Current status of molecular-targeted drugs for endometrial cancer (Review)

Abstract

Endometrial cancer is a common gynecological malignant tumor in Western countries and its incidence has also been on the increase in Asia. Genetic abnormalities related to onset and progression of malignancy in the endometrial membrane and signaling system have been identified and the developmental mechanism of endometrial cancer is becoming elucidated. The identification of the molecules related to these abnormalities has led to new potential treatment regimens for endometrial cancer, using molecular-targeted drugs. The current chemotherapy for endometrial cancer often causes systemic side effects that require discontinuation of the treatment. Furthermore, a treatment regimen for cancers of rare histological types has not been established. Recent studies on endometrial cancer revealed patterns of genetic disorders that differ among the histological types. Genetic and molecular information that underlie pathological changes and is associated with DNA mismatch repair genes and epigenetic regulation was also identified. Targeting of these mechanisms with molecular-targeted drugs has been performed with the aim of linking treatment to the carcinogenic mechanism at the molecular and genetic levels. However, the response rates with single-agent therapy are generally low and several problems remain unresolved. Trials of combinations of molecular-targeted drugs with currently available treatments and identification of factors determining sensitivity are required to overcome these difficulties.

Past, Present and Future Perspectives on the Management of Endometrial Cancer— A Comprehensive Review

“…As opposed to conventional cytotoxic drugs, molecular-targeted cytotoxic drugs are able to differentiate between normal cells and cancerous cells, and therefore specifically damage only the cancerous cells by inhibiting the cellular molecules/pathways associated with neoplastic proliferation and metastasis [109].…”

“…PTEN genetic mutations are associated with reduced apoptosis and are implicated in more than 80% of endometrioid cancer of the uterus [109]. The effects of PTEN genetic mutations can be decreased by utilizing mammalian target of rapamycin (mTOR) inhibitors (for example, temsirolimus, ridaforolimus, everolimus, and AP2357) by interrupting phosphoinositide 3-kinaseAKTmTOR pathway [109,110].…”

“…PTEN genetic mutations are associated with reduced apoptosis and are implicated in more than 80% of endometrioid cancer of the uterus [109]. The effects of PTEN genetic mutations can be decreased by utilizing mammalian target of rapamycin (mTOR) inhibitors (for example, temsirolimus, ridaforolimus, everolimus, and AP2357) by interrupting phosphoinositide 3-kinaseAKTmTOR pathway [109,110]. In a phase II clinical trial of temsirolimus in previously chemotherapy-untreated patients with recurrent endometrial cancer, 26% and 63% of patients experienced partial response and stable disease, respectively [111].…”

“…There is an ongoing randomized controlled trial single-agent temsirolimus versus a combination of temsirolimus and hormonal therapy [109]…”

“…Only two (20%) and three (30%) patients responded to treatment and experienced stable disease, respectively. A GOG 229-E phase II clinical trial of single-agent bevacizumab, and GOG 229-G phase II clinical trial of a combination of bevacizumab and temsirolimus in management of patients with metastatic endometrial cancer are still ongoing [109,110].…”