Cancer Res.
2008 Apr 15;68(8):3037-42.
Links
Gender-related survival differences associated
with EGFR polymorphisms in metastatic colon
cancer.
Press
OA, Zhang
W, Gordon
MA, Yang
D, Lurje G, Iqbal S, El-Khoueiry A, Lenz
HJ.
Division of
Medical Oncology, University of Southern California/Norris Comprehensive
Cancer Center, Keck School of Medicine, Los Angeles, CA 90033, USA.
Evidence is accumulating
supporting gender-related differences in the development of colonic
carcinomas. Sex steroid hormone receptors are expressed in the colon and
interact with epidermal growth factor receptor (EGFR), a gene widely
expressed in colonic tissue. Increased EGFR expression is linked with poor
prognosis in colon cancer. Within the EGFR gene there are two functional
polymorphisms of interest: a polymorphism located at codon
497 (HER-1 R497K) and a dinucleotide (CA)(n) repeat polymorphism located within intron 1. These germ-line polymorphisms of EGFR were
analyzed in genomic DNA from 318 metastatic colon
cancer patients, 177 males and 141 females, collected from 1992 to 2003.
Gender-related survival differences were associated with the HER-1 R497K
polymorphism (P(interaction) = 0.003). Females
with the HER-1 497 Arg/Arg variant had better
overall survival (OS) when compared with the Lys/Lys
and/or Lys/Arg variants. In males the opposite
was true. The EGFR dinucleotide (CA)(n) repeat also trended with a gender-related OS
difference (P(interaction) = 0.11). Females with both short <20 (CA)(n) repeat alleles had better OS than those with any
long >or=20 (CA)(n) repeats. In males the opposite was true. Combination
analysis of the two polymorphisms taken together also revealed the same
gender-related survival difference (P(interaction)
= 0.002). These associations were observed using multivariable analysis.
The two polymorphisms were not in linkage disequilibrium and are
independent of one another. This study supports the role of functional EGFR
polymorphisms as independent prognostic markers in metastatic
colon cancer. As a prognostic factor, these variants had opposite
prognostic implications based on gender.
PMID: 18413774 [PubMed
- in process]
Mol
Cancer Res. 2007 Mar;5(3):283-93.
Links
Activation of the EGFR gene target EphA2
inhibits epidermal growth factor-induced cancer cell motility.
Larsen
AB, Pedersen
MW, Stockhausen
MT, Grandal MV, van
Deurs B, Poulsen HS.
Department
of Radiation Biology, Section 6321, Copenhagen University Hospital,
Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
EphA2 overexpression
has been reported in many cancers and is believed to play an important role
in tumor metastasis and angiogenesis. We show that the activated epidermal
growth factor receptor (EGFR) and the cancer-specific constitutively active
EGFR type III deletion mutant (EGFRvIII) induce
the expression of EphA2 in mammalian cell lines, including the human cancer
cell lines A431 and HN5. The regulation is partially dependent on
downstream activation of mitogen-activated
protein kinase/extracellular signal-regulated kinase kinase and is a direct
effect on the EphA2 promoter. Furthermore, EGFR and EphA2 both localize to
the plasma membrane and EphA2 coimmunoprecipitates
with activated EGFR and EGFRvIII. Ligand activation of EphA2 and EphA2 knockdown by small
interfering RNA inhibit EGF-induced cell motility of EGFR-overexpressing human cancer cells, indicating a
functional role of EphA2 in EGFR-expressing cancer cells.
PMID: 17374733 [PubMed
–
Stem Cells. 2007 Jun;25(6):1410-22.
Epub 2007 Mar 1.
Links
Epidermal growth factor signaling mediated by
grb2 associated binder1 is required for the spatiotemporally regulated
proliferation of olig2-expressing progenitors in the embryonic spinal cord.
Hayakawa-Yano
Y, Nishida
K, Fukami S, Gotoh Y, Hirano
T, Nakagawa
T, Shimazaki T, Okano
H.
Department
of Physiology, Keio University School of Medicine, 35 Shinanomachi,
Shinjuku-ku, Tokyo
160-8582, Japan.
