Validation of LDHC as a novel target for precision medicine in breast cancer

Breast cancer treatment is moving away from one-size-fits-all traditional care towards precision medicine. The lack of durable treatment responses in patients with triple negative breast cancer (TNBC) has paved the way for exploration of novel, personalized treatment approaches. Approximately 15% of these tumors harbor germline mutations in BRCA1/BRCA2, impairing DNA damage repair by homologous recombination (HR), and show clinical benefit from treatment with drugs that interfere with the DNA damage response pathway. TNBC tumors without such mutations often display HR deficiency through other mechanisms and may benefit from similar interventions. We recently demonstrated that targeting Lactate Dehydrogenase C (LDHC) promotes DNA damage accumulation in breast cancer cells through cell cycle checkpoint dysregulation, and significantly improves in vitro treatment response to the DNA damaging agent cisplatin and the DNA damage repair inhibitor olaparib. LDHC is a highly-tumor specific antigen, and hence could be targeted with limited to no offtarget effects. In this project, we will validate its therapeutic potential in combination with cisplatin and olaparib in breast cancer organoids and xenograft mouse models. To this end, we will develop a clinically relevant, cell penetrating, peptide-assisted shRNA delivery system with tumor homing abilities to enable tumor cell-specific uptake of LDHCsilencing molecules.

Hamad Bin Khalifa University (HBKU)