**3.1 Collectively migrating cell clusters may be targeted to reduce cancer spread**

Current cancer therapies are mainly evaluated by cytotoxicity and their effect on tumour shrinkage; however, bulk tumour regression is not the only factor in effective cancer therapies [85]. In OC, the majority of patients are diagnosed with metastatic disease which is associated with a significantly poorer prognosis, hence strategies to interrupt metastasis through the disruption of cell motility, collective movement, directed cell migration and invasion have gained interest [86]. Targeting the cytoskeletal stability through actin is one such approach that has shown inhibitory effects on invadopodia formation and outgrowth in lung [87, 88], melanoma [88] and prostate [89] cancers. Unfortunately, these drugs are usually associated with significant toxicities due to the lack of discriminative drug effects between the malignant and healthy cells [88, 89]. Targeting other processes involved in actin polymerisation such as Rho GTPases and RhoA/Rho-associated kinase (ROCK) signalling pathway is potentially beneficial since the cytoskeletal dynamics play an important role during invasion and metastasis of a collectively

**145**

in (**Figure 2**).

**OC leader cells**

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

invading cluster [90, 91]. However, cancer cells generally are able to establish alternative mechanisms to bypass these targets leading to early drug resistance [92].

**3.2 Targeting LCs within the collectively migrating cluster may be a better** 

**3.3 Disrupting the PI3K/AKT/mTOR pathway is an attractive therapeutic** 

There is an enrichment of LCs observed in late-stage OC associated with the up-regulation of the PI3K/AKT/mTOR pathway [37, 93]. Yamaguchi et al.'s study revealed the up-regulation of PI3K in kidney epithelial LCs [44] implicating this pathway as a potential target for LC inhibition. The PI3K/AKT/mTOR signalling pathway mediates major cellular events such as growth, motility, metabolism, and

PI3Ks are a group of membrane-associated kinases that form heterodimeric structures comprised of regulatory and catalytic subunits classified based on their structure, regulation and substrates [95]. Class I PI3Ks are hugely implicated in cancer and are comprised of a p85 regulatory and a p110 catalytic subunit [96]. The catalytic subunit in class IA has three variants including p110α, p110β, and p110δ encoded by *PIK3CA*, *PIK3CB* and *PIK3CD* respectively, whilst the catalytic subunit of the only class IB PI3K, p110γ, is produced from *PIK3CG* gene [96]. Class IA PI3Ks are activated via ligand binding to receptor tyrosine kinases (RTKs), while activation IB PI3Ks is mediated by G-protein-coupled receptors (GCPRs) [97]. Upon ligand binding, activated PI3Ks catalyse phosphorylation of phosphatidylinositol (PtdIns) [4, 5] P2 (PIP2) to produce PtdIns [3–5] P3 (PIP3), an event that is inhibited by the tumour suppressor Phosphatase and tensin homologue (PTEN) in normal cells [94]. Following PIP2 to PIP3 conversion, proteins with a PH domain are recruited to the plasma membrane to activate downstream signalling proteins such as AKT, triggering multiple downstream pathways regulating survival, growth and invasion [94, 98]. AKT, also known as protein kinase B (PKB) is the main effector of PI3K and other than direct activation by PI3K, can be activated indirectly by mTOR and phosphoinositide-dependent kinase-1 (PDK1) that phosphorylate AKT at Ser 473 and Tyr 308 residues, respectively [99–101]. A schematic overview of the PI3K/AKT/mTOR pathway is demonstrated

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

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

As highlighted earlier, the molecular features of LCs are cancer-specific and this represents a challenge for developing clinically relevant therapies against LCs. Despite this, multiple targets have emerged from LCs studies (listed in **Table 1**: Summary of studies investigating LCs profile). These include targeting the LC stimulatory pathways such as the PI3K/mTOR pathway (with tyrosine kinase inhibitors and Ivermectin), metabolic/energy pathways (statins, cardiac glycosides and metformin) and inflammatory pathways (non-steroidal anti-inflammatory drugs).

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

**strategy to inhibit LCs**

survival [94].

**therapeutic option for the treatment of OC**

invading cluster [90, 91]. However, cancer cells generally are able to establish alternative mechanisms to bypass these targets leading to early drug resistance [92].
