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The New Generation of Targeted Therapies for Breast Cancer
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The New Generation of Targeted Therapies for Breast Cancer
Review Article [1] | October 01, 2003 | Breast Cancer [2], Oncology Journal [3]
By Samira Syed, MD [4] and Eric Rowinsky, MD [5]
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
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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 overPage 2 of 17
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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
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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
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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
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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
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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. Raf
Inhibitors
Downstream effectors of Ras, particularly Raf-1, are also being characterized and targeted
with a variety of therapeutic agents. The Raf family is composed of three related
serine/threonine protein kinases (Raf-1, A-Raf, and B-Raf) that act, in part, as downstream
effectors of the Ras pathway.[35] Activated Ras interacts directly with the amino-terminal
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regulatory domain of the Raf kinase, resulting in a cascade of reactions that include direct
activation of MEK. Like mutated ras, constitutively active mutated raf can transform cells in
vitro. However, Raf may play a broader role in tumorigenesis because it can be activated by
protein kinase C-alpha and promotes expression of the multidrug resistance gene MDR-1.[35]
By targeting Raf, one can inhibit mutated raf and upstream signals coming in from mutant
ras and growth factor receptors such as erbB1 and erbB2. Raf inhibitors currently under
evaluation include the c- Raf-1 antisense oligonucleotide ISIS 5132 (CGP 69846A) and BAY
43- 9006, a small molecule inhibitor of Raf kinase.[35-40] ISIS 5132 inhibits both the
expression of c-raf messenger RNA and the proliferation of cancer cell lines in vitro.[35]
Evidence also shows that this agent augments the cytotoxic effects of the chemotherapeutic
agents carboplatin and paclitaxel.[40] Phase I studies have evaluated the safety of escalating
doses of ISIS 5132 administered in three schedules: a 2-hour IV infusion three times per week
for 3 consecutive weeks; a continuous IV infusion for 3 weeks in each 4-week period; and a
weekly 24-hour infusion.[ 35] Both the 2-hour and 3-week continuous IV infusion schedules
were well tolerated, with the most common toxicities being fever, fatigue, and a transient
prolongation of activated partial thromboplastin time. Reductions in c-Raf-1 expression
relative to pretreatment were observed in the peripheral blood mononuclear cells of some
patients.[35,36] Phase II studies of ISIS 5132 in relevant tumor types are under way. BAY
43-9006 is a small-molecule Raf-1 kinase inhibitor that has significant dose-dependent
antitumor activity in a variety of cancer cell lines.[35] In xenograft models, an additive
antitumor effect was observed when BAY 43-9006 was combined with gemcitabine (Gemzar),
irinotecan (CPT-11, Camptosar), or vinorelbine (Navelbine).[ 38] The results of a phase I
study of BAY 43-9006 in patients with solid tumors including advanced breast cancer were
reported recent- ly.[39] At a twice-daily dose of 800 mg, the dose-limiting toxicity was
diarrhea. Other clinical toxicities included fatigue and skin rash (erythema, desquamation). In
phase I/II trials, responses have been seen in colorectal, hepatocellular, and renal cancers.
