Molecular target therapies in endometrial cancer: from the basic research to the clinic.
Molecular targeted therapies represent an interesting field of pharmacological research in endometrial cancer. The loss of PTEN (phosphatase and tensin homolog deleted on chromosome 10) function, with consequent activation of the PI3K (phosphatidylinositol-3-kinase)-AKT (serine/threonine-specific protein kinase)-mTOR (mammalian target of rapamycin) signaling pathway, occurs in 32-83% of endometrioid-type endometrial carcinomas, thus suggesting a role for mTOR inhibition in this malignancy. Some analogues of rapamycin (CCI-799, RAD-001, AP-23573) have been developed and tested in different tumors including endometrioid-type endometrial carcinoma. For example, AP-23573 achieved a clinical benefit response in 33% of 27 heavily pretreated patients, and CCI-799 obtained a 26% partial response rate and a 63% stable disease rate in 19 patients. Overexpression of ErbB-2 (epidermal growth factor type II receptor) has been detected in 18-80% of uterine papillary serous carcinomas (UPSCs), thus providing a biological rationale for the use of trastuzumab in these aggressive tumors. UPSC often overexpresses claudin-3 and claudin-4, which represent the epithelial receptors for Clostridium perfringens enterotoxin (CPE). CPE-mediated therapy might be a novel treatment modality for UPSC resistant to chemotherapy. A better understanding of the signaling transduction pathways that are dysregulated in endometrioid-type endometrial carcinoma and UPSC will allow the development of novel molecular targeted therapies.
Department of Procreative Medicine, Division of Gynecology and Obstetrics, University of Pisa, Pisa, Italy. a.gadducci@obgyn.med.unipi.it
Angiolo
A
Gadducci
Roberta
R
Tana
Stefania
S
Cosio
Antonio
A
Fanucchi
Andrea Riccardo
AR
Genazzani
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018269:Carcinoma, Endometrioid / Q000188:drug therapy / Q000378:metabolism; D018283:Cystadenocarcinoma, Papillary / Q000188:drug therapy / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004768:Enterotoxins / Q000494:pharmacology; D005260:Female; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004768:Enterotoxins; D051059:PTEN Phosphohydrolase; D011494:Protein Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D000068878:Trastuzumab; C035598:enterotoxin, Clostridium; C515074:ridaforolimus; C401859:temsirolimus; C546842:MTOR protein, human; C494929:PTEN protein, human