Exploiting the therapeutic potential of the PI3K-AKT-mTOR pathway in enriched populations of gynecologic malignancies

Abstract

Given the prevalence of phosphatase & tensin homolog mutations in histologic specimens harvested from patients with endometrial cancer, significant interest in systemic treatment with PI3K/Akt/mTOR inhibitors has emerged. Several Phase II trials have been completed studying mTOR inhibitors in advanced/recurrent endometrial cancer. The mTOR pathway also appears to be important in some cervical cancers. Finally, because clear cell carcinoma of the ovary and renal cell carcinoma have a shared histology, the potential for activity of mTOR inhibitors in clear cell cancer of the ovary is implicit. This article reviews the results of Phase II clinical trials of PI3K/Akt/mTOR pathway inhibitors in patients with endometrial cancer, and discusses the potential therapeutic landscape of mTOR inhibition in enriched populations in gynecologic cancers.

Keywords::

• cervical cancer
• clear cell ovarian cancer
• endometrial cancer
• mTOR inhibitors
• PI3K/AKT/mTOR pathway
• PTEN

Financial & competing interests disclosure

This article was supported by an institutional NIH T-32 training grant (Ruth L Kirschstein, NRSA Institutional Training Research Grant, 2T32 CA-060396-11). The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Endometrial cancer is the most common gynecologic malignancy for which there are no US FDA approved nonhormonal biologic targeted agents.

• The tumor suppressor gene, phosphatase and tensin homolog (PTEN), is altered or mutated in 46–83% of endometrial cancer.

• PTEN mutations lead to aberrant signaling of the phospahtidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (Akt)/mTOR pathway.

• mTOR inhibitors (mTORi) have demonstrated promising clinical activity in patients with advanced or recurrent endometrial cancer in Phase II trials.

• Combining mTORi with hormonal therapy or with cytotoxic and anti-angiogenic drugs may represent a therapeutic strategy in advanced and recurrent endometrial cancer.

• PI3K-specific inhibitors and Akt-specific inhibitors have also been developed and studies are underway combining these agents with mTORi in patients with advanced or recurrent endometrial cancer.

• Patients treated with mTORi may develop hyperglycemia and hyperlipidemia, and may also experience thrombocytopenia, anemia, asthenia, diarrhea, rash and fever.

• The diabetes drug metformin also inhibits mTOR signaling and is being studied by the Gynecologic Oncology Group in protocol 286B, a randomized Phase II/III clinical trial combining metformin with chemotherapy in women with advanced or recurrent endometrial cancer.

• The PI3K/Akt/mTOR pathway is an important pathway in some cases of cervical carcinoma.

• Shared histology may govern response to specific therapeutics, suggesting that clear cell ovarian cancer may respond to mTORi just as renal cell carcinomas do.

Notes