Abstract 1706: Establishment and characterization of a panel of ovarian XPDX models from patients with clinical resistance to anti-folate receptor therapies
Authors: Alyssa Simonson, Johnnie Flores, Anna Stackpole, Jennifer Garcia, Crystal Moreno, Gabriella Graciano, Erika Mata, Danielle Trevino, Rodolfo Castellanos, Sarah Lopez, Leatrice Wilson, Maria Jose de Miguel, Sreenivasa Chandana, Andrew Cunningham, Michael J. Wick
Journal: Cancer Research (2025)

Abstract Background: Folate receptor α is an actionable therapeutic target in cancer. Mirvetuximab (MIRV) is an antibody-drug conjugate (ADC) consisting of a humanized anti-folate receptor alpha (FRα) IgG1 antibody conjugated to soravtansine (DM4) recently approved for treatment of FRα-positive, platinum refractory ovarian cancer. MIRV has been shown effective; however, patients that progress on this therapy often have few remaining treatment options. To better understand mechanisms of resistance to FRα-targeting therapies, we established four XPDX models from three ovarian cancer patients who progressed clinically on MIRV or farletuzumab, a humanized anti-FRα antibody. These models were characterized by DNA and RNA sequencing, folate receptor expression, and in vivo sensitivity to various therapies including MIRV. Methods: Four post-FRα ovarian XPDX models were established and characterized: ST409 was from a 59-year-old Hispanic female pretreated with chemotherapy and eleven months of farletuzumab; ST6205B and ST6205D were collected two months apart from a 74-year-old Hispanic female pretreated with chemotherapy, four months of niraparib, and seven months of MIRV; STM476 was from a 65-year-old Caucasian female pretreated with chemotherapy, eleven months of rucaparib, and two months of MIRV. Models were passaged, banked, and profiled using genomic analysis, including WES and RNAseq, receptor expression, and in vivo drug sensitivity studies. For in vivo studies, each model was tested against cisplatin, a PARP inhibitor, and MIRV. In vivo study endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a %T/C of ≤ 20% versus control was considered sensitive. Results: All models were positive for FRα staining with values of 2+ or 3+. Genomic characterization identified a BRCA1L1254X truncation in ST409 and an RB1 frameshift in ST6205B and ST6205D; TP53 mutations were identified in all models. In vivo, ST409 was found sensitive to single agent cisplatin (%T/C&amp;lt;0%) but resistant to MIRV (%T/C=73%), while STM476 was resistant to cisplatin (%T/C=41%) and MIRV (%T/C=78%). ST6205B and ST6205D were resistant to cisplatin and MIRV (%T/C&amp;gt;30%); no model was sensitive to PARPi at the evaluated treatment regimens. Conclusion: We have established and characterized a panel of ovarian XPDX models from patients with clinical resistance to anti-folate receptor therapies. These models can be utilized as a valuable tool in better understanding mechanisms of resistance to FRα-targeting therapies and in developing novel therapies for patients who progress clinically on MIRV or similar agents. Citation Format: Alyssa Simonson, Johnnie Flores, Anna Stackpole, Jennifer Garcia, Crystal Moreno, Gabriella Graciano, Erika Mata, Danielle Trevino, Rodolfo Castellanos, Sarah Lopez, Leatrice Wilson, Maria Jose de Miguel, Sreenivasa Chandana, Andrew Cunningham, Michael J. Wick. Establishment and characterization of a panel of ovarian XPDX models from patients with clinical resistance to anti-folate receptor therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1706.