Further studies of BAY 43-9006 as a single agent and in combination with chemotherapy are
in progress. In addition, BAY43-9006 is being evaluated in a unique treatmentdiscontinuation
study. MEK Inhibitors
Another component of the signal transduction pathway that has been targeted recently is
MEK. MEK1 and MEK2 are tyrosine kinases downstream of Ras and Raf in the
mitogenactivated Ras/Raf/MEK/ERK cascade, and they represent a crucial point of
convergence that integrates input from a variety of protein kinases through Ras. A selective
small-molecule inhibitor of MEK currently undergoing clinical evaluation is CI-1040. In phase I
studies, this agent was well tolerated, with fatigue, rash, and diarrhea the commonly
reported toxicities.[35,41] Ras, Raf, and MEK have emerged as key protein kinase targets for
anticancer drug design, and preliminary results with these agents are encouraging. Further
research should focus on identifying characteristics that predict antitumor activity with these
agents. In particular, sensitive and reliable methods to determine the molecular phenotype of
tumors that are likely to be sensitive to agents that target components of the Ras/Raf/ MEK
pathway need to be developed and validated in clinical trials. Targeting the PI3K/AkT
Pathway and mTOR The molecular target of rapamycin (mTOR), a downstream effector of
the PI3K/Akt signaling pathway, mediates cell survival and proliferation and is a prime
strategic target in the development of anticancer therapeutics (Figure 3). By targeting mTOR,
the immunosuppressant and antiproliferative agent rapamycin inhibits signals required for
cell-cycle progression, cell growth, and proliferation. Both rapamycin and novel rapamycin
analogs with more favorable pharmaceutical properties (such as CCI-779, RAD001, and
AP23573) are highly specific inhibitors of mTOR.[35,42] In essence, these agents gain
function by binding to the immunophilin FK506 binding protein 12, and the resulting complex
inhibits the activity of mTOR. Because mTOR activates both the 40S ribosomal protein S6
kinase and the eukaryotic initiation factor 4E-binding protein-1, rapamycin-like compounds
block the action of these downstream signaling elements, and result in cell-cycle arrest in the
G1 phase. Rapamycin and its analogs also prevent cyclin-dependent kinase activation, inhibit
retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, leading to
a deficiency of active cyclin-dependent kinase 4/cyclin D1 complexes- all of which potentially
contribute to the prominent inhibitory effects of rapamycin at the G1/S boundary of the cell
cycle.[42] Moreover, rapamycin and its analogs have demonstrated impressive growth
inhibitory effects against a broad range of human cancers, including breast cancer, in both
preclinical and early clinical evaluations.[42,43] In breast cancer cells, PI3K/Akt and mTOR
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pathways seem to be critical for the proliferative responses mediated by the EGFR, the
insulin growth factor receptor, and the estrogen receptor.[35] Breast tumors, particularly
hormone-independent cancers, often harbor genetic alterations in the PI3K/Akt pathway and
exhibit high levels of constitutive Akt activity. The loss of PTEN suppressor gene function has
also been linked to Akt activation. Although mutations of PTEN occur in less than 5% of
breast cancers, a recent report suggests that the complete lack of PTEN protein in breast
cancers with hemizygous deletions of PTEN is not uncommon.[44] Therefore, the
development of inhibitors of mTOR and related pathways is a rational therapeutic strategy
for breast cancer. CCI-779
The water-soluble rapamycin ester CCI-779 was selected for development as an anticancer
agent based on its prominent antitumor profile and favorable pharmaceutical and toxicologic
characteristics in preclinical studies.[42] In vitro, the breast cancer cell lines BT-474, SK-BR-3,
and MCF-7 have demonstrated extraordinary sensitivity to CCI-779.[45] Interestingly,
elements of the PI3K/Akt pathway in these breast cancer cell lines appear to be constitutively
overactive, possibly due to upstream activating aberrations involving erbB1 and/or the
estrogen receptor.[44] Similar results were reported by Yu et al,[46] who demonstrated that
the preponderance of breast cancer cell lines found to be remarkably sensitive to CCI-779
were estrogendependent, overexpressed erbB2, and/ or had PTEN deletions, whereas
resistant breast cancer cell lines lacked these features. In this study, the correlation between
