Expert Opinion on Therapeutic Targets

Glucose-6-phosphate dehydrogenase: a therapeutic target for ovarian cancer

Ovarian cancer (OC) is a gynecological tumor disease, which is usually diagnosed at an advanced stage and has a poor prognosis. It has been established that the glucose metabolism rate of cancer cells is significantly higher than that of normal cells, and the pentose phosphate pathway (PPP) is an important branch pathway for glucose metabolism. Glucose-6-phosphate dehydrogenase (G6PD) is the key rate-limiting enzyme in the PPP, which plays an important role in the initiation and development of cancer (such as OC), and has been considered as a promisinganti-cancer target. In this review, based on the structure and biological function of G6PD, recent research on the roles of G6PD in the progression, metastasis, and chemoresistance of OC are summarized and accompanied by proposed molecular mechanisms, which may provide a systematic understanding of targeting G6PD for the treatment of patients with OC. Accumulating evidence demonstrates that G6PD is a promising target of cancer. The development of G6PD inhibitors for cancer treatment merits broad application prospects.

Uterine fibroids: current research on novel drug targets and innovative therapeutic strategies

Uterine fibroids, the most common nonmalignant tumors affecting the female genital tract, are a significant medical challenge. This article focuses on the most recent studies that attempted to identify novel non-hormonal therapeutic targets and strategies in UF therapy. This review covers the analysis of the pharmacological and biological mechanisms of the action of natural substances and the role of the microbiome in reference to UFs. This study aimed to determine the potential role of these compounds in UF prevention and therapy. While there are numerous approaches for treating UFs, available drug therapies for disease control have not been optimized yet. This review highlights the biological potential of vitamin D, EGCG and other natural compounds, as well as the microbiome, as promising alternatives in UF management and prevention. Although these substances have been quite well analyzed in this area, we still recommend conducting further studies, particularly randomized ones, in the field of therapy with these compounds or probiotics. Alternatively, as the quality of data continues to improve, we propose the consideration of their integration into clinical practice, in alignment with the patient's preferences and consent.

Myricetin, a natural inhibitor of CD147, increases sensitivity of cisplatin in ovarian cancer

Ovarian cancer (OC) is the most lethal gynecological tumor, but it currently lacks effective therapeutic targets. CD147, which is overexpressed in OC, plays a crucial role in promoting malignant progression and is associated with poor prognosis in patients. Therefore, CD147 has been identified as a potential therapeutic target. However, there is a limited amount of research on the development of CD147 inhibitors. Surface plasmon resonance (SPR) assay and virtual molecular docking analysis were performed to identify potential natural compounds targeting CD147. The anti‑tumor effects of myricetin were evaluated using various assays, including CCK8, Alkaline comet, immunofluorescence and xenograft mouse models. The underlying mechanism was investigated through western blot analysis and lentivirus short hairpin RNA (LV-shRNA) transfection. Myricetin, a flavonoid commonly found in plants, was discovered to be a potent inhibitor of CD147. Our findings demonstrated that myricetin exhibited a strong affinity for CD147 and down-regulated the protein level of CD147 by facilitating its proteasome-dependent degradation. Additionally, we observed synergistic antitumor effects of myricetin and cisplatin both in vivo and in vitro. Mechanistically, myricetin suppressed the expression of FOXM1 and its downstream DNA damage response (DDR) genes E×O1and BRIP1, thereby enhancing the DDR induced by cisplatin. Our data demonstrate that myricetin, a natural inhibitor of CD147, may have clinical utility in the treatment of OC due to its ability to increase genomic toxicity when combined with cisplatin.

Exploring the tumor immune microenvironment in ovarian cancer: a way-out to the therapeutic roadmap

Despite cancer treatment strides, mortality due to ovarian cancer remains high globally. While immunotherapy has proven effective in treating cancers with low cure rates, it has limitations. Growing evidence suggests that both tumoral and non-tumoral components of the tumor immune microenvironment (TIME) play a significant role in cancer growth. Therefore, developing novel and focused therapy for ovarian cancer is critical. Studies indicate that TIME is involved in developing ovarian cancer, particularly genome-, transcriptome-, and proteome-wide studies. As a result, TIME may present a prospective therapeutic target for ovarian cancer patients. We examined several TIME-targeting medicines and the connection between TIME and ovarian cancer. The key protagonists and events in the TIME and therapeutic strategies that explicitly target these events in ovarian cancer are discussed. We highlighted various targeted therapies against TIME in ovarian cancer, including anti-angiogenesis therapies and immune checkpoint inhibitors. While these therapies are in their infancy, they have shown promise in controlling ovarian cancer progression. The use of 'omics' technology is helping in better understanding of TIME in ovarian cancer and potentially identifying new therapeutic targets. TIME-targeted strategies could account for an additional treatment strategy when treating ovarian cancer.

