Current Drug Targets - Volume 21, Issue 10, 2020

Aims: In this narrative review, we summarize the role and significance of PI3K-AKTmTOR (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 PAMinhibitors (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 rationale 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.

Triple-negative breast cancer (TNBC) can be distinguished from other breast malignancies by the lack of expression of estrogen receptors (ER), progesterone receptors (PR) as well as human epidermal growth factor receptor 2 (HER2). TNBC is associated with adverse clinical outcomes and high risk of metastasis. Currently, several clinical and translational reports are focusing on developing targeted therapies for this aggressive cancer. In addition to approved targeted drugs such as poly(ADP-ribose) polymerase inhibitors (PARPi) and immune-checkpoint inhibitors, platinum-based chemotherapy is still a cornerstone therapeutic option in TNBC. However, despite the observed improved outcomes with platinum- based chemotherapy in TNBC, there is still a large proportion of patients who do not respond to this treatment, hence, the need for predictive biomarkers to stratify TNBC patients and therefore, avoiding unwanted toxicities of these agents. With the emergence of genetic testing, several recent studies suggested mutations in breast cancer susceptibility gene (BRCA) in TNBC patients as important predictors of outcomes. These mutations alter the homologous recombination repair (HRR) mechanisms leading to genomic instability. Consequently, sensitivity to platinum-based treatments in this subpopulation of TNBC patients may be explained by cell death enhanced by deoxyribonucleic acid (DNA) damage induced by these potent anticancer drugs. Through this paper, we review several recent studies on this topic to better understand the mechanisms and discuss the potential of BRCA mutational status as a predictive biomarker of platinum-based chemotherapy in TNBC.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Although initial response rates to standard platinum-based treatment are at 70–80%, long-term response in advanced EOC disease is rarely achieved with the development of chemoresistance and recurrence, contributing to overall survival rates below 45%. Additional challenges stem from EOC heterogeneity, reflecting at least five histological subtypes, each with different underlying molecular characteristics and clinicopathology that have significant implications in treatment effectiveness and management. Since the last decade, technologies in genomics, proteomics and pathology have been deployed to find reliable clinical markers that can identify patients sensitive to standard chemotherapy treatments and stratify patients for more suitable targeted therapies. These efforts have identified several molecular markers of prognostic value that have been validated as biomarkers, such as BRCA and KRAS mutations, or are currently under investigation in clinical trials, such as CD8 T cells, immune checkpoint inhibitors and progesterone receptor. Recent advancements in biomarker research have also revealed new targets that have expanded treatment options, introducing poly (ADP-ribose) polymerase (PARP) inhibitors, anti-angiogenic agents, inhibitors targeting signaling pathways, and immunotherapy to improve maintenance therapies or enhance first-line therapy. This review presents a summary of current biomarkers, in clinical use or under evaluation, demonstrating a potential to inform on patient selection for treatment efficacy and predict response to EOC therapies, with particular focus on the serous subtypes, including high-grade and low-grade serous carcinomas.

The use of predictive biomarkers provides potential individualized cancer therapeutic options to prevent therapy failure as well as serious toxicities. Several recent studies showed that predictive and prognostic biomarkers are a notable personalized strategy to improve patients’ care in several cancers. Trabectedin (Yondelis®) is a cytotoxic agent, derived from a marine organism, harbouring a significant antitumor activity against several cancers such as soft tissue sarcoma, ovarian, and breast cancers. Recently and with the advent of molecular genetic testing, BRCA mutational status was found as an important predictor of response to this anticancer drug, especially in gynecological cancers. The aim of this updated review is to discuss the mechanisms of action of trabectedin against the wellknown cancer hallmarks described until today. The current advances were also examined related to genomic biomarkers that can be used in the future to predict the efficacy of this potent anticancer natural molecule in various gynecological cancers.

Recently, a significant number of breast cancer (BC) patients have been diagnosed at an early stage. It is therefore critical to accurately predict the risk of recurrence and distant metastasis for better management of BC in this setting. Clinicopathologic patterns, particularly lymph node status, tumor size, and hormonal receptor status are routinely used to identify women at increased risk of recurrence. However, these factors have limitations regarding their predictive ability for late metastasis risk in patients with early BC. Emerging molecular signatures using gene expression-based approaches have improved the prognostic and predictive accuracy for this indication. However, the use of their based-scores for risk assessment has provided contradictory findings. Therefore, developing and using newly emerged alternative predictive and prognostic biomarkers for identifying patients at high- and low-risk is of great importance. The present review discusses some serum biomarkers and multigene profiling scores for predicting late recurrence and distant metastasis in early-stage BC based on recently published studies and clinical trials.

Notwithstanding important advances in the treatment of epithelial ovarian cancer (EOC), this disease is still a leading cause of global high mortality from gynecological malignancies. Recurrence in EOC is inevitable and it is responsible for poor survival rates. There is a critical need for novel effective biomarkers with improved accuracy compared to the standard carbohydrate antigen-125 (CA-125) for follow-up. The human epididymis protein 4 (HE4) is used for early detection of EOC (ROMA algorithm) as well as for predicting optimal cytoreduction after neoadjuvant chemotherapy and survival outcomes. Notably, the emerging HE4 is a promising prognostic biomarker that has displayed better accuracy in various recent studies for detecting recurrent disease. In this mini-review, we discussed the potential of HE4 as an accurate predictor of EOC recurrence.

Neuropathic pain is caused by a damage to or dysfunction of the somatosensory nervous system. The main mechanisms underlying neuropathic pain include ectopic activity in nociceptive nerves, peripheral and central sensitization, impaired inhibitory modulation, and microglial activation. Fibroblast growth factors (FGFs) make up a large family of growth factors that mediate neural development, metabolism, and function through three main key signaling pathways, including RAS/MAP kinase pathway, PI3 kinase/Akt pathway, and PLCγ. An association between the members of the FGF system and the improvement of neuropathic pain has become evident, recently. These signaling molecules may be expected to provide new drug targets for the treatment of neuropathic pain. To the best of our knowledge, it is the first study that reviews the relationship between some members of the FGF system and neuropathic pain.