The Next Frontier in Pancreatic Cancer: Targeting the Tumor Immune Milieu and Molecular Pathways

SIMPLE SUMMARY: Pancreatic ductal adenocarcinoma (PDAC) has a notoriously bad prognosis due to its high mortality and lack of good therapies. Chemotherapy is the current standard of treatment for PDAC, yet survival for most PDAC remain at around one year. Better therapeutic options are in dire need. Unlike other cancer types where targeted therapies and immunotherapies have changed the treatment landscape, their uses in pancreatic cancer are limited. However, there is increasing evidence in preclinical and early clinical studies that suggest these agents hold the key to the next frontier in PDAC treatment. We herein review some selected evidence. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with abysmal prognosis. It is currently the third most common cause of cancer-related mortality, despite being the 11th most common cancer. Chemotherapy is standard of care in all stages of pancreatic cancer, yet survival, particularly in the advanced stages, often remains under one year. We are turning to immunotherapies and targeted therapies in PDAC in order to directly attack the core features that make PDAC notoriously resistant to chemotherapy. While the initial studies of these agents in PDAC have generally been disappointing, we find optimism in recent preclinical and early clinical research. We find that despite the immunosuppressive effects of the PDAC tumor microenvironment, new strategies, such as combining immune checkpoint inhibitors with vaccine therapy or chemokine receptor antagonists, help elicit strong immune responses. We also expand on principles of DNA homologous recombination repair and highlight opportunities to use agents, such as PARP inhibitors, that exploit deficiencies in DNA repair pathways. Lastly, we describe advances in direct targeting of driver mutations and metabolic pathways and highlight some technological achievements such as novel KRAS inhibitors.