Simultaneous Delivery of Dual Inhibitors of DNA Damage Repair Sensitizes Pancreatic Cancer Response to Irreversible...

Area of Science:

• Oncology
• Nanomedicine
• Cancer Immunotherapy

Background:

• Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with limited treatment options.
• Irreversible electroporation (IRE) treats PDAC by inducing cell death but can lead to tumor relapse due to incomplete cell ablation (reversible electroporation, RE).
• RE activates DNA damage repair (DDR) pathways in surviving tumor cells, contributing to relapse.

Purpose of the Study:

• To investigate if targeting DDR pathways can enhance the efficacy of IRE in PDAC treatment.
• To develop and evaluate a novel nanoformulation combining PARP and ATM inhibitors for use with IRE.

Main Methods:

• Development of ROS-sensitive polymeric micelles (M-TK-OA) co-loaded with Olaparib (PARP inhibitor) and AZD0156 (ATM inhibitor).
• Assessment of M-TK-OA's effect on RE-treated pancreatic cancer cells in vitro, focusing on DDR inhibition and colony formation.
• Evaluation of the combined IRE and M-TK-OA treatment in subcutaneous and orthotopic murine PDAC models.

Main Results:

• RE induced DNA double-strand breaks and activated DDR pathways in pancreatic cancer cells.
• M-TK-OA effectively disrupted homologous recombination and nonhomologous end joining DDR pathways, impairing colony formation after RE.
• Combined IRE and M-TK-OA treatment significantly prolonged survival in PDAC mouse models.
• The combination therapy elicited CD8+ T cell-mediated antitumor immunity and activated STING innate immune responses.

Conclusions:

• Dual inhibition of PARP and ATM using nanomedicine (M-TK-OA) is a promising strategy to overcome resistance to IRE in pancreatic cancer.
• This combination therapy not only enhances direct tumor cell killing but also stimulates a robust anti-tumor immune response.
• The findings suggest a novel therapeutic approach for locally advanced and unresectable PDAC.