Gab1 (Grb2 associated binder1)
has been identified as an adaptor molecule downstream of many growth
factors, including epidermal growth factor (EGF), fibroblast growth factor,
and platelet-derived growth factor, which have been shown to play crucial
roles as mitotic signals for a variety of neural progenitor cells,
including stem cells, both in vitro and in vivo. Here, we show that Gab1
deficiency results in a reduction in the number of Olig2-positive (Olig2(+)) progenitor cells in the developing mouse
spinal cord after embryonic day 12.5 (E12.5), when gliogenesis
starts in the pMN domain where the EGF receptor
(EGFR) is expressed predominantly. Our in vitro analysis further revealed
that Gab1 is essential for EGF-dependent proliferation of Olig2(+)
progenitor cells derived from the E12.5 ventral and E14.5 dorsal but not
ventral spinal cord, whereas Gab1 is always required for the activation of
Akt1 but not of ERK1/2. Moreover, we found that the action of the Gab1/Akt
pathway is context-dependent, since constitutively active Akt1 could rescue
the proliferation defect only in the E12.5 spinal cord of the Gab1-deficient
mouse in vitro. Finally, we demonstrated that EGFR-deficient mice and
Gab1-deficient mice showed a similar reduction in the number of Olig2(+) progenitor cells in the developing spinal cord.
These findings indicate that EGFR-mediated signaling through Gab1/Akt
contributes to the sufficient expansion of Olig2(+)
progenitor cells in a spatiotemporally regulated manner, which represents
the origin of glial cells in the developing
spinal cord. Disclosure of potential conflicts of interest is found at the
end of this article.
PMID: 17332510 [PubMed
- indexed for MEDLINE]
EGFR expression and HER2/neu overexpression/amplification
in endometrial carcinosarcoma.
Livasy
CA, Reading FC,
Moore DT, Boggess
JF, Lininger
RA.
Department of Pathology and Lab Medicine, University of North Carolina,
Chapel Hill, NC 27599-7525, USA; Lineberger
Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC
27599-7525, USA.
OBJECTIVE.: Endometrial carcinosarcomas
are aggressive biphasic neoplasms traditionally
treated as a high-grade uterine sarcoma. Epidermal growth factor receptor
(EGFR) and HER2/neu (HER2) tyrosine kinases have
been implicated in the development and progression of several human cancers
and are targets for therapeutic intervention. The aim of this study was to
evaluate for HER2 and EGFR expression in cases of endometrial carcinosarcoma. METHODS.:
Formalin-fixed, paraffin-embedded sections from 55 cases of confirmed
endometrial carcinosarcoma were immunostained with commercially available antibodies to
EGFR and HER2. Fluorescent in situ hybridization for HER2 gene
amplification was performed on all cases showing 2+ or 3+ HER2 staining by immunohistochemistry. HER2 gene amplification and EGFR
expression were correlated with several prognostic variables. RESULTS.: EGFR expression was identified in the majority
of tumors (45/55, 82%). HER2 overexpression (3+)
was seen in 14/55 (25%) cases and HER2 gene amplification was seen in 11
(20%) cases. EGFR expression and HER2 gene amplification did not show
significant correlation with disease progression, disease-free survival or
overall survival. The carcinomatous component of
tumors more frequently showed HER2 overexpression
as compared to the sarcomatous component (25% vs.
4%, P = 0.008). The sarcomatous component of
tumors more frequently showed EGFR overexpression
as compared to the carcinomatous component (44%
vs. 24%, P = 0.04). CONCLUSIONS.: EGFR and HER2
appear to play a role in the carcinogenesis of endometrial carcinosarcomas. The carcinomatous
and sarcomatous elements of these tumors showed
consistent differences in HER2 and EGFR expression patterns supporting
biologic differences between these components. Studies evaluating the
clinical utility of HER2 or EGFR targeted therapy in these tumors appear
warranted.
PMID: 16157366 [PubMed - as supplied
Humanization of a recombinant monoclonal antibody
to produce a therapeutic HER dimerization
inhibitor, pertuzumab.
Adams CW, Allison DE,
Flagella K,
Presta L, Clarke J, Dybdal N, McKeever K,
Sliwkowski MX.
Genentech Inc., One DNA Way, South San Francisco,
CA, 94080, USA, adams.camellia@gene.com.
Dimerization is essential for activity of human epidermal growth factor
receptors (HER1/EGFR, HER2/ErbB2, HER3/ErbB3, and ErbB4) and mediates
intracellular signaling events leading to cancer cell proliferation,
survival, and resistance to therapy. HER2 is the preferred dimerization partner. Activation of HER signaling
pathways may be blocked by inhibition of dimer
formation using a monoclonal antibody (MAb)
directed against the dimerization domain of HER2.
The murine MAb 2C4 that
specifically binds the HER2 dimerization domain
was cloned as a chimeric antibody, humanized
using a computer-generated model to guide framework substitutions, and
variants were tested as Fabs. Pharmacokinetics
and toxicology were evaluated in rodents and cynomolgus
monkeys. Cloning the variable domains of MAb 2C4
into a vector containing human kappa and CH1 domains allowed construction
of a mouse-human chimeric Fab.
