Targeting the heparin-binding epidermal growth factor-like growth factor in ovarian cancer therapy.
OBJECTIVE
Therapeutics targeting the ErbB protein family receptors have not always yielded favorable or successful results in present cancer therapy. This review discusses the possibility of the clinical adaptation of targeting against heparin-binding epidermal growth factor-like growth factor (HB-EGF), one of the ligands of the ErbB system, in ovarian cancer therapy.


RESULTS
We have previously described the results of studies concerning roles of HB-EGF in tumor formation in ovarian cancer. In brief, lisophosphatidic acid (LPA) and HB-EGF are predominantly expressed in advanced ovarian cancer, and LPA-induced, a disintegrin and metalloprotease-mediated ectodomain shedding of HB-EGF was found to be critical to tumor formation. We also noted that exogenous expression of HB-EGF enhanced tumor formation but inhibition blocked both extracellular signal-related kinase and serine/threonine protein kinase activation. Finally we investigated the antitumor effects of CRM197 - a specific HB-EGF inhibitor - on ovarian cancer cells by evaluating human ovarian cancer cell proliferation.


CONCLUSIONS
We discuss alternative strategies to develop the chemotherapeutic agent based on targeting ErbB family ligands rather than their receptors. A phase I study of CRM197 for advanced ovarian cancer has already begun, which is the first approved trial of ErbB-ligand-targeted therapy. We also discuss clinical adaptations based on combination of CRM197 with other conventional chemotherapeutic agents.
Tsujioka
Hiroshi
H
Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
Yotsumoto
Fusanori
F
Hikita
Shoko
S
Ueda
Taeko
T
Kuroki
Masahide
M
Miyamoto
Shingo
S
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D017321:Clinical Trials, Phase I as Topic; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors*; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction
D000970:Antineoplastic Agents; D001426:Bacterial Proteins; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008246:Lysophospholipids; C028581:CRM197 (non-toxic variant of diphtheria toxin); D004815:Epidermal Growth Factor; D017346:Protein Serine-Threonine Kinases; C032881:lysophosphatidic acid