Therapeutic trends in pancreatic ductal adenocarcinoma (PDAC)

ABSTRACT

Introduction: Prognosis remains dismal for pancreatic ductal adenocarcinoma (PDAC). Genomics and proteomics have depicted heterogeneity in PDAC. Collectively, this information could be useful in improving diagnosis, prognosis, modalities of therapy, treatment responses, deciphering drug resistance and new drug development.

Areas covered: We describe major advances in the cellular and molecular subtypes based on next-generation sequencing and their predictive and prognostic value in PDAC patients. We review aberrant genes involving in defined cellular processes in PDAC. Finally, the current state of drug development with novel investigational agents targeting cell fate, cell survival, genomic instability, tumor-stroma, and immune checkpoints are discussed.

Expert opinion: Molecular techniques have revealed distinct driver mutations in PDAC. Common genes and cellular processes are dysregulated in the pathogenesis of PDAC. These cellular processes categorized by aberrant pathways include control cell fate, genome maintenance, and cell survival. Dysregulation of the tumor microenvironment promotes an intense fibrosis and immune suppression that play a major role in drug resistance. New information on tumor biology has led to the development of targeted/stromal therapies, immunotherapies or combinations with current chemotherapy in PDAC. New drug development targeting multiple hallmarks of PDAC we hope will positively impact the quality and survival of PDAC patients.

KEYWORDS:

• Pancreatic ductal adenocarcinoma
• molecular subtypes
• driver mutations
• targeted therapy
• immunotherapy
• precision medicine

Article highlights

In this comprehensive review, we discussed the following topics in PDAC

• Germline and sporadic common/uncommon mutations in PDAC

• Role of next-generation sequencing and – omic technologies in dissecting the pathophysiology and development of novel therapeutics

• Novel targets involving cell survival, cell fate and genomic maintenance and therapies targeting these processes in PDAC

• Role of the tumor microenvironment, in particular, tumor-stroma interactions, desmoplastic reaction, and novel therapies that inhibit the key molecular drivers of adhesion-dependent fibrosis

• Immunotherapy strategies to disrupt the suppressive immune environment an establish host immunity in PDAC

• Expert opinion emphasizing the need for precision and personalized treatments with enhanced participation in clinical trials in PDAC

This box summarizes key points contained in the article.

Acknowledgments

We wish to acknowledge the P30 supplement of NCI 2P30CA023074 grant to the University of Arizona Cancer Center..

Declaration of interest

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the NCI 2P30CA023074 grant to the University of Arizona Cancer Center.