3
    diarrhea, rash, or nausea and vomiting
    developed in approximately 25%
    of the patients. One patient achieved
    a partial response, and two patients
    had stable disease for an excess of
    6 months, yielding a clinical benefit
    rate of 4.8%. An additional six patients
    had stable disease for up to
    6 months. The median time to progression
    was 57 days, and about 42%
    of patients reported diminished pain
    during therapy. Objective evidence of
    activity using a rigid definition was
    low in this heavily pretreated population.
    However, a considerable proportion
    of patients (14.3%) achieved
    a partial response or maintained stable
    disease for up to 6 months, and
    therefore, may have derived benefit
    from this therapy.

  • Erlotinib-Another agent that has
    been studied in women with advanced
    breast cancer is erlotinib. Much like
    gefitinib, erlotinib is orally active and
    was well tolerated in phase I trials.[
    1,16] An open-label phase II trial
    of erlotinib in metastatic breast cancer
    was recently completed.[17] Two
    cohorts of patients were accrued to
    this study. The first cohort of 47 patients
    was required to have received
    prior therapy with an anthracycline, a
    taxane, and capecitabine (Xeloda).
    The second cohort of 22 patients merely
    had to have had tumor progression
    during chemotherapy. Again, study
    participants were not prospectively
    screened for erbB1 overexpression.
    Erlotinib was administered at 150 mg
    once daily until tumor progression
    with dose reduction permitted for
    treatment-related side effects.

    In the first cohort, one patient
    achieved a partial response, and two
    additional patients had stable disease.
    In the second cohort, no objective
    responses were observed, but one patient
    exhibited stable disease. Treatment-
    related side effects included
    acneiform rash, diarrhea, asthenia, and
    nausea. Correlative studies demonstrated
    that only 12% of patients had
    overexpression of erbB1. This suggests
    that an insufficient number of
    patients may have had the target to
    validly test this agent.

  • Study Validity-The modest clinical
    benefit seen in these phase II stud-
    ies of the erbB1 tyrosine kinase inhibitors
    likely reflects the indiscriminate
    treatment of unscreened tumors
    that may or may not possess the appropriate
    target or determinants for
    response. The importance of appropriate
    identification of patients who
    are most likely to respond to a targeted
    approach is well illustrated in the
    success of trastuzumab in breast cancer.
    The survival benefits seen with
    trastuzumab therapy would not have
    been appreciated if patients had not
    been screened before treatment for
    overexpression of erbB2, the principal
    target of the drug.

    Equally important is the appropriate
    selection of end points for phase II
    studies, ie, those that will allow the
    appreciation and quantification of tumor
    growth delay, the predominant
    benefit of erbB-targeted therapeutics
    noted in preclinical studies. Therefore,
    both the identification of predictive
    biomarkers and a careful trial
    design are needed to ensure that the
    usefulness of erbB-targeted therapy
    is correctly assessed.

  • New Directions in Research-
    More recently, attention has focused
    on evaluating the feasibility and efficacy
    of a multitargeted approach. The
    combination of trastuzumab and
    erbB1 inhibitors and the dual administration
    of endocrine therapy and
    erbB1 inhibitors are subjects of ongoing
    clinical trials in breast cancer. In
    addition, the irreversible, pan-erbB
    tyrosine kinase inhibitor CI-1033, the
    irreversible erbB1/erbB2 tyrosine kinase
    inhibitor EKB-569, and the
    reversible erbB1/erbB2 tyrosine kinase
    inhibitor GW572016 are undergoing
    clinical evaluation.[18-24] The
    relative merits of these mechanisms
    will be better understood following
    trials of CI-1033, EKB-569, and
    GW572016 in relevant tumor types.

    The rationale for the development
    of irreversible tyrosine kinase inhibitors
    such as CI-1033 and EKB-569
    was, in part, the higher concentrations
    of erbB inhibitors required to
    continuously block erbB1 phosphorylation
    in intact cells where intracellular
    adenosine triphosphate (ATP)
    concentrations are higher. The approximately
    80% homology between the
    erbB1 and erbB2 tyrosine kinase has
    allowed the generation of these receptor
    tyrosine kinase inhibitors with
    activity in multiple erbB receptor families.
    Such agents have potential in
    patients who are resistant to trastuzumab,
    as compensatory signaling by
    other erbB receptors may contribute
    to trastuzumab resistance.

