Oncometabolites in pancreatic cancer: Strategies and its implications

Table 1 Overview of inhibitors of metabolism in pancreatic cancer

Agent	Target	Combined with	Ref.
CG-5	GLUT1	-	[1]
		Gemcitabine
2-DG	Glycolysis	-	[2]
		Gemcitabine
3-BP	Glycolysis	-	[3]
BNBZ	HK2	-	[4]
PGMI-004A	PGAM1	-	[4]
KH3	PGAM1	-	[4]
CPI-613	PDH	-	[5]
		Galloflavin
		Cyano-4-hydroxycinnamic acid
Rotenone	OXPHOS: Complex I	-	[6]
Metformin
Phenformin
IACS-010759
Atovaquone	OXPHOS: Bc1 complex	-	[7]
N-hydroxyindoles	LDHA	-	[8]
N-hydroxyindole-NHI-1		Gemcitabine	[8]
Galloflavinin	LDHA	Metformin	[9]
Gossypol		-	[10]
FX11		-	[1]
Avasimibe	ACAT1	-	[11]
Luteolin	FASN	-	[12]
C75		-	[11]
Palbociclib		-	[13]
Paclitaxel nano-formulation		-	[14]
Orlistat	FASN	-	[15]
		Gemcitabine	[1]
EGCG	FASN, GLUD1 & PGAM1	-	[1,4]
Lansoprazole	FASN	-	[11]
Pantoprazole
Rabeprazole
Omeprazole
DEAB	ALDH	-	[16]
		Gemcitabine
Disulfiram	ALDH		[16]
A939572	SCD	-	[17]
CAY10566	SCD	-	[18]
		Gemcitabine
SB-204990	ACLY	-	[11]
BAY ACC022		-
TOFA	Fatty acid synthesis	-	[19]
Silibinin	Lipid metabolism	-	[20,21]
Atorvastatin,	HMG-CoA reductase	-	[22]
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Etomoxir	FAO	Carnitine palmitoyl transferase I inhibitor	[11]
Artesunate	Lipid metabolism		[11]
Zalcitabine
Avasimin	SOAT1		[11]
Opaganib	SK2		[23]
Vitamin D	Lipid metabolism		[24]
DON	Gln	-	[25]
Sirpiglenastat	Gln	-	[25]
		Trametinib
ss-lapachone	GLS	-	[1]
Thiazolidine-2,4-dione derivatives
BPTES	GLS	-	[26]
		ß-lapachone (ß-lap)	[27]
968	GLS	-	[26]
CB-839	GLS	-	[26]
		ß-lap	[27]
		BSO
BPTES encapsulated nanoparticles	GLS	-	[26]
		Metformin
GPNA	Gln transporter	-	[28]
ASNase	Asparagine	GCN2iA/B	[29]
		PD-325901
Indoximod	IDO	-	[30]
Carbidopa		-
Epacadostat	IDO	-	[27]
PEG-ADI	Arginine metabolism	-	[23]
		Radiotherapy	[27]
		Gemcitabine
		Gemcitabine + docetaxel
		Panobinostat
SM-88	Mucin-1 synthesis	-	[23]
AG-270	MAT2A	-	[23]
		Taxane-based chemotherapy

FASN: Fatty acid synthase; GLUT: Glucose transporter; OXPHOS: Oxidative phosphorylation; PEG-ADI: Pegylated arginine deiminase; SCD: Stearoyl-CoA desaturase; IDO: Indoleamine 2,3-dioxygenase.

Table 2 Overview of inhibitors of metabolism, evaluated through clinical trials in pancreatic cancer

Agent	Target	Combined with	NCT No.
HCQ	Glucose uptake/autophagy	