An antibody to amphiregulin, an abundant growth factor in patients' fluids, inhibits ovarian tumors.
Growth factors of the epidermal growth factor (EGF)/neuregulin family are involved in tumor progression and, accordingly, antibodies that intercept a cognate receptor, epidermal growth factor receptor (EGFR)/ERBB1, or a co-receptor, HER2, have been approved for cancer therapy. Although they might improve safety and delay onset of chemoresistance, no anti-ligand antibodies have been clinically approved. To identify suitable ligands, we surveyed fluids from ovarian and lung cancer patients and found that amphiregulin (AREG) is the most abundant and generalized ligand secreted by advanced tumors. AREG is a low affinity EGFR ligand, which is upregulated following treatment with chemotherapeutic drugs. Because AREG depletion retarded growth of xenografted ovarian tumors in mice, we generated a neutralizing monoclonal anti-AREG antibody. The antibody inhibited growth of ovarian cancer xenografts and strongly enhanced chemotherapy efficacy. Taken together, these results raise the possibility that AREG and other low- or high-affinity binders of EGFR might serve as potential targets for cancer therapy.
Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
S
S
Carvalho
Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
M
M
Lindzen
Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
M
M
Lauriola
Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
N
N
Shirazi
Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
S
S
Sinha
Kaplan Medical Center, Rehovot, Israel.
A
A
Abdul-Hai
The Dr. Pinchas Borenstein Talpiot Medical Leadership Program and Institute of Oncology, The Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan, Israel.
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K
Levanon
Department of Gynecologic Oncology, Chaim Sheba Medical Center, Ramat Gan, Israel.
J
J
Korach
Department of Pathology, Sheba Medical Center, Ramat Gan, Israel.
I
I
Barshack
Institutional Tissue Banks, Sheba Medical Center, Ramat Gan, Israel.
Y
Y
Cohen
Institute of Pulmonary Oncology, Chaim Sheba Medical Center Ramat Gan, Israel.
A
A
Onn
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
G
G
Mills
Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
Y
Y
Yarden
D066258:Amphiregulin; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000032:analysis; D066255:EGF Family of Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D016211:Transforming Growth Factor alpha / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays
C587848:AREG protein, human; D066258:Amphiregulin; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D017077:Culture Media, Conditioned; D066255:EGF Family of Proteins; D016211:Transforming Growth Factor alpha; C512478:EGFR protein, human; D066246:ErbB Receptors