Current Drug Targets

Molecular and Biological Functions of Melatonin in Endometrial Cancer

Endometrial cancer is the fifth leading cancer among women. This rate is higher in developed countries and its incidence is increasing worldwide. Diabetes mellitus, obesity, hypertension and arteriosclerosis are major risk factors for endometrial cancer. Melatonin is a hormone synthesized in the pineal and extra-pineal organs such as the digestive tract, bone marrow, retina and more. Evidence shows the potential effects of melatonin in endometrial cancer inhibition. Therefore, the focus of this paper is to review this outstanding evidence and to summarize the molecular and biological mechanisms of melatonin for the inhibition of endometrial cancer.

Advances in the Treatment of Ovarian Cancer Using PARP Inhibitors and the Underlying Mechanism of Resistance

The standard treatment for advanced ovarian cancer is cytoreductive surgery followed by cytotoxic chemotherapy. However, it has high risk of recurrence and poor prognosis. Poly(ADPribose) polymerase (PARP) inhibitors selectively target DNA double-strand breaks (DSBs) in tumor cells that cannot be repaired and induce the synthetic lethality of BRCA1/2 mutation cancers. PARP inhibitors are clinically used to treat recurrent ovarian cancer and show significant efficacy in ovarian cancer patients with homologous recombination repair (HRR) pathway defects. PARP inhibitors also have significant clinical benefits in patients without HR defects. With the increasingly extensive clinical application of PARP inhibitors, the possibility of acquiring drug resistance is high. Therefore, clinical strategies should be adopted to manage drug resistance of PARP inhibitors. This study aims to summarize the indications and toxicity of PARP inhibitors, the mechanism of action, targeted treatment of drug resistance, and potential methods to manage drug-resistant diseases. We used the term “ovarian cancer” and the names of each PARP inhibitor as keywords to search articles published in the Medical Subject Headings (MeSH) on Pubmed, along with the keywords “clinicaltrials.gov” and “google.com/patents” as well as “uspto.gov.” The FDA has approved olaparib, niraparib, and rucaparib for the treatment of recurrent epithelial ovarian cancer (EOC). Talazoparib and veliparib are currently in early trials and show promising clinical results. The mechanism underlying resistance to PARP inhibitors and the clinical strategies to overcome them remain unclear. Understanding the mechanism of resistance to PARP inhibitors and their relationship with platinum resistance may help with the development of antiresistance therapies and optimization of the sequence of drug application in the future clinical treatment of ovarian cancer.

GPR56, an Adhesion GPCR with Multiple Roles in Human Diseases, Current Status and Future Perspective

: Human G protein-coupled receptor 56 (GPR56) belongs to a member of the adhesion G-protein coupled receptor (aGPCR) family and widely exists in the central nervous system and various types of tumor tissues. Recent studies have shown that abnormal expression or dysfunction of GPR56 is closely associated with many physiological and pathological processes, including brain development, neuropsychiatric disorders, cardiovascular diseases and cancer progression. In addition, GPR56 has been proven to enhance the susceptibility of some antipsychotics and anticarcinogens in response to the treatment of neuropsychological diseases and cancer. Although there have been some reports about the functions of GPR56, the underlying mechanisms implicated in these diseases have not been clarified thoroughly, especially in depression and epilepsy. Therefore, in this review, we described the molecular structure and signal transduction pathway of GPR56 and carried out a comprehensive summary of GPR56's function in the development of psychiatric disorders and cancer. Our review showed that GPR56 deficiency led to depressive-like behaviors and an increase in resistance to antipsychotic treatment. In contrast, the upregulation of GPR56 contributed to tumor cell proliferation and metastasis in malignant diseases such as glioblastoma, colorectal cancer, and ovarian cancer. Moreover, we elucidated specific signaling pathways downstream of GPR56 related to the pathogenesis of these diseases. In summary, our review provides compelling arguments for an attractive therapeutic target of GPR56 in improving the therapeutic efficiency for patients suffering from psychiatric disorders and cancer.

Carbon Dots: Emerging Nanomaterials for Ovarian Cancer Diagnosis and Therapy

Delayed diagnosis and limited treatment options make ovarian cancer difficult to treat. This paper examines the growing role of Carbon Dots (CDs) in ovarian cancer diagnosis and treatment. Photoluminescence and biocompatibility make CDs ideal for biomedical use. We emphasize their ability to improve fluorescence and molecular imaging in radiology and diagnostics. We also demonstrate the efficacy of carbon dots in targeted drug delivery systems in overcoming drug resistance and improving therapeutic outcomes. Photodynamic and photothermal therapies are used to show that CDs can treat hypoxic ovarian cancer tumours. We also discuss CD safety issues and constraints, emphasising the need for thorough assessments and fine-tuning. Future research focuses on personalised medicine and CD integration with other therapies. This text concludes by discussing CDs' clinical use and the challenges of production and regulatory approval. CDs can improve ovarian cancer diagnosis and treatment, improving patient outcomes and survival.

Exploring the Clinical Impact of Predictive Biomarkers in Serous Ovarian Carcinomas

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.

Research Progress of PARP Inhibitor Monotherapy and Combination Therapy for Endometrial Cancer

: Endometrial cancer is one of the three most common malignant tumors in the female reproductive system. Advanced and recurrent endometrial cancers have poor prognoses and lack effective treatments. Poly (ADP-ribose) polymerase (PARP) inhibitors have been applied to many different types of tumors, and they can selectively kill tumor cells that are defective in homologous recombination repair. Endometrial cancer is characterized by mutations in homologous recombination repair genes; accordingly, PARP inhibitors have achieved positive results in off-label treatments of endometrial cancer cases. Clinical trials of PARP inhibitors as monotherapies and within combination therapies for endometrial cancer are ongoing. For this review, we searched PubMed with “endometrial cancer” and “PARP inhibitor” as keywords, and we used “olaparib”, “rucaparib”, “niraparib” and “talazoparib” as search terms in clinicaltrials.gov for ongoing trials. The literature search ended in October 2020, and only English-language publications were selected. Multiple studies confirm that PARP inhibitors play an important role in killing tumor cells with defects in homologous recombination repair. Its combination with immune checkpoint inhibitors, PI3K/AKT/mTOR pathway inhibitors, cell cycle checkpoint inhibitors, and other drugs can improve the treatment of endometrial cancer.

Is HE4 Superior over CA-125 in the Follow-up of Patients with Epithelial Ovarian Cancer?

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.