activation of the Akt pathway and sensitivity to CCI-779 was strong. In vivo studies of
CCI-779 administered on intermittent schedules demonstrated antitumor activity and
resolution of biologic evidence of immunosuppression within 24 hours. In consideration of the
possibility that continuous drug administration may predispose patients to
immunosuppression, two intermittent CCI-779 schedules were initially selected for clinical
development: a 30-minute IV infusion administered weekly and a 30-minute IV infusion
administered daily for 5 days every 2 weeks. The principal toxicities of CCI-779 on both
schedules included dermatologic toxicity, myelosuppression, reversible elevations in liver
function tests, and asymptomatic hypocalcemia.[47-50] Further evidence that CCI-779 may
possess notable antitumor activity in patients with advanced breast carcinoma was provided
from a multicenter European phase II study. A total of 109 patients with metastatic breast
cancer that had progressed on taxanes and anthracyclines were enrolled in this study.[51]
CCI-779 was administered at two IV doses (75 and 250 mg) on a weekly schedule. At the
time of the preliminary report, 106 patients had been treated. Clinical benefit was observed
in 49% of patients, with 1 complete response, 8 partial responses, and 43 patients with
stable disease lasting ≥ 8 weeks. Activity was seen at both doses, and the principal toxicities
were asthenia, leukopenia, thrombocytopenia, transaminitis, hypercholesterolemia,
hyperglycemia, stomatitis, depression, and somnolence. These encouraging preliminary
results have prompted further studies of CCI-779 in breast cancer. Because hormone
resistance has been associated with activation of the PI3K and mTOR pathways, studies
combining CCI-779 with hormonal agents are also in progress, including a randomized phase
II study evaluating the feasibility and activity of CCI-779 and the aromatase inhibitor letrozole
(Femara) in patients with estrogendependent breast cancer. In addition, on the basis of
preclinical data suggesting synergy between CCI-779 and chemotherapy,[52] combination
studies with cytotoxic agents are being planned. RAD001 and AP23573
RAD001, an orally bioavailable hydroxyethyl ether of rapamycin, and AP23573, a nonprodrug
rapamycin analog, are also undergoing early clinical evaluations.[35,53-57] Both agents have
demonstrated impressive antiproliferative activity against a wide variety of tumor cell lines in
vitro and in vivo.[53-57] In phase I studies, RAD001 was well tolerated with only mild degrees
of anorexia, fatigue, rash, mucositis, headache, hyperlipidemia, and gastrointestinal
disturbance.[57] Further phase I/II studies with RAD001 and phase I studies with AP23573
have recently been initiated. Inhibiting Tumor Angiogenesis The development of
antiangiogenic drugs as a novel strategy in cancer treatment is based on preclinical evidence
that angiogenesis plays an integral role in tumor growth, progression, and metastasis (Table
2). In breast cancer, both in vitro experiments and clinical studies suggest that tumor
progression and metastases are dependent on angiogenesis.[58-60] A significant correlation
between the degree of intratumoral microvessel density and the probability of the formation
of metastases has been observed, and intratumoral microvessel density has been shown to
be an independent prognostic marker in patients with invasive breast cancer.[61,62] Invasive
human breast cancers express multiple angiogenic factors. Vascular endothelial growth
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factor (VEGF) is among the most specific and potent, inducing endothelial cell migration,
invasion, and in vitro formation of tubelike structures at picomolar concentrations.[63] VEGF
receptors are expressed almost exclusively on endothelial cells, and through VEGF binding
and dimerization of the receptors, their intrinsic intracellular tyrosine kinase and downstream
signaling functions are activated. VEGF is capable of inducing vas cular permeability, which
allows plasma proteins to diffuse into the interstitium and form a lattice network that acts as
a substrate for endothelial and tumor cell growth. In addition, VEGF acts as an endothelial
cell survival factor, with experimental evidence suggesting that inhibition of VEGF activity
induces endothelial cell apoptosis.[ 63-65] Given the importance of VEGF in tumor growth
and metastases, several strategies have been developed to inhibit this pathway.
