Folate and folate receptor alpha antagonists mechanism of action in ovarian cancer

- Folate metabolism disruption by use of thymidylate inhibitors (pemetrexed, BGC 945, ZD-9331) has shown promising results in ovarian cancer treatment.
- Farletuzumab, a monoclonal antibody targeting the folate receptor, has shown trends toward PFS in certain patient subsets in some trials.
- Conjugation of chemotherapeutic agents with folate has prolonged survival in phase II trials; phase III trials are ongoing.

ObjectiveThe goal of this report is to review the activity of promising antifolate and folate receptor agents being developed for ovarian cancer including thymidylate synthase inhibitors, antifolate receptor antibodies, and folate-chemotherapy conjugates.MethodsA literature search was performed over the last 5 years using the terms “folate receptor” and “ovarian cancer” and those that specifically addressed the MOA were included. Abstracts presented within the last 3 years were also searched and included in this review where appropriate.ResultsThymidylate synthase inhibitors are a promising avenue for ovarian cancer treatment. Phase II trials have shown pemetrexed to have activity in patients with platinum resistant ovarian cancer. Several other thymidylate synthase inhibitors are in the early phase of development including BGC 945 and ZD-9331. Monoclonal antibodies that target the folate receptor have also shown potential in the development of ovarian cancer therapies. Farletuzumab is one of these antibodies. A recent phase III trial found that farletuzumab in combination with carboplatin and taxane did not meet the study's primary endpoint of progression-free survival (PFS). The post hoc exploratory analysis showed, however, a trend toward improved PFS in some patient subsets and further analysis is ongoing. The folate receptor is also utilized through folate conjugates. Vintafolide is one such agent which is currently in phase III development. Encouraging data from phase II trials showed an improvement in PFS from 2.7 months to 5 months. Folate can also be conjugated to radioisotopes for both therapeutic and imaging purposes, and early studies have shown correlation with amount of disease to therapy response.ConclusionFolate targeted agents continue to show promising antitumor activity in ovarian malignancy and initial clinical experience has demonstrated favorable toxicity profiles. Further development and resources targeted toward these therapies appear to be warranted.