Investigational PI3K/AKT/mTOR inhibitors in development for endometrial cancer

ABSTRACT

Introduction: Endometrial cancer (EC) is the most common neoplasm of the female genital tract in developed countries. Despite the progress in early detection and treatment, a significant number of cases of advanced ECs are still diagnosed. These patients have few treatment options and a poor prognosis. Our understanding of EC pathogenesis and progression has been enhanced by recent genomic studies. Among the relevant biological pathways, phosphatidylinositol 3-kinase/AKT (PIK3/AKT)-mammalian target of rapamycin (mTOR) signaling is frequently upregulated in this cancer.

Areas covered: This review covers investigational EC therapeutics acting on the PI3K/AKT/mTOR pathway. The authors review the results of clinical studies and highlight ongoing trials.

Expert opinion: Several new agents are under evaluation for treating patients with metastatic, recurrent, and persistent EC. Clinical trials investigating PI3K/AKT/mTOR inhibitors have yielded controversial results. In the near future, new studies with dual inhibitors or multi-pathways inhibitors as mono or combination therapies with conventional chemotherapy (CT) or other targeted drugs may provide more promising data. Moreover, the evaluation of new serum and histological biomarkers is an attractive strategy for patient selection.

KEYWORDS:

• Endometrial cancer
• mTOR
• AKT
• PI3K
• PI3K/AKT/mTOR pathway
• targeted therapy

Article highlights

• Endometrial cancer (EC) is the most common neoplasm of the female genital tract in the developed countries. Despite progress in early detection and treatment, a significant number of advanced cases are still diagnosed. New treatment options are necessary for these patients;

• Scientific advances have recognized four classes of EC with distinct molecular features. An improved understanding of abnormal molecular pathways paved the way to the investigation of specific targeted therapies.

• Drugs acting on phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) are under intense clinical evaluation;

• Most published studies on this topic have been based on the use of mTOR inhibitors. Everolimus, ridaforolimus, and temsirolimus showed modest RRs when administered for treating advanced EC;

• Few preliminary data are available on the use of PI3K and AKT inhibitors. Anyway, they do not seem to support their clinical use in this setting;

• Dual inhibitors (on MTORC1 and MTORC 2, on mTOR and PI3K) that interfere with primary escape pathways involved in resistance to conventional therapies could offer promise of a new synergistic tumor inhibition. Numerous dual inhibitors are in early clinical investigation. Their activity and safety for treating patients with advanced cancers, including EC, are being evaluated;

• Although it has been reported that patients with specific mutations (PIK3CA, PTEN) tend to benefit when receiving PI3K/AKT/mTOR pathway inhibitors, validated predictive biomarkers for selecting patients and for monitoring drug efficacy are lacking in the clinical practice. Further research on this topic is needed.

This box summarizes key points contained in the article.

Declaration of interest

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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.