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Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma
- Source :
- Journal of Hematology & Oncology, Vol 13, Iss 1, Pp 1-20 (2020), Journal of Hematology & Oncology
- Publication Year :
- 2020
- Publisher :
- BMC, 2020.
-
Abstract
- Pancreatic ductal adenocarcinoma (PDAC) is a malignancy characterized by a poor prognosis and high mortality rate. Genetic mutations and altered molecular pathways serve as targets in precise therapy. Using next-generation sequencing (NGS), these aberrant alterations can be identified and used to develop strategies that will selectively kill cancerous cells in patients with PDAC. The realization of targeted therapies in patients with PDAC may be summarized by three approaches. First, because oncogenes play a pivotal role in tumorigenesis, inhibition of dysregulated oncogenes is a promising method (Table 3). Numerous researchers are developing strategies to target oncogenes, such as KRAS, NRG1, and NTRK and related molecules, although most of the results are unsatisfactory. Accordingly, emerging strategies are being developed to target these oncogenes, including simultaneously inhibiting multiple molecules or pathways, modification of mutant residues by small molecules, and RNA interference. Second, researchers have attempted to reactivate inactivated tumour suppressors or modulate related molecules. TP53, CDKN2A and SMAD4 are three major tumour suppressors involved in PDAC. Advances have been achieved in clinical and preclinical trials of therapies targeting these three genes, and further investigations are warranted. The TGF-β-SMAD4 signalling pathway plays a dual role in PDAC tumorigenesis and participates in mediating tumour-stroma crosstalk and modulating the tumour microenvironment (TME); thus, molecular subtyping of pancreatic cancer according to the SMAD4 mutation status may be a promising precision oncology technique. Finally, genes such as KDM6A and BRCA have vital roles in maintaining the structural stability and physiological functions of normal chromosomes and are deficient in some patients with PDAC, thus serving as potential targets for correcting these deficiencies and precisely killing these aberrant tumour cells. Recent clinical trials, such as the POLO (Pancreas Cancer Olaparib Ongoing) trial, have reported encouraging outcomes. In addition to genetic event-guided treatment, immunotherapies such as chimeric antigen receptor T cells (CAR-T), antibody-drug conjugates, and immune checkpoint inhibitors also exhibit the potential to target tumours precisely, although the clinical value of immunotherapies as treatments for PDAC is still limited. In this review, we focus on recent preclinical and clinical advances in therapies targeting aberrant genes and pathways and predict the future trend of precision oncology for PDAC.
- Subjects :
- 0301 basic medicine
Cancer Research
Synthetic lethality
Immunoconjugates
DNA Repair
Oncogene Proteins, Fusion
medicine.medical_treatment
Review
medicine.disease_cause
Immunotherapy, Adoptive
Targeted therapy
Pancreatic ductal adenocarcinoma
chemistry.chemical_compound
0302 clinical medicine
CDKN2A
Antibodies, Bispecific
Tumor Microenvironment
Molecular Targeted Therapy
Precision Medicine
Immune Checkpoint Inhibitors
High-Throughput Nucleotide Sequencing
Precision oncology
Hematology
lcsh:Diseases of the blood and blood-forming organs
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Neoplasm Proteins
ErbB Receptors
Gene Expression Regulation, Neoplastic
Oncology
Tumour suppressors
030220 oncology & carcinogenesis
Epigenetics
Immunotherapy
Carcinoma, Pancreatic Ductal
Antineoplastic Agents
lcsh:RC254-282
Olaparib
Proto-Oncogene Proteins p21(ras)
03 medical and health sciences
Pancreatic cancer
medicine
Humans
Therapeutic targets
Molecular Biology
Protein Kinase Inhibitors
Cyclin-Dependent Kinase Inhibitor p16
business.industry
lcsh:RC633-647.5
Oncogenes
medicine.disease
Chimeric antigen receptor
digestive system diseases
Pancreatic Neoplasms
030104 developmental biology
chemistry
Mutation
Cancer research
Carcinogenesis
business
Synthetic Lethal Mutations
Genes, Neoplasm
Subjects
Details
- Language :
- English
- ISSN :
- 17568722
- Volume :
- 13
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of Hematology & Oncology
- Accession number :
- edsair.doi.dedup.....bf313cb1d3b37c162ab504886dbdad60