**6. Other novel agents**

The aforementioned systemic strategies are of most relevance because they are either already in (or close to) the clinic. There are however various other strategies being explored, some of which have already been trialled in clinical studies. One approach involves targeting folate receptor and, specifically, the α isoform (FRα). This receptor is absent from normal ovarian epithelium but expressed on the majority of EOC [83]. The receptor has been targeted by various classes of therapy including folate-drug conjugates, small molecule FRα inhibitors, monoclonal antibodies, vaccines and oncolytic viruses. The phase III trial of vintafolide (folate conjugated with a derivative of vinblastine) in combination with PLD (NCT01170650) was discontinued for futility. Further trials of folate-drug conjugates are ongoing [84]. Farletuzumab, a monoclonal antibody that causes antibody and complement- dependant cellular cytotoxicity is being investigated in combination with platinum-based chemotherapy in patients with relapsed EOC and low ca125 following promising sub-group analysis from a previous phase III trial (NCT02289950). Phase I results for ONX-0801, a FRα-targeted thymidylate synthase inhibitor that accumulates in EOC cells generated a PR in 5/11 patients at the MTD with 4/4 FRα expressing tumours showing response [85].

Aside from FRα targeting therapy, there are multiple other targeted strategies in EOC in pre-clinical and early clinical phases. Cell cycle targeting with WEE-1 inhibition has been discussed but other strategies including CHK1/2 inhibition with prexasertib (which yielded a PR in 5/13 patients in cohort 1 of a recent phase II trial [86]) are being explored. PI3k/AKT/ mTOR, Her2 and molecules in the apoptotic machinery are amongst a plethora of other avenues being explored. As our understanding of the molecular basis of EOC progresses, future therapies are likely to employ biomarker or other selection criteria within trial protocols. For example, clear cell ovarian carcinoma is known to harbour mutations in the PI3K/AKT/mTOR pathway and the GOG-0268 trial of temsirolimus in addition to carboplatin/paclitaxel as firstline therapy was restricted to the clear cell population for this reason. Beyond the 'traditional' histological subtyping of EOC, analysis of TCGA data and recent advances in bioinformatics as led different groups to propose various molecular classifications of high grade serous EOC. Once such classification proposes four subtypes; mesenchymal, immunoreactive, differentiated and proliferative. Prospectively defined subgroup analysis of future trials using such novel molecular classifications may allow us to tailor therapy to maximise efficacy.

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