Bevacizumab
Bevacizumab (Avastin), a recombinant humanized anti-VEGF neutralizing antibody, has
entered clinical trials and recently received fast-track status from the US Food and Drug
Administration. The antibody blocks the binding of all VEGF isoforms to the receptors and
inhibits the biologic activities of VEGF as measured by assays for endothelial mitogenesis,
vascular permeability, and in vivo angiogenesis.[ 66] Bevacizumab was evaluated in a phase
I study in 25 patients with advanced solid tumors,[ 67] and like other antibodies, was
delivered intravenously. The serum half-life of this agent was approximately 21 days, and at
doses ≥ 0.3 mg/kg, it provided complete suppression of free serum VEGF. The toxicities that
occurred during the first several hours after infusion of the antibody were limited to grade
1/2 headache, nausea, asthenia, and low-grade fever, which occurred in a minority of
patients. Intratumoral hemorrhage was reported in two patients treated at the 3 mg/kg dose
level. The favorable antitumor activity of antibodies to VEGF, combined with cytotoxic
chemotherapy (doxorubicin), has been demonstrated in MCF-7 breast cancer cell lines.[68] In
addition, phase I studies have assessed the feasibility of combining bevacizumab with
chemotherapy. In a recently completed phase I study,[66] bevacizumab at 3 mg/kg/wk was
combined with three standard chemotherapy regimens: doxorubicin at 50 mg/m2 every 4
weeks, carboplatin at an area under the concentration-time curve (AUC) of 6 plus paclitaxel
at 175 mg/m2 every 4 weeks, and fluorouracil (5-FU)
at 500
mg/m2 with leucovorin at 20 mg/m2 weekly. This study demonstrated that bevacizumab could
be delivered safely in combination with chemotherapy at doses associated with VEGF
blockade without synergistic toxicity. Bevacizumab was recently evaluated in patients with
previously treated metastatic breast cancer.[69] This twoinstitution phase II study enrolled
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75 patients in three cohorts representing three dose levels: 3, 10, and 20 mg/kg every other
week. Overall, 17% of patients responded or achieved stable disease at 5 months, and three
patients continued therapy without disease progression for more than 12 months. The agent
was generally well tolerated, with several patients developing mild hypertension and
proteinuria. No episodes of significant bleeding were noted. These encouraging results led to
two additional phase III studies of bevacizumab in advanced breast cancer. The first
study[70] compared capecitabine, with or without bevacizumab, in women with metastatic
breast cancer who had progressed despite prior therapy with both an anthracycline and a
taxane. The study demonstrated a doubling of the response rate from 19% to 30% in patients
treated with the combination of bevacizumab and capecitabine. However, the responses
were not durable and did not have an impact on progression- free survival, the major end
point of this trial. As in prior studies, the main toxicities of bevacizumab were modest
degrees of hypertension and low-grade bleeding. The failure of this trial to demonstrate an
impact on survival may be due to the advanced disease of the patients, which has led to the
evaluation of bevacizumab in patients with less advanced disease. One such multicenter
phase III trial (E2100), initiated by the Eastern Cooperative Oncology Group, is randomizing
patients with newly diagnosed metastatic breast cancer to treatment with either paclitaxel as
a single agent administered on a weekly schedule or the combination of paclitaxel and
bevacizumab. VEGF Tyrosine Kinase Inhibitors
An alternative strategy for inhibiting VEGF activity is through selective inhibition of
membrane receptor tyrosine kinases. These competitive tyrosine kinase inhibitors localize to
the ATP-binding site and inhibit phosphorylation and activation of downstream signaling
following binding of the VEGF receptor. In human tumor cell line xenografts, these agents
elicit substantial delay of growth in a broad spectrum of tumors.[71] The development of
SU5416, a small-molecule VEGF tyrosine kinase inhibitor, has been halted because of its lack
of target specificity and unfavorable pharmaceutical properties. However, other similar VEGF
tyrosine kinase inhibitors such as CP-547,632 and PTK787/ZK222584 remain in clinical
trials.[72-74] In addition, agents that inhibit multiple tyrosine kinase pathways are being
actively explored. These include ZD6474 and PKI 166, inhibitors of both VEGF receptor
tyrosine kinase and EGFR tyrosine kinase, and SU11248, a small-molecule, multitargeted
receptor kinase inhibitor of platelet-derived growth factor (PDGF), VEGF, KIT, and
FLT3.[73,75-78]
ZD6474-ZD6474 has also exhibited antitumor activity in a variety of human cancer
cells lines and in xenograft models.[76] In addition, in vitro studies have
demonstrated an additive effect on inhibition of tumor growth when ZD6474 was
combined with taxanes.[76] In phase I studies, ZD6474 administered on a daily oral
dosing schedule was generally well tolerated, with diarrhea and rash as the main
toxicities. Asymptomatic prolongation of the QT interval was also observed in 7 of the
49 patients included in the study.[73] This agent is now being evaluated in phase II
trials in patients with metastatic breast cancer.
