Targeted Therapy in Ovarian Cancer. A Comprehensive Systematic Review of Literature

Search Strategy

An inclusive literature search was accomplished by cross-referencing of keywords and ensuing second stage use of the references of the literature categorized in the preliminary sequence to condense the search operational. Consequent to the documentation of this principal collection of studies, formulation of the inclusion and exclusion criteria was achieved.

The exploration included literature pertaining to targeted therapy in the treatment of ovarian cancer; the relevance of targeted therapy for the treatment of the disease; specificity of targeted therapy in ovarian cancer treatment; assessment of post-treatment response; enduring surveillance and recurrence of ovarian cancer. The evaluation terms included targeted therapy, targeted therapy in the evaluation of ovarian cancer, targeted therapeutics in ovarian cancer, recent innovations in targeted therapy for the treatment of ovarian cancer, evaluation studies on targeted therapy in ovarian cancer and comparison of assorted targeted therapeutics for ovarian cancer treatment.

One hundred and fifty three studies were obtained in the initial pursuit on recent trends and publications selected based on inclusion and exclusion criteria. One hundred and one studies were excluded as not pertaining to studies on ovarian cancer. Thirteen studies were excluded as not pertaining to specific manifestation, more recent diagnostic and treatment procedures. Seven studies were excluded as being editorials instead of being research publications. Two studies were excluded as letters to the editor. In the final selection, thirty studies were designated and implied as highly apposite to the current review.

Studies on Targeting Signaling Pathways

Numerous studies have shown that targeting specific signaling pathways involved in cancer progression could be a promising molecular therapeutic choice in combating cancer in terms of inhibition of cell migration, invasion and tumor growth.

Recent studies have revealed that targeting GRB7/ERK/FOXM1 signaling pathway impairs aggressiveness of ovarian cancer cells. Subsequent to the findings that inhibition of ERK signaling by U0126 (1,4-diamino-2,3-dicyano-1,4-bis (2-aminophenylthio)butadiene) or PD98059 (2-(2-Amino-3-methoxyphenyl)-4H-1-benzopyran-4-one) could reduce the level of FOXM1 in GRB7-overexpressing ovarian cancer cells, it is suggested that GRB7, ERK and FOXM1 are regulated in a cascade or orderly sequence. In vitro and in vivo studies have shown that inhibition of ERK activity by U0126 or PD98059, or decreased FOXM1 expression by Thiostrepton drastically inhibits cell migration, invasion and tumor growth (21).

Sufficient attention has been drawn on the Sphingosine kinase 1 (SPHK1), the enzyme that produces Sphingosine 1 phosphate (S1P). Studies have confirmed the extensive expression of SPHK1 in the tumor stroma of High-grade serous ovarian cancer (HGSC) and its pivotal role in the differentiation and tumor promoting function of cancer-associated fibroblasts (CAFs). These studies have further exhibited that pharmacological inhibition of SPHK1 in ovarian fibroblasts could attenuate TGF-β-induced expression of CAF markers, reducing their capacity to stimulate ovarian cancer cell migration and invasion. Elucidation of the mechanism by which SPHK1 mediates TGF-β signaling through transactivation of S1P receptors (S1PR2 and S1PR3), leading to p38 MAPK phosphorylation and in vivo confirmation of reduction of tumor growth and metastasis in SPHK1 knockout mice have further widened the scope for further investigations on the potential of SPHK1 inhibition as a novel stroma-targeted therapy in HGSC cases (22).

It is imperative to mention the focus on targeting cyclin-dependent kinase pathways in the treatment of ovarian and other gynaecological cancers. The new class of targeted-therapeutic agents known as the CDK 4/6 inhibitors target the CDK 4/6 kinases that promote transition through the cell cycle. Some of the oral CDK 4/6 inhibitors now under active clinical trials include palbociclib, abemaciclib and ribociclib and have been reported to have negligible toxicity (23).

A recent study has shown that a chemically synthesized isoflavone analog (RY-2f), suppressed PI3K/AKT/mTOR signaling and is a potential targeted therapeutic. In vivo studies have revealed that RY-2f could effectively block an A2780-induced xenograft tumor growth with no detectable toxicity in the animals at the therapeutic doses. Studies have also implied that that this isoflavone analog, inhibits ovarian cancer cell proliferation, blocks cell cycle in G₂/M phase and induces cellular apoptosis through up-regulation of p21, cyclin B1, Bax, Bad and cleaved-PARP, and suppression of cyclin A, CDK2 and Bcl-2. An improved synergistic therapeutic effect of RY-2f and cisplatin has also been elucidated in cell proliferation and colony formation assays as well (24).

Importunate activation of STAT3 activated by janus family kinases (JAK) via cytokine receptors, growth factor receptor, and non-growth factor receptor tyrosine kinases is often detected in ovarian cancer. Moreover, studies have shown that activation of STAT3 mediates tumor cell proliferation, survival, motility, invasion, and angiogenesis, suppresses antitumor immune responses and supports tumor-promoting inflammation. An elucidation and evaluation study on targeted blockade of JAK/STAT3 signaling in inhibition of ovarian cancer is worth the mention in this context. Evaluation of AZD1480, a novel ATP-competitive JAK inhibitor, on cell viability, apoptosis, proliferation, migration, and adhesion of ovarian carcinoma cells in vitro and in vivo assessment of tumor growth, progression, gene expression, tumor-associated matrix metalloproteinase (MMP) activity, and immune cell populations in a transgenic mouse model of ovarian carcinoma has shown that AZD1480 treatment inhibits STAT3 phosphorylation, DNA binding, migration and adhesion of cultured ovarian carcinoma cells with a diminished ovarian tumor growth rate, volume, and ascites production. Thus, therapeutic pharmacologic inhibition of the JAK2/STAT3 pathway can disrupt ovarian tumor growth and warrants further investigation as a targeted therapy (25).

Studies involving the treatment of isolated tumor cells from the ascites of ovarian cancer patients and HEY ovarian cancer cell line with paclitaxel in a mouse xenograft model and in vitro assays have shown that the inhibition of the JAK2/STAT3 pathway in ovarian cancer results in the loss of cancer stem cell-like characteristics (2) and a reduced tumor burden. Subsequent to the findings that treatment of isolated tumor cells from the ascites of ovarian cancer patients and HEY ovarian cancer cell line with paclitaxel results in a CSC-like residual population which goes in tandem with the activation of Janus activated kinase 2 (JAK2) and Signal transducer/activation of transcription 3 (STAT3) pathway in paclitaxel surviving cells, it has been established that a low dose JAK2-specific small molecule inhibitor (Momelotinib) CYT387 (1 μM) inhibits paclitaxel-induced JAK2/STAT3 activation and CSC-like characteristics in vitro and a reduced tumor burden in vivo (2).

Sufficient attention has been drawn on the phosphatidylinositol 3 kinase (PI3K) pathway, which is frequently altered in ovarian cancer patients. Quite a number of novel therapeutics including dual mTORC1/mTORC2, Akt, and PI3K inhibitors are under active investigation. Given the fact that a random inhibition of the PI3K/Akt/mTOR pathway in a nonspecific ovarian cancer cohort could have little or no effect, it is recommended to select specific histological types, like clear cell or endometrioid ovarian cancer with phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and/or phosphatase and tensin homolog (PTEN) alterations in such studies. It is further suggested that the PI3K pathway inhibition could be more effective in combination with either chemotherapy or other targeted therapies, including MEK inhibitors, anti-angiogenic therapy in specific histological types of the ovarian cancer due to the intricacy of the PI3K signaling mechanism (26).

Studies on Induction of Apoptosis

Previous studies on apoptosis induction in cancer cells have demonstrated that an adenovirus type 5 E1A enhances the sensitivity of paclitaxel in paclitaxel-resistant HER-2/neu-overexpressing human ovarian cancer cells in vitro by inducing apoptosis. The studies have further elaborated that apoptosis induction is largely dependent on activation of the caspase-3 pathway (27).

A study designed to explore the effects of liposome-survivin antisense oligonucleotide (Lip-ASODN) on the growth and apoptosis of human ovarian cancer cell lines, A2780 and SKOV3 and investigate the use of survivin as a therapeutic target on ovarian cancer has established that the overexpression of survivin leads to infinite carcino-proliferation, and survivin expression in the survivin-positive ovarian cancer cell line A2780 and SKOV3 cells could be significantly and gradually reduced when transfected with Lip-ASODN at concentrations of 200, 400 and 600 nM. The study has further shown that Lip-ASODN transfection induces greater apoptosis rates in the human ovarian cancer cell lines A2780 and SKOV3 (p<0.05) (28).

Enzastaurin (LY317615.HCl), a selective inhibitor of protein kinase C beta (PKCbeta), is yet another entity that causes induction of apoptosis. Studies have shown that a combination of enzastaurin and pemetrexed inhibits cell growth and induces apoptosis of chemoresistant ovarian cancer cells regulating extracellular signal-regulated kinase 1/2 phosphorylation (29).

Recent studies to evaluate the ability of metformin to induce apoptosis in epithelial ovarian cancer cell lines and to identify the pathways involved have established that metformin induced apoptosis in OVCAR-3 and OVCAR-4 cell lines in an Adenosine monophosphate activated protein kinase (AMPK)-independent mode and metformin would induce apoptosis in OVCAR-3 and OVCAR-4 cells by activating caspases 3/7, down-regulating Bcl-2 and Bcl-xL expression, and up-regulating Bax and Bad expression (30).

More recent studies have established that the targeted inhibition of FAK, PYK2 and BCL-XL synergistically enhances apoptosis in ovarian clear cell carcinoma cell lines. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is another targeted therapeutic strategy for ovarian cancer. A Mitochondrial division inhibitor-1 (Mdivi-1) has been shown to enhance the sensitivity of human ovarian cancer cells to death receptor ligands including TRAIL, FAS ligands, and TNF-α. The absence of significant cytotoxic effects on non-transformed human cells with the combination of TRAIL and mdivi-1 enhances the scope further (31).