Abstract
Epithelial ovarian cancer is a disease with the highest mortality rate among gynecological tumors. After years of studies, despite targeted drugs and immunotherapies have been developing, their therapeutic effects are still not ideal. Statins, as lipid-lowering medicines, have many findings beyond expectation in the fight against cancer, and have shown promisingly positive results in clinical trials. Actually, statins cannot be used as a monotherapy to achieve complete remission due to its efficacy established, but for its great potential lying in effects about synergism and sensibilization with other drugs, and even the reduction of side effects of anti-cancer treatment. This review summarizes the evidence and potential of combining statins with first-line chemotherapy, bevacizumab, PARP inhibitors and immunotherapy drugs in the pharmacotherapy of ovarian cancer, and proposes hypothesises about new combination therapies based on the current mechanisms and theories, to provide a new perspective to further experimental research and clinical trials.
Key words: Statins; Ovarian cancer; Combination therapy
Introduction
With the highest mortality rate among gynecologic cancers, ovarian cancer (OC) is the third most common gynecological tumor in the world. Based on the source of OC, epithelial cancers (EOC) are the most common subtype, accounting for 90% of all case, devided by tumor cytohistology into serous, endometrioid, mucinous, clear cell, and the rest being rarer subtypes or unspecified[1]. Among these cytohistologic subtypes, serous carcinoma consistently has the highest incidence and lowest 5-year survival rate of patients[2]. The high mortality rate is related to the declining effectiveness of pharmacological therapies besides late diagnosis and lack of early detection of the disease[3].
Generally, combination platinum derivatives with taxane is recognized as the first-line pharmacological therapy, but it often ends up with disease recurrence and the acquisition of platinum resistance defined as progression occurring within 6 months after the last dose of platinum-based therapy. There is also about 20% of patients are primary platinum refractory, who have progression within 4 weeks of platinum-based treatment[4].
In recent years, targeted therapy and immunotherapy have provided a new direction for the treatment of EOC. Bevacizumab has shown positive results in standard chemotherapy, even in platinum-resistant relapsed disease[5]. PARP inhibitors, such as olaparib, niraparib and rucaparib, are managed to do good to patients whose tomors with a BRCA1 and/or BRCA2 mutation (BRCAm) or homologous recombination deficiency (HRD)[6]. Unfortunately, their clinical efficacy is still limited[7], and many subsequent novel therapies have no positive clinical outcome, such as Ofra-vec (an gene agent to inhibit angiogenesis and tumor response)[8], Lurbinectedin (carcinogenic transcription inhibitors)[9]. Therefore, developing new treatment options and identifying biomarker oriented strategies is still critical to personalize treatment for EOC patients.
Actually, the area of combination regimens remain active. Comparison with exploring new drugs with enormous costs, it seems like a good idea to make statins as complementary drugs of pharmacological therapies mentioned above. Statins, as old medicines, have great potential anti-tumor effects, while reducing the costs borne by patients.
Statins, originally used as a class of lipid-lowering drugs by inhibiting enzyme hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR) in the rate-limiting step in cholesterol hepatic biosynthesis, in the treatment and prevention of cardiovascular diseases[10]. However, it has received increasing attention due to its anti-inflammatory, antiproliferative, anti-invasive, radiosensitive, radioprotective and immune-activating[11]effects, which has gone far beyond its lipid-lowering effects. Massive efforts have been made to determine their utility in cancer prevention, as well as their potential use in combination therapies for treatment of certain malignancie. Currently, prospective studies and retrospective studies had been reported that statins improved OC prognosis[12]. Its treatment effect is intensely associated with some factors about the type (lipophilic or hydrophilic), dose (high or low), usage of statin use (continuous statin users or post-diagnostic statin users), subtype of ovarian cancer tissue (Serous, endometrioid, clear cell or mucinous OC), grades of serous OC (high-grade or low-grade)[12],[13]. Some biomarkers has been found to identify patients who will respond to statin treatment[13], but have not been practiced in clinic. Even though we found that statins could not achieve the target effect of complete remission, their greater potential lies in acting as adjuncts to other drugs to achieve synergistic and sensitizing effects, which still exists lots of room to explore.
This review summarizes the mechanism based on characteristics of ovarian cancer associated with statins, and displays the existing evidence from the preclinical studies involving statins combining with other promising agents for treatment of EOC (Figure 1 ), also puts forward hypothesis of new treatment options based on the existing theoretical research to expect to get attention in practical application.
Mechanisms based on characteristics of ovarian cancerconnecting with statins