DNA sequencing of the chimeric clone permitted
identification of CDR residues. The full-length IgG1 of variant F-10 was
equivalent in binding to chimeric IgG1 and was
designated pertuzumab (rhuMAb
2C4; Omnitarg). Pertuzumab
pharmacokinetics was best described by a two-compartment model with a
distribution phase of <1 day, terminal half-life of ~10 days, and volume
of distribution of ~40 mL/kg that approximates
serum volume. With the exception of diarrhea, pertuzumab
was generally well tolerated in cynomolgus
monkeys. Pertuzumab, a recombinant humanized IgG1
MAb, is the first of a new class of agents known
as HER dimerization inhibitors. Inhibition of HER
dimerization may be an effective anticancer
strategy in tumors with either normal or elevated expression of HER2.
PMID: 16151804 [PubMed - as supplied by
publisher]
Prime-boost vaccination with plasmid and
adenovirus gene vaccines control HER2/neu+ metastatic
breast cancer in mice.
Wang X, Wang JP, Rao XM, Price JE, Zhou HS, Lachman LB.
Department of Experimental Therapeutics, The University
of Texas MD Anderson
Cancer Center,
Houston, TX, USA.
xiaoyanwang@mdanderson.org
INTRODUCTION: Once metastasis has occurred, the possibility of completely
curing breast cancer is unlikely, particularly for the 30 to 40% of cancers
overexpressing the gene for HER2/neu. A vaccine
targeting p185, the protein product of the HER2/neu gene, could have
therapeutic application by controlling the growth and metastasis of highly
aggressive HER2/neu+ cells. The purpose of this study was to determine the
effectiveness of two gene vaccines targeting HER2/neu in preventive and
therapeutic tumor models. METHODS: The mouse breast cancer cell line A2L2,
which expresses the gene for rat HER2/neu and hence p185, was injected into
the mammary fat pad of mice as a model of solid tumor growth or was
injected intravenously as a model of lung metastasis. SINCP-neu, a plasmid containing Sindbis
virus genes and the gene for rat HER2/neu, and Adeno-neu,
an E1,E2a-deleted adenovirus also containing the
gene for rat HER2/neu, were tested as preventive and therapeutic vaccines.
RESULTS: Vaccination with SINCP-neu or Adeno-neu before tumor challenge with A2L2 cells
significantly inhibited the growth of the cells injected into the mammary
fat or intravenously. Vaccination 2 days after tumor challenge with either
vaccine was ineffective in both tumor models. However, therapeutic
vaccination in a prime-boost protocol with SINCP-neu
followed by Adeno-neu significantly prolonged the
overall survival rate of mice injected intravenously with the tumor cells.
Naive mice vaccinated using the same prime-boost protocol demonstrated a
strong serum immunoglobulin G response and p185-specific cellular immunity,
as shown by the results of ELISPOT (enzyme-linked immunospot)
analysis for IFNgamma. CONCLUSION: We report
herein that vaccination of mice with a plasmid gene vaccine and an
adenovirus gene vaccine, each containing the gene for HER2/neu, prevented
growth of a HER2/neu-expressing breast cancer cell line injected into the
mammary fat pad or intravenously. Sequential administration of the vaccines
in a prime-boost protocol was therapeutically effective when tumor cells
were injected intravenously before the vaccination. The vaccines induced
high levels of both cellular and humoral immunity
as determined by in vitro assessment. These findings indicate that clinical
evaluation of these vaccines, particularly when used sequentially in a
prime-boost protocol, is justified.
PMID: 16168101 [PubMed - in process]
Combined Radioimmunotherapy and
Chemotherapy of Breast Tumors with Y-90-Labeled Anti-Her2 and Anti-CEA
Antibodies with Taxol.
Crow DM, Williams L,
Colcher
D, Wong JY, Raubitschek
A, Shively JE.
Department of Radioimmunotherapy, Division of
Radiation Oncology, City of Hope National Medical Center, Duarte,
California 91010, Division of Radiology, City of Hope National Medical
Center, Duarte, California 91010, and Division of Immunology, Beckman
Research Institute of the City of Hope, Duarte, California 91010.
Because breast cancer cells often express either Her2/neu or carcinoembryonic antigen (CEA) or both, these tumor markers
are good targets for radioimmunotherapy using
Y-90-labeled antibodies. We performed studies on nude mi
ce
bearing xenografts from MCF7, a cell line that
has low Her2 and CEA expression, to more accurately reflect the more usual
situation in breast cancer. Although uptake of In-111 anti-CEA into tumors
was lower than that for In-111-labeled anti-Her2, radioimmunotherapy
(RIT) with Y-90 anti-CEA was equivalent to that of Y-90 anti-Her2. When
either Y-90 antibody was combined with a split-dose treatment with Taxol, the antitumor effect
was greater than with either agent alone. When Y-90 anti-CEA was combined
with a single dose of Taxol, the results were
equivalent to the split-dose regimen. RIT plus cold Herceptin
had no additional effects on tumor size reduction over RIT alone. When
animals were first treated with Y-90 anti-Her2 and imaged 1-2 weeks later
with In-111 anti-CEA or anti-Her2, tumor uptake was higher for anti-CEA and
improved over tumor uptake with no prior RIT. These results suggest that a split
dose of RIT with anti-Her2 antibody followed by anti-CEA antibody would be
more effective than a single dose of either. This prediction was partially
confirmed in a controlled study comparing single- vs
split-dose anti-Her2 RIT followed by either anti-Her2 or anti-CEA RIT.
