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