Csongor György Lengyel*, Sara Cecilia Altuna, Baker Shalal Habeeb, Dario Trapani and Shah Zeb Khan Pages 1 - 16 ( 16 )
Aims: In this narrative review, we summarize the role and significance of PI3K-AKT-mTOR (PAM) pathway in ovarian and endometrial cancers, providing the most recent and relevant literature on the topic and addressing options for targeting PAM along with future perspectives of drug development.
Background: Alterations of the PAM-pathway are common in both endometrial and ovarian cancers, and are described in specific histology-defined subtypes. PAM seems to be involved in critical steps of endometrial and ovarian carcinogenesis, often mechanistically involved in the acquisition of a phenotype of treatment resistance, which could be targetable. However, early clinical trials with PAM-inhibitors (PAMi) have provided disappointing results, particularly when non isoform-specific inhibitors were tested in unselected populations, accompanied by an adverse safety profile. Since then, more encouraging observations have been collected when targeting specific isoforms of PAM proteins with more selective drugs, resulting in encouraging activity and more manageable toxicity.
Conclusion: Although the rational of inhibiting the PAM-pathway has been demonstrated in several promising preclinical studies, no Phase III clinical trial is available to demonstrate a significant benefit of PAM-inhibitors. A way to manage targeted agents is to tailor their use to particular subpopulations most likely to obtain a considerable benefit, namely pursuing an individualized, precision-medicine approach.
PI3K-AKT-Mtor Pathway, Precision Medicine, Targeted Therapy, Ovarian Cancer, Endometrial Cancer, Gynaecological Cancer, Platinum Resistance
Head and Neck Surgery, National Institute of Oncology Hungary, Budapest, Oncomédica C.A, Caracas, Medical Oncology Department, Shaqlawa Teaching Hospital, Erbil, Department of Oncology and Haematology (DIPO), University of Milan, Milan, Italy and Division of Early Drug Development for Innovative Therapy, IEO, European Institute of Oncology IRCCS, Milan, Department of Clinical Oncology, Bannu Institute Nuclear Medicine Oncology and Radiotherapy, Bannu