Hacking Pancreatic Cancer: Present and Future of Personalized Medicine

Abstract

Pancreatic cancer (PC) is a recalcitrant disease characterized by high incidence and poor prognosis. The extremely complex genomic landscape of PC has a deep influence on cultivating a tumor microenvironment, resulting in the promotion of tumor growth, drug resistance, and immune escape mechanisms. Despite outstanding progress in personalized medicine achieved for many types of cancer, chemotherapy still represents the mainstay of treatment for PC. Olaparib was the first agent to demonstrate a significant benefit in a biomarker-selected population, opening the doors for a personalized approach. Despite the failure of a large number of studies testing targeted agents or immunotherapy to demonstrate benefits over standard chemotherapy regimens, some interesting agents, alone or in combination with other drugs, have achieved promising results. A wide spectrum of therapeutic strategies, including immune-checkpoint inhibitors tyrosine kinase inhibitors and agents targeting metabolic pathways or the tumor microenvironment, is currently under investigation. In this review, we aim to provide a comprehensive overview of the current landscape and future directions of personalized medicine for patients affected by PC.

Keywords: DNA damage; PARP inhibitors; genomic; immunotherapy; metabolism; pancreatic cancer; personalized medicine; targeted therapy; tumor microenvironment; tyrosine kinase inhibitor.

Figure 1

Main transmembrane receptor and intracellular pathways evaluated as potential therapeutic targets in PC. EGFR: epidermal growth factor receptor; HER-2: human epidermal growth factor receptor 2; NTRK: neurotrophic tyrosine receptor kinase; PTCH1: 12-transmembrane patched protein 1; SMO: 7-transmembrane smoothened protein: RAS: rat sarcoma; RAF: rapidly accelerated fibrosarcoma; MEK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase; JAK: Janus kinase; STAT: signal transducer and activator of transcription; PI3K: phosphoinositide-3-kinase; mTOR: mechanistic target of rapamycin; Gli: 5-zinc-finger transcription factor; SSB: single-stranded break; DSB: double-stranded break; PARP: poly ADP-ribose polymerase. Created with BioRender.com (accessed on 14 July 2021).

Figure 2

Main immune checkpoints acting on cancer cell recognition by effector immune cells. PD-1: programmed death-1; PD-L1: programmed death ligand 1; CTLA-4: cytotoxic T-lymphocyte antigen 4; TCR: T-cell receptor; MHC I: major histocompatibility complex I; + (plus sign): activating signal; − (minus sign): inhibitory signal. Created with BioRender.com (accessed on 14 July 2021).