Update value and clinical application of MUC16 (cancer antigen 125)

The largest transmembrane mucin, mucin 16 (MUC16), contains abundant glycosylation sites on the molecular surface, allowing it to participate in various molecular pathways. When cells lose polarity and become cancerous, MUC16 is overexpressed, and more of the extracellular region (cancer antigen [CA]125) is released into serum and possibly, promote the development of diseases. Thus, MUC16 plays an indispensable role in clinical research and application. This review summarizes the update proposed role of MUC16 in carcinogenesis and metastasis. Most importantly, we prospect its potential value in targeted therapy after screening 1226 articles published within the last 10 years from PubMed. Two reviewers screened each record and each report retrieved independently. We have summarized the progress of MUC16/CA125 in basic research and clinical application, and predicted its possible future development directions. As an important noninvasive co-factor in the diagnosis of gynecological diseases, MUC16 has been used for a long time, especially in the diagnosis and treatment of ovarian cancer. The overexpression of MUC16 plays a very obvious role in regulating inflammatory response, supporting immune suppression, and promoting the proliferation, division, and metastasis of cancer cells. In the next 20 years, there will be a luxuriant clinical application of MUC16 as a target for immune monitoring and immunotherapy.

Tumor cells-derived extracellular vesicles carry circ_0064516 competitively inhibit microRNA-6805-3p and promote cervical cancer angiogenesis and tumor growth

The current study tried to elucidate the regulatory role of tumor cell-derived exosomes (Exos)-circ_0064516 in angiogenesis and growth of cervical cancer. Related cirRNAs and downstream target genes were identified through bioinformatics analysis. Exos were isolated from cervical cancer cell line CaSki, followed by co-cultured with human umbilical vein endothelial cells (HUVECs). Then, the roles of circ_0064516, miR-6805-3p, and MAPK1 in migration and angiogenesis of HUVECs were assayed. Furthermore, xenografted tumors were transplanted into nude mice for in vivo validation. In vitro assay validated highly expressed circ_0064516 in cervical cancer cells. Tumor cell-derived Exos carried circ_0064516 to HUVECs. circ_0064516 increased MAPK1 expression by binding to miR-6805-3p, thus enhancing migration and angiogenesis. Exos containing circ_0064516 also promoted tumorigenesis of cervical cancer cells in nude mice. We confirmed the oncogenic role of tumor cell-derived Exos carrying circ_0064516 in cervical cancer progression through miR-6805-3p/MAPK1.

New therapeutic targets for endometrial cancer: a glimpse into the preclinical sphere

Endometrial cancer (EC) is the only gynecologic malignancy showing increasing trends in incidence and mortality. While standard treatment has been effective primarily for early-stage EC, precision medicine with tailored therapy has revolutionized the management of this disease. Genome sequencing analyses have identified four sub-types of EC. Treatments for primary and metastatic disease can now be tailored more accurately to achieve better oncologic results. This review provides an overview of the most relevant and updated evidence in the literature regarding EC molecular analysis and its role in risk classification, prognostication, and guidance for tailored and target therapies in early and advanced/metastatic stages. In addition, it provides updated information on optimal surgical management based on molecular classification and highlights key advances and future strategies. EC molecular analysis yields the potential of tailoring adjuvant treatment by escalating or deescalating therapy, as shown for POLE-mutated and p53-mutated tumors. Moreover, the expression of specific molecular signatures offers the possibility to employ novel target therapies, such as immune-checkpoint inhibitors that have demonstrated a significant benefit on prognosis. New treatment guidelines are still being established, and ongoing studies are exploring the potential prognostic role of further sub-stratifications of the four molecular classes and treatment options.