    CI-1033 and EKB-569 are comprised
    of chemical moieties that form
    covalent bonds with the receptor tyrosine
    kinase domain, resulting in irreversible
    receptor binding and
    sustained inhibition of tyrosine kinase
    in vitro. This feature may also circumvent
    drug-binding competition
    due to high intracellular ATP concentrations.
    In addition, irreversible
    compounds require that plasma concentration
    be attained only long
    enough to briefly expose the receptors
    to drug, which would then permanently
    suppress kinase activity.
    This process is in contrast to reversible
    erbB tyrosine kinase inhibitors
    that require adequate plasma concentrations
    and/or agents with relatively
    long half-lives to keep the target
    suppressed.[1]

    CI-1033 binds irreversibly within
    the ATP-binding pocket of erbB tyrosine
    kinase and inhibits both activation
    and downstream signaling
    emanating from erbB1, erbB2, erbB3,
    and erbB4. In preclinical models, CI-
    1033 has been shown to inhibit erbB1
    phosphorylation in A341 carcinoma
    and MDA-MB-453 human breast carcinoma
    cells and the growth of several
    human tumor xenografts.[1,18,19]
    The results of studies of long-term
    administration of CI-1033 indicate that
    it maintains tumor suppression for
    extended periods without the emergence
    of drug resistance.

    Like other erbB1 inhibitors, CI-
    1033 has demonstrated synergy with
    other therapeutic modalities. For example,
    it enhances the cytotoxic effects
    of the topoisomerase inhibitors,
    SN-38 and topotecan (Hycamtin) in
    vitro, possibly interfering with a relevant
    drug-resistance mechanism.[1]
    Synergistic in vitro growth inhibition
    of the erbB1-overexpressing cell line
    A341 has also been demonstrated with
    CI-1033 and cisplatin.[19,20] This
    enhanced chemosensitivity was shown
    not to be the result of inhibition of
    DNA repair of cisplatin-DNA adducts,
    and it has been proposed that blockage
    of erbB signaling by CI-1033 enables
    cisplatin to inhibit key genes
    required for cell survival.

    In phase I studies, when CI-1033
    was administered as a single oral dose
    weekly for 3 out of 4 weeks and daily
    for 7 days every 3 weeks, the most
    common toxicities were mild-to-moderate
    vomiting, diarrhea, and acneiform
    rash.[21,22] Antitumor activity
    has also been observed, with one partial
    response and stable disease in 30%
    of patients including one with heavily
    pretreated breast cancer.[22] Further
    clinical development of this agent is
    ongoing for patients with erbB-overexpressing
    advanced breast cancer.

    EKB-569 also binds covalently and
    irreversibly to erbB1. Consistent with
    its ability to irreversibly bind to erbB1
    and erbB2, inhibition of receptor
    phosphorylation is sustained far longer
    than are plasma levels of the compound.[
    1,23] Phase I evaluations of
    EKB-569 administered continuously
    once daily and for 3 weeks every
    4 weeks have been completed, and
    phase II studies of this agent are
    ongoing.

    The agent GW572016 inhibits
    erbB1 and erbB2 tyrosine kinase in a
    reversible manner. This drug has demonstrated
    potent inhibition of tumor
    growth in vitro and appears selective
    for tumor cells relative to normal cells.
    In vivo, GW572106 has antitumor
    activity against erbB2-overexpressing
    breast carcinoma xenografts.[24] Clinical
    evaluation of GW572016 administered
    on a once-daily continuous
    schedule is ongoing in breast cancer.
    In addition, combination studies with
    other cytotoxic agents (such as capecitabine)
    are in progress.