SU11248-Clinical development of SU11248 is also under way. This agent has
exhibited broad and potent antitumor activity in preclinical studies, causing
regression, growth arrest, or substantially reduced growth of various established
xenografts.[77,78] A recent study assessed the safety and tolerability of SU11248
administered daily for either 2 or 4 weeks followed by 2 weeks' rest in patients with
advanced solid tumors.[79] The most frequent adverse events were constitutional
(fatigue, asthenia), gastrointestinal (nausea, vomiting, and diarrhea), and
hematologic (neutropenia, thrombocytopenia). Fatigue/ asthenia, which was readily
reversible upon discontinuation of the drug, proved to be the dose-limiting toxicity.
The clinical responses observed in this phase I study included 1 partial response and
Modulating
12 patients
Apoptosis
with stable
Antiapoptotic
disease.mutations significantly contribute to the malignant
phenotype by allowing the cell to survive under conditions that would normally trigger its
demise. The bcl-2 gene product has been implicated in the growth and development of a
variety of tumors including breast cancer and has the potential to confer chemoresistance
and radioresistance to established tumors.[80-82] The Bcl-2 protein dimerizes both with itself
and with other members of the Bcl-2 family (Bcl-xL, Bax, and Bcl-xS), and the interaction of
these protein dimers influences sensitivity to apoptotic stimuli. Bcl-2 Antisense Therapy
Preclinical data demonstrate that Bcl-2 antisense therapy with oblimersen (G3139,
Genasense) has antitumor effects against breast cancer.[83] Treatment with oblimersen is
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well tolerated and leads to a reduction in intratumoral Bcl-2 protein levels.[80,84] Oblimersen
has been combined with cytotoxic chemotherapy.[85,86] In human breast cancer xenograft
models, the combination of oblimersen and docetaxel produced an enhanced antitumor
effect, leading to durable tumor regression. These preclinical data provided the basis for
evaluation of this combination in breast cancer. In a recent phase I trial, oblimersen and
weekly docetaxel were tolerable and resulted in a tumor response in two of the five patients
with advanced breast cancer included in this study.[85] These initial data support the further
development of this combination for metastatic breast cancer. TNF-Related Apoptosis
Ligand
Mutations in survival factors at the cell surface including death receptors of the TNF receptor
family may also lead to dysregulation of apoptosis. The TNF-related apoptosis ligand (TRAIL)
is a member of the TNF ligand superfamily with high homology to the Fas/Apo1 ligand.
Although the biologic functions of TRAIL remain incompletely defined, strong evidence of
TRAIL's ability to trigger apoptosis in numerous cancer cell lines supports a physiologic role
for TRAIL in mediating apoptosis. TRAIL mediates apoptosis through two death receptors,
TRAIL-R1 (death receptor 4, DR4) and TRAIL-R2 (death receptor 5, DR5). These receptors
were isolated and named based on the presence of a death domain in their cytoplasmic tails
that is capable of initiating a cascade of caspase activation and ultimate cell death.