These studies suggest that combined RIT and Taxol
therapy are suitable in breast cancers expressing either low amounts of
Her2 or CEA, thus expanding the number of eligible patients for combined
therapies. They further suggest that split-dose RIT using different
combinations of Y-90-labeled antibodies is effective in antitumor
therapy.
PMID: 16173788 [PubMed - as supplied by
publisher]
.
Phase I clinical study of the recombinant antibody toxin scFv(FRP5)-ETA
specific for the ErbB2/HER2 receptor in patients with advanced solid malignomas.
von Minckwitz G, Harder S, Hovelmann
S, Jager
E, Al-Batran SE, Loibl
S, Atmaca
A, Cimpoiasu
C, Neumann A,
Abera
A, Knuth A, Kaufmann M,
Jager
D, Maurer AB,
Wels
WS.
Department of Gynecology and Obstetrics, University Hospital
Frankfurt, Germany.
INTRODUCTION: ScFv(FRP5)-ETA is a recombinant antibody toxin with binding
specificity for ErbB2 (HER2). It consists of an N-terminal single-chain
antibody fragment (scFv), genetically linked to
truncated Pseudomonas exotoxin A (ETA). Potent antitumoral activity of scFv(FRP5)-ETA against
ErbB2-overexpressing tumor cells was previously demonstrated in vitro and
in animal models. Here we report the first systemic application of scFv(FRP5)-ETA
in human cancer patients. METHODS: We have performed a phase I dose-finding
study, with the objective to assess the maximum tolerated dose and the
dose-limiting toxicity of intravenously injected scFv(FRP5)-ETA. Eighteen
patients suffering from ErbB2-expressing metastatic
breast cancers, prostate cancers, head and neck cancer, non small cell lung
cancer, or transitional cell carcinoma were treated. Dose levels of 2, 4,
10, 12.5, and 20 microg/kg scFv(FRP5)-ETA were
administered as five daily infusions each for two consecutive weeks. RESULTS:
No hematologic, renal, and/or cardiovascular
toxicities were noted in any of the patients treated. However, transient
elevation of liver enzymes was observed, and considered dose limiting, in
one of six patients at the maximum tolerated dose of 12.5
microg/kg, and in two of three patients at
20 microg/kg. Fifteen minutes after injection,
peak concentrations of more than 100 ng/ml scFv(FRP5)-ETA
were obtained at a dose of 10 microg/kg,
indicating that predicted therapeutic levels of the recombinant protein can
be applied without inducing toxic side effects. Induction of antibodies
against scFv(FRP5)-ETA was observed 8 days after
initiation of therapy in 13 patients investigated, but only in five of
these patients could neutralizing activity be detected. Two patients showed
stable disease and in three patients clinical signs of activity in terms of
signs and symptoms were observed (all treated at doses > or = 10 microg/kg). Disease progression occurred in 11 of the
patients. CONCLUSION: Our results demonstrate that systemic therapy with scFv(FRP5)-ETA
can be safely administered up to a maximum tolerated dose of 12.5 microg/kg in patients with ErbB2-expressing tumors,
justifying further clinical development.
PMID: 15611632 [PubMed - as supplied by publisher]
Mutations in BRCA1 and BRCA2 show different
expressivity wit
h respect to cancer risk, and
allelic heterogeneity may be present in both genes. We collected 179
pedigrees with identified germline mutation (104
BRCA1 and 75 BRCA2), ascertained in six collaborating centers of the
Italian Consortium for Hereditary Breast and Ovarian Cancer. Significant
heterogeneity was detected for several variables, and a logistic regression
model including age of diagnosis in the proband,
presence of ovarian cancer in the family, presence of prostate or
pancreatic cancer in the family, and presence of male breast cancer in the
family proved to be effective in predicting the presence of a mutation in a
gene rather than the other. Excess of familial aggregation of both breast
and ovarian cancer was observed in both genes. Proportion of ovarian cancer
was increased in the 5' portion of BRCA1, and presence of prostate or
pancreatic cancer in a family was correlated with presence of ovarian cancer
in BRCA2
PMID: 14531499 [PubMed - in process]