Targeting the
Ras/Raf/MAPK Pathway

The Ras proteins are guanine nucleotide-
binding proteins that play a
pivotal role in the control of normal
and transformed cell growth. Following
stimulation by several growth
factors and cytokines, Ras activates
multiple downstream effectors. The
Ras/mitogen-activated protein kinase
(Ras/MAPK) pathway plays an
important role in breast cancer
(Figure 2).[25]

Although ras is functionally mutated
in < 5% of breast cancers, an
upregulation of the classic mitogenic
Ras/Raf/MAPK cascade occurs, stimulated
by overexpression or amplification
of oncogenic protein
tyrosine kinase activity (eg, erbB2 or
erbB1).[26] Phospholipase-C, one of
the signaling proteins activated by receptor
dimerization of activated erbB1
and erbB2 enhances Ras activity
through its SH3 domain.[27] In addition,
the adaptor protein Grb2 that
links protein tyrosine kinases to Ras
and is overexpressed in breast cancer,
may amplify signaling through the Ras
pathway in response to growth
factors.[28]

The amplification of Ras signaling
as a result of overexpression of these
oncogenes and intermediate signaling
molecules leads to increased stimulation
of downstream effector
molecules including phosphatidylinositol
3-kinase (PI3K) and protein
kinase B (Akt). Such oncogenic activation
not only confers a proliferative
and survival advantage to cancer cells
but also supports tumor growth
through its proangiogenic effect.

Farnesyl Transferase Inhibitors
The Ras pathway may be targeted
through the inhibition of farnesylation.
This key step in the posttranslational
modification of Ras is necessary
for membrane localization and function.
Initial studies of farnesyl transferase
inhibitors (FTIs) suggested that
these agents selectively inhibit the
anchorage-independent growth of rastransformed
cells and reverse the
transformational phenotype of rasmutated
cells.[26] Recently, the role
of Ras proteins in mediating the antitumor
effects of FTIs has become less
certain.

FTIs have demonstrated insufficient
activity in tumors with K-ras
mutations such as pancreas and colorectal
cancers, presumably because
another prenylating enzyme, geranylgeranyl
transferase, can alternatively
prenylate or activate K-ras. In
addition, FTIs have demonstrated antiproliferative
activity in tumor cell

lines with wild-type Ras, suggesting
that mechanisms other than inhibition
of Ras farnesylation may be
involved.[29] The prevailing explanation
for the activity of FTIs in tumors
such as breast cancer-which
rarely involves ras mutations-
includes the fact that FTIs prevent
signaling through wild-type Ras
caused by upstream aberrations (eg,
erbB1, erbB2) or that they inhibit farnesylation
(activation) of other critical
proteins.

  • Clinical Trials-Various farnesyl
    transferase inhibitors have been evaluated
    in phase I/II clinical trials. These
    include R115777, SCH66336, and
    BMS 214662.[26,30-34] In addition,
    interest has been generated in optimizing
    the use of FTIs by combining
    them with cytotoxic agents. Certainly
    the synergy between cytotoxic agents
    (particulary taxanes) and FTIs observed
    in breast cancer cell lines with
    wild-type Ras supports this approach.[
    30] The prinicipal toxicities
    encountered with FTIs include
    schedule-dependent myelosuppression,
    gastrointestinal effects, and fatigue.
    Although many of the observed
    toxicities are common, certain side
    effects are unique and may be structurally
    related. Peripheral neuropathy
    is unique to R115777, whereas transaminitis
    appears to be encountered
    more often with BMS 214662.

    The first phase II study of an FTI
    in breast cancer was conducted using
    R115777.[32] Preliminary results indicate
    that R115777 has single-agent
    activity in advanced breast cancer,
    with a clinical benefit rate of 25%. It
    has also been evaluated in combination
    with chemotherapy. In a phase I
    study in patients with solid tumors,
    R115777 was combined with docetaxel.[
    33] Of 15 patients with breast
    cancer, 1 achieved a complete response,
    and 2 achieved partial responses.
    The dose-limiting toxicity was
    mostly febrile neutropenia, and the
    nonhematologic toxicities were diarrhea,
    fatigue, and vomiting. No
    discernable pharmacokinetic interaction
    between the two drugs was
    documented.

    The combination of R115777 and
    capecitabine has also been evaluated in
    a phase I trial.[34] Diarrhea and handfoot
    syndrome were the dose-limiting
    toxicities, and partial responses were

    seen in various malignancies including
    breast cancer. More recently, the
    concurrent inhibition of both erbB2
    and Ras signaling is being studied in
    breast cancer. The rationale for the
    use of this combination is that inhibition
    of abnormal Ras expression and
    normal Ras signaling may enhance
    the growth inhibitory effects of trastuzumab
    in erbB2-expressing tumor
    cells.

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