Resistance to TRAIL-induced apoptosis has been demonstrated via in vitro studies of breast
cancer cell lines, with inactivating mutations in the TRAIL-R1 and -R2 genes being particularly
important.[ 87,88] Therapies targeting TRAIL-R1 and TRAIL-R2 are under development. One
such agent, TRM-1, a fully humanized agonist monoclonal antibody to the TRAIL-R1 receptor,
is currently in phase I trials. TRM-1 has been shown to induce apoptosis in cancer cell lines,
and investigators have predicted that it will display activities similar to the TRAIL-R1 agonistic
ligand.[89]Role of Histone Deacetylase Inhibitors Another attractive target for
intervention in breast cancer is histone acetylation. The acetylation and deacetylation of
histones plays an important role in the regulation of gene expression. Hypoacetylation of
histones is associated with a condensed chromatin structure that results in the repression of
gene transcription, whereas acetylated histones are associated with a more open chromatin
structure and activation of transcription. Histone deacetylase and the family of acetyl
transferases are involved in determining the acetylation of histones. Inhibition of histone
deacetylase increases histone acetylation, which, in turn, leads to the transcription of a few
genes whose expression causes inhibition of tumor growth.[90-92] The mechanism of
selectivity of gene expression is currently not understood but is an area of intense study.
Inhibitors of histone deacetylase have been shown to induce growth arrest, differentiation,
and apoptosis in a variety of tumors, including human breast cancer cell lines.[90,93] In
preclinical studies, treatment with LAQ824, a hydroxamic acid analog inhibitor of histone
deacetylation, led to downregulation of HER2 in human breast cancer SKBR-3, BT-474, and
MB-468 cells and sensitized these cells to the apoptotic effects of trastuzumab and
polymerizing agents (docetaxel and epothilone B).[93] Histone deacetylase inhibitors cause
acetylated histones to accumulate in both tumor and peripheral circulating mononuclear
cells, and this accumulation has been used as a marker of biologic activity. Several drugs
that inhibit histone deacetylation are being evaluated in phase I/II clinical trials as single
agents or in combination with cytotoxic chemotherapy.[90-95] These include suberoylanilide
hydroxamic acid, pyroxamide, depsipeptide, MS-275, CI-994, and LAQ824. Results of a phase
I trial of suberoylanilide hydroxamic acid in heavily pretreated patients with hematologic
malignancies were recently reported.[ 95] The major toxicities observed included fatigue,
diarrhea, anorexia, dehydration, and myelosupression. Among the clinical responses in this
refractory group of 29 patients was a reduction in measurable tumor (seen in 6 patients).
Encouraging data from preclinical and phase I studies have prompted further evaluation of
this class of agents in patients with metastatic breast cancer. Conclusions Improvements in
our understanding of the molecular events that mediate tumor growth and metastases have
enabled the design and development of novel therapeutic agents that specifically target
intrinsic aberrancies in cancer cells. New combinations of cytotoxic chemotherapy and
targeted agents are being explored in breast cancer, generating much excitement and
expectation that these innovative therapies will improve the outcome of patients with this
disease. The increasing use of molecular profiling techniques should give us the opportunity
to select the most active agents for a given tumor and thereby reduce unnecessary side
effects. In addition, genomics and proteomics provide us with the potential for discovering
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the hidden targets of our current therapeutic arsenal. In order to improve the efficiency of
the evaluation process and increase the probability of success, the future development of
molecularly targeted agents needs to incorporate assays to assess the suitability of the
patient population, the target, and the effects of the target. Such assays may lead to
enrichment of early proof-of-principle studies in patients who are most likely to benefit from
these agents or who might achieve responses that are easy to detect in nonrandomized
trials. New initiatives in clinical trial design including novel correlative imaging, alternative
end points such as time to progression, and novel approaches such as randomized
discontinuation schemes, are needed to determine the future utility of these agents.
Disclosures: The author(s) have no significant financial interest or other relationship with the
manufacturers of any products or providers of any service mentioned in this article.
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Source URL:
http://www.cancernetwork.com/review-article/new-generation-targeted-therapies-breast-cancer-1
Links:
[1] http://www.cancernetwork.com/review-article
[2] http://www.cancernetwork.com/breast-cancer
[3] http://www.cancernetwork.com/oncology-journal
[4] http://www.cancernetwork.com/authors/samira-syed-md
[5] http://www.cancernetwork.com/authors/eric-rowinsky-md
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