Laura F. Mortan

Identification and Experimental Validation of Triosephosphate Isomerase 1 as a Functional Biomarker of SHetA2 Sensitivity in Ovarian Cancer

Background: Our objective was to identify and validate proteins that predict which patients with ovarian cancer will respond to SHetA2, an investigational drug in a phase 1 trial for patients with advanced or recurrent solid tumors (clinicaltrials.gov: NCT04928508). Methods: Cells were cultured from ascites from nine consented patients under an institutional review board-approved protocol. SHetA2 or olaparib sensitivities were determined using metabolic viability assays in ascites-derived cultures or ovarian cancer cell lines. Expression of four SHetA2 target proteins and sixteen proteins previously identified in an ovarian cancer mouse model were measured using microcapillary electrophoresis. Triosephosphate isomerase 1 (TPI1) was modulated by siRNA or lentivirus vector-mediated overexpression. Metabolites were measured using mass spectrometry. Results: TPI1 was elevated in SHetA2-sensitive compared to SHetA2-resistant ascites-derived cultures (two-way ANOVA q-value = 0.0003). The majority of (5/9) cultures were olaparib-resistant and SHetA2-sensitive. TPI1 was higher in olaparib-resistant cultures (two-way ANOVA q-value = 0.0003). Reduction in or overexpression of TPI1 reduced or increased SHetA2 potency, respectively, in two ovarian cancer cell lines (t-tests; p < 0.05). SHetA2 reduced the metabolites in glycolysis downstream of TPI1, the tricarboxylic acid cycle and oxidative pentose phosphate pathway. Conclusions: TPI1 is a candidate functional biomarker of SHetA2 sensitivity in ovarian cancer.