Mentor Name: Eric Raabe

LP-184 is a novel DNA-damaging agent that targets the nucleotide excision repair (NER) pathway of brain tumors like Atypical Teratoid Rhabdoid Tumor (ATRT). Poly(ADP-ribose) polymerase inhibitor (PARPi) is another cancer therapy that blocks PARP enzymes critical to repairing double-stranded breakage. Together, the drugs cause an accumulation of DNA damage that leads to apoptosis. Pamiparib (BGB-290) is a next-generation PARPi that has superior brain penetration and potency compared with previous versions. This makes it a prime candidate for combination therapy in central nervous system tumors. Our lab finds that combining LP-184 with the PARPi rucaparib enhances their ability to treat ATRT compared with either agent alone. The combination led to greater growth inhibition and increased markers of DNA damage and apoptosis, supporting the mutually beneficial interaction between LP-184–induced DNA damage and PARP inhibition. These findings provide a strong rationale to evaluate a more brain-penetrant and potent PARPi, such as pamiparib, in combination with LP-184. We hypothesize that combining LP-184 with pamiparib will produce synergistic anti-tumor activity in ATRT. By increasing unrepaired DNA damage, there will be enhanced apoptosis and tumor growth suppression relative to either agent alone. Improved CNS targeting of pamiparib should further increase the efficacy of this therapy toward treating pediatric brain tumors. In vitro studies: ATRT cell lines representing the 3 molecular subgroups will be treated with LP-184 alone, pamiparib alone, and a combination across a range of concentrations. Cell viability will be measured using Cell Titer Blue, apoptosis will be evaluated by caspase-3 cleavage, DNA damage will be assessed using the ?H2AX marker, and cell proliferation will be determined using BrdU. In vivo studies: Efficacy will be evaluated in ATRT xenograft models through flank and brain injections. LP-184 will be administered on a weekly schedule, with pamiparib given on the same day and the following day. Tumor growth, survival, and tolerability will be assessed. Further analyses will examine DNA damage and apoptosis in tumor tissue to confirm the mechanism of action.