**3.4 Dual PI3K/mTOR kinase inhibitors may be required to effectively suppress OC leader cells**

Activation of PI3K/AKT/mTOR pathway is frequently observed in oncogenic events contributing to tumour development, metastasis and therapy resistance [98] and irregularities in the PI3K/AKT/mTOR pathway corresponds with a poor prognosis in OC patients [99, 102, 103]. Activating mutations and genomic amplification of *PIK3CA* [104] and AKT and mTOR are more prevalent in women with

### **Figure 2.**

*Overview of the PI3K/AKT/mTOR pathway. Class IA PI3Ks are activated via ligand binding of receptor tyrosine kinases (RTKs), while class IB PI3Ks depend on G protein-coupled receptor (GPCRs) activation. Activated PI3K facilitates the conversion of PIP2 to PIP3 and in turn induces AKT phosphorylation. Activated AKT mediates the phosphorylation mTOR and a signalling cascade that drives cellular proliferation and cell death. In concert, the RAS/RAF/MEK/ERK pathway is activated by RTKs, acting as an escape mechanism for PI3K inhibition. The focal adhesion kinase (FAK) pathway also feeds into the PI3K pathway through c-Src activated by integrin-based adhesion molecules including integrin* α*5*β*1.*

clear cell ovarian carcinoma and associated with drug resistance phenotype [101]. Importantly, pharmaceutical inhibition of the PI3K/AKT/mTOR pathway was shown to increase *in vitro* sensitivity of OC cell lines to multiple chemotherapy agents [105, 106]. Moreover, PI3K inhibition via LY294002 disrupted the directional movement of kidney LCs [44], further highlighting the importance of the PI3K pathway for LC function. Inhibition of PI3K/AKT/mTOR pathway can be achieved via pan or isoform specific PI3K inhibitors, AKT inhibitors or dual pan PI3K/mTOR inhibitors [107–109]. However, PI3K/AKT/mTOR inhibition as a therapeutic option can be challenging due to the potential toxicities compounded by the activation of compensatory pathways and enhanced insulin production upon inhibition of PI3K [94, 98, 100, 101, 104, 110]. Currently, the PI3K inhibitor idelalisib and the mTOR inhibitor everolimus have gained FDA approval for the treatment of lymphoma [111] and renal cancer [112], respectively. Unfortunately, the clinical use of single agent inhibitors has shown minimal efficacy and high toxicities in treatment of OC [113–115].

The PI3K/AKT/mTOR pathway is interconnected with other signalling pathways including focal adhesion kinases [116] and RAS/RAF/MEK/ERK [117]. There are multiple canonical and non-canonical crosslinked pathways that could bypass single protein inhibition resulting in therapeutic failure. Therefore, targeting the pathway cascade at multiple levels via dual PI3K/mTOR inhibitors, might circumvent the negative feedback loops that occur with single target inhibitors [118]. Pre-clinical data from the PI3K/mTOR dual inhibitors omipalisib (GSK2126458), CMG002 and BEZ235 have indicated effective inhibition of ovarian cancer tumour growth and progression *in vitro* and *in vivo* [93, 106, 119, 120]. Currently, there are no ongoing clinical trials investigating the efficacy of dual inhibitors in OC patients mainly due to toxicity and off target effects of the dual inhibitors in clinical setting [121].

**147**

*Targeting Leader Cells in Ovarian Cancer as an Effective Therapeutic Option*

**chemotherapy by disrupting the AKT/mTOR pathway**

**3.5 Anti-helminth, Ivermectin, may be effective in sensitising OC LCs to** 

Ivermectin belongs to a family of drugs widely used to treat parasites and pest insects [122]. The anti-cancer property of ivermectin can be related to the inhibition of the Pgp pumps and MDR protein expression [123], inhibition of AKT/mTOR pathway [124], and targeting the yes-associated protein 1 (YAP1) [125], all of which are involved in the OC tumorigenesis [100, 126–128]. *In vivo,* ivermectin treatment of a xenograft mouse model of EOC showed a significant reduction in tumour growth and a reversal in tumour growth without severe toxicity effects when the drug was combined with cisplatin [129]. Currently there is a phase II clinical trial in recruitment to study the long-term effect of ivermectin treatment (NCT02366884).

**3.6 The mevalonate pathway in LC can be potentially targeted with HMG-CoA** 

Statins are among the most commonly prescribed medications to reduce cholesterol and inflammation through blocking 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase [130]. Inhibiting the mevalonate pathway can have a protective effect against cancer progression and reduce LC activity [131, 132]. Furthermore, the mevalonate pathway has been shown to be significantly activated in *TP53* mutated cells [133]. Therapeutic effects of statins in OC are further supported by the *in vitro* studies showing anti-metastatic and anti-tumorigenic effects through the inhibition of MAPK and mTOR pathways [134]. Lovastatin significantly reduced the development of serous tubal intraepithelial carcinomas, the purported precursor ovarian cancer lesions, in mice through the inhibition of the mevalonate pathway and dysregulation of the Rho signalling pathway [135]. Currently, a phase III clinical study for evaluating the safety, tolerability and effects on tumour progression of Atorvastatin is at the recruitment stage for ovarian and

**3.7 Cardiac glycosides, such as digoxin, may be able to suppress LC population**

Cardiac glycosidases (CGs) are a family of drugs used for the treatment of congestive heart failure and cardiac arrhythmia by regulating cardiac muscle

anti-proliferative effects of CGs were reported more than five decades ago in HeLa cells [137] and since then, multiple studies have highlighted the anti-neoplastic effects of CGs by inducing cancer cell apoptosis [138], activating autophagic cell death through the Ras-dependent extracellular signal-regulated kinase (ERK1/2) pathway [139], inhibiting hypoxia-inducible factor-1 alpha (HIF-1α) protein synthesis [140] and inhibiting FA/BRCA pathway activation [141]. CGs have been shown to have a higher cytotoxicity effect when combined with chemotherapy in prostate, breast, non-small cell lung, colorectal, and pancreatic cell lines as well as advanced stage melanoma patients compared to single agents [141–144]. However, so far epidemiological studies have yielded inconsistent results. For example, while digoxin was found to inhibit tumour growth *in vitro* and was associated with a 25% lower prostate cancer risk [145], systematic review and meta-analyses indicated an increased prostate cancer risk in digoxin users [146]. Nevertheless, the number of clinical trials specifically designed for cancer patients being treated with CGs is very limited and most of these conflicting results come from re-analysing data present in the medical databases with limited numbers of patients. So far, there are no clinical



*DOI: http://dx.doi.org/10.5772/intechopen.98689*

pancreatic cancer patients (NCT 02201381).

contraction through the inhibition of the NA<sup>+</sup>

**inhibitors**
