Abstract LB-054: FKBPL as a novel therapeutic target and prognostic biomarker in high grade serous ovarian cancer
Authors: Stephanie Annett, Gillian Moore, Amy Short, Neermeen Moustafa, Sudipto Das, Darran O'Connor, Cian McCrudden, Adrien Kissenpfenning, Laura Nelson, Ian Harley, Ken Arthur, Anita Yakkundi, Glen McCluggage, Andrea Marshall, Fiona Furlong, Helen O. McCarthy, Graham Cotton, Timothy Harrison, Lana McClements, Tracy Robson
Journal: Cancer Research (2018)

Abstract FKBPL is a secreted protein with well-established anti-angiogenic and anti-cancer stem cell activity. A novel therapeutic peptide, ALM201, derived from this protein has successfully completed a phase I clinical trial and was granted orphan drug status, by the FDA, for the treatment of ovarian cancer. Ovarian cancer is the most lethal gynecological cancer and there are no prognostic biomarkers currently used in the clinic. It is associated with a high incidence of recurrent chemo-resistant disease and this has been attributed to a treatment-resistant subpopulation of CD44+ cancer stem cells (CSCs). Previously, we presented evidence that CD44 is a potential target of ALM201 and here, for the first time, we investigate its ability to target both angiogenesis and CSCs in HGSOC. Tumorsphere and flow cytometry assays demonstrated that ALM201 is effective at reducing CSCs in a range of HGSOC cell lines and primary patient samples in vitro. Clonogenic assays demonstrated that ALM201 is not cytotoxic, but rather mediates ovarian CSC differentiation. In vitro, ALM201 displayed potent anti-CSC activity in the HGSOC cell line, OVCAR3. However, OVCAR3 tumor xenografts are not dependent on angiogenesis for their growth and therefore ALM201 did not elicit a strong response in this model. Furthermore, OVCAR3 xenografts dramatically upregulated the inflammatory cytokines IL-6 and IL-8, which is consistent with the lack of anti-CSC activity of ALM201 in vivo compared to in vitro. In contrast, treatment of highly angiogenic Kuramochi tumor xenografts, another HGSOC cell line, resulted in a statistically significant delay in both tumor growth and tumor initiation. This was associated with disruption of the CD31+ vascular network and a 10 fold decrease in the CSC population. Finally, using HGSOC tissue microarrays we demonstrated that high endogenous expression of FKBPL correlated with increased progression free interval; indicating the potential for FKBPL to be used as a prognostic biomarker in HGSOC. HGSOC cell lines display marked differences in tumor vascularisation in vivo. ALM201, a peptide fragment of FKBPL, has potent anti-CSC and anti-angiogenic activity in an HGSOC xenograft which is dependent on angiogenesis for growth; an important finding for the clinical development of ALM201. Our data also strongly suggest that FKBPL is a potential novel prognostic biomarker in HGSOC, supporting its endogenous anti-tumor activity. Citation Format: Stephanie Annett, Gillian Moore, Amy Short, Neermeen Moustafa, Sudipto Das, Darran O'Connor, Cian McCrudden, Adrien Kissenpfenning, Laura Nelson, Ian Harley, Ken Arthur, Anita Yakkundi, Glen McCluggage, Andrea Marshall, Fiona Furlong, Helen O. McCarthy, Graham Cotton, Timothy Harrison, Lana McClements, Tracy Robson. FKBPL as a novel therapeutic target and prognostic biomarker in high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-054.