mRNA-Based Therapy for Ovarian Cancer
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Ovarian cancer (OC) is well known as the most lethal gynecologic malignancy. This is because of a lack of effective detection strategies in the early stage and high relapse rate after treatment (such as cytoreductive surgery and chemotherapy). Since there are differences in epidemiologic and risk factors, molecular events, premalignant lesions, prognosis as well as the response to chemotherapy, OC is thought as a group of different diseases. According to molecular, histologic, and clinical factors, epithelial ovarian cancer (EOC) can be divided into five main subtypes: ovarian clear cell carcinoma (OCCC), endometrioid ovarian cancer (EnOC), mucinous, low-grade serous ovarian carcinoma (LGSOC), and high-grade serous ovarian carcinoma (HGSOC). Among them, HGSOC is the most common type, accounting for approximately 70% in all cases. Due to the lack of specific symptoms and limited screening marker, 60% of OC patients OC are diagnosed at an advanced stage, in which OC has spread within the pelvis and abdomen and is more difficult to treat. At present, the common standard of care for OC treatment is radical surgical with consistent chemotherapy (such as platinum-based and taxane-based chemotherapy). However, because some patients are insensitive to chemotherapeutic drugs, the treatment effect is not very satisfactory. Therefore, there is a crucial need to develop novel therapeutic modalities to enhance clinical outcomes and achieve durable clinical prognosis in OC.
Gene mutation in ovarian cancer
Thanks to the advances of next generation sequencing technologies, previous known mutated genes have been confirmed as well as new candidate genes have been identified in OC. There are four most common mutations associated with EOC, including KRAS, BRCA1/2, PIK3CA, and TP53. And their frequency varies among different EOC subtypes. Since the association between clinical phenotype of cancers and gene mutations has been demonstrated in multiple studies. The use of gene mutations sites as prognosis and therapeutic targets has broad prospects.
mRNA-based therapy for ovarian cancer
Despite numerous efforts have been made in OC treatment, the mortality of OC has hardly decreased in the past two decades. Thus, there is a necessity to explore novel therapeutic modalities. The delivery of mRNA is emerging as a highly promising option for OC treatment. Recently, based on the approval of the first-in-human, open label phase I study in ovarian cancer patients, a liposome formulated mRNA vaccine encoding three ovarian cancer- tumor-associated antigens (TAAs) is combined with the (neo-) adjuvant chemotherapy for OC treatment. Furthermore, the intratumoral administration of mRNA-2416, a lipid nanoparticle mediated therapeutic agent expressing the wild-type human OX40L, showed a best overall response of stable disease along with noted clinical observation of tumor regression in OC patients. And the evaluation of combination intratumoral mRNA-2416 with the anti-PD-L1 inhibitor durvalumab advanced ovarian carcinoma is ongoing. In addition to lipid nanoparticles (LNPs), a previous study had pointed out that the feasibility of mRNA delivery in ovarian cancer using a cell-penetrating peptide (CPP)-based delivery vector (PepFect 14, PF14). CPPs are considered short-chain polyamides with excellent degradation capability and have been widely used for delivery of other types of oligonucleotides. In addition, ex vivo IVT mRNA dendritic cells (DCs) also have been explored for the treatment of OC.
Peptide-mediated delivery of therapeutic mRNA in ovarian cancer. (van den Brand, et al, 2019)
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- Guo, T., et al. (2021). "Cellular Mechanism of Gene Mutations and Potential Therapeutic Targets in Ovarian Cancer." Cancer Management and Research, 13, 3081.
- van den Brand, et al. (2019). "Peptide-mediated delivery of therapeutic mRNA in ovarian cancer." European Journal of Pharmaceutics and Biopharmaceutics, 141, 180-190.