Deoxyribonucleic acid methylation driven aberrations in pancreatic cancer-related pathways

Table 1 Targeting various characteristics of pancreatic carcinomas and their associated therapeutic strategies

Potent therapeutics	Cancer Hallmarks
TGF-β pathway inhibitors HGF; Met pathway inhibitors	Activating invasion/metastasis
JAK/STAT pathway inhibitors; BTK inhibitors; Src inhibitors; COX-2 inhibitors	Tumour-promoting inflammation
NRF2 pathway inhibitors; HIF-1 pathway inhibitors; PKCδ-PKD1 inhibitors; Amino acid transporter inhibitors; α-Glucosidase inhibitors	Deregulating cellular metabolism
EGF pathway inhibitors; Ras/Raf/ MEK/ERK pathway inhibitors; PI3K/AKT/mTOR pathway inhibitors; Wnt pathway inhibitors; PDGF pathway inhibitors; SCF/c-Kit pathway inhibitors; ALK pathway inhibitors; Hedgehog pathway inhibitors	Sustaining proliferative signalling
IGF pathway inhibitors; NF-κB pathway inhibitors	Resisting apoptosis
VEGF pathway inhibitors	Inducing angiogenesis
Shh pathway inhibitors; FAK inhibitors; Src inhibitors; EGFR inhibitors	Expansive desmoplasia
Aurora kinase inhibitors; Cyclin-dependent kinase inhibitors	Eluding growth suppressors
PD-L1 inhibitors; CTLA-4 inhibitors	Avoiding immune destruction
PARP inhibitors Photodynamic agents; Bromodomain inhibitors; HDAC inhibitors	Genome instability and damage

EGF: Epidermal growth factor; Ras/Raf/MEK/ERK: Rat sarcoma virus/Rapidly Accelerated Fibrosarcoma/Mitogen-activated protein kinase/extracellular-signal-regulated kinase; PI3K/AKT/mTOR: Phosphoinositide 3-kinases/Ak strain transforming/Mammalian target of rapamycin; Wnt: Wingless-related integration site; PDGF: Platelet-derived growth factor; SCF/c-Kit: Stem cell factor/receptor tyrosine kinase; ALK: Anaplastic lymphoma kinase; TGF-β: Transforming growth factor beta; HGF: Hepatocyte growth factor; JAK/STAT: Janus kinase/signal transducers and activators of transcription; BTK: Bruton tyrosine kinase; Src: Tyrosine-protein kinase (sarcoma); COX-2: Cyclooxygenase 2; NRF2: Nuclear factor erythroid 2–related factor 2; HIF-1: Hypoxia-inducible factor-1; PKCδ-PKD1: Protein Kinase Cδ-Polycystin 1, Transient Receptor Potential Channel Interacting; IGF: Insulin like growth factor; VEGF: Vascular endothelial growth factor.

Table 2 Current ongoing trails targeting epigenetic therapy (combination drugs) in Pancreatic Cancer

Drug names	Combination agents	Trail phase	NCT number
Panobinostat vorinostat	Various antineoplastic drugs	Phase 1	NCT03878524
Vorinostat	Capecitabine + radiation	Phase 1/2	NCT00948688
Tazemetostat	Durvalumab/gemcitabine	Phase 2 recruiting	NCT04705818
Durvalumab	Tazemetostat	Phase 2	NCT04705818
Romidepsin, azacitidine	Durvalumab, lenalidomide, nab-paclitaxel	Phase 1/2 recruiting	NCT04257448
Azacitidine	Chemotherapy after progression	Phase 2 active	NCT01845805
Vorinostat	Gemcitabine, sorafenib +/−, radiation	Phase 1 active	NCT02349867
CC-486 (oral azacitidine)	–	Phase 2 active	NCT01845805
Azacitidine, not recruiting	Pembrolizumab	Phase 2 active	NCT03264404
Tazemetostat	Durvalumab	Phase 2	NCT04705818
MK-8628	-	Phase 1 completed	NCT02259114
Rx-3117	Nab-paclitaxel	1,2	NCT03189914
Entinostat	Nivolumab	Phase 2 completed	NCT03250273
Decitabine	Tetrahydrouridine	Phase 1 completed	NCT02847000
Vorinostat	Capecitabine	Phase 1 completed	NCT00983268
Azacitidine	nab-Paclitaxel, carboplatin	Phase 1 completed	NCT01478685
Vorinostat	NPI-0052 (marizomib)	Phase 1 completed	NCT00667082
Azacitidine	Pembrolizumab	Phase 2 recruiting	NCT03264404
Azacitidine	Abraxane, gemcitabine	Phase 2 active	NCT01845805
Entinostat	Nivolumab	Phase 2 active	NCT03250273