Abstract 2033: Identification of biomarkers for drug candidate LP-184 in precision oncology applications

Abstract LP-184, Lantern Pharma’s acylfulvene small-molecule alkylator currently being evaluated in a Phase 1a trial, exhibits potent preclinical activity against multiple solid tumors. LP-184 is a prodrug bioactivated intracellularly by the enzyme prostaglandin reductase 1 (PTGR1), often elevated in cancer. In cell line experiments, PTGR1 expression by RNAseq was found to be highly concordant with that by RT-PCR (r = -0.975, p < 0.0001). The assay identified a ΔCt value of 7.5 as the PTGR1 (normalized to housekeeping genes ACTB and GAPDH) expression threshold associated with LP-184 sensitivity (IC50 < 300 nM) and with average peak plasma exposure from preliminary clinical pharmacokinetics. We then established an RT-PCR assay for PTGR1 quantification in FFPE tissue samples. In the ongoing Phase 1a trial, 80% of analyzed tumor samples showed PTGR1 expression greater than this threshold. In silico analysis of 20 solid tumor TCGA histologies showed that 78% of samples expressed PTGR1 levels greater than the corresponding RNAseq expression threshold (4.5 log2TPM+1) associated with LP-184 sensitivity. In cancer cell lines, LP-184 induced DNA double strand breaks (DSBs) and triggered DNA repair as measured by the SensiTive Recognition of Individual DNA Ends (STRIDE) assay. 24-hour LP-184 treatment in parental and engineered DLD1 colon cancer cell lines led to 2-fold elevated levels of DSBs and γH2AX (phosphorylated H2AX, DNA damage marker) in BRCA2 knockout cells compared to wild type. LP-184 demonstrated 3-fold higher in vitro sensitivity in DNA Damage Repair (DDR) deficient tumor models compared to non-DDR altered cell lines, along with complete, durable tumor regressions in multiple xenograft DDR deficient tumor models. Preclinical data on LP-184 anti-tumor activity and biomarker status indicate that the inactivation of BRCA1/2, ATM/ATR, and ERCC3/4, and the activation of EGFR are key biomarker candidates predicting response to LP-184. In addition, a genome-wide CRISPR chemogenetic screen of LP-184 in the TNBC cell line MDAMB231, suggested that ATRX, EZH2, HSP90AA1, CDKN2B, MAD2L2, PSMA6, NDUFA1, and BRAF are other potential predictive biomarkers of LP-184 activity. Drug-gene associations derived from preclinical studies have identified a panel of biomarkers associated with LP-184 bioactivation (PTGR1:RT-PCR/tissue), pharmacodynamics (DNA DSB, γH2AX: Multiplexed STRIDE or IF assay/tissue), and response prediction (BRCA1/2 etc.: liquid biopsy or tissue/ TSO500 NGS panel). A retrospective biomarker validation will be performed using established NGS assays to analyze liquid biopsy and/or tissue samples from the ongoing Phase 1a LP-184 trial. Future directions include determining associations between biomarker expression or mutation and clinical outcomes, refining PTGR1 expression threshold, and utilizing emerging biomarkers to guide patient selection in subsequent expansion studies. Citation Format: Aditya Kulkarni, Jianli Zhou, Giulia Agnello, Reggie Ewesuedo, Marc Chamberlain, Kishor Bhatia. Identification of biomarkers for drug candidate LP-184 in precision oncology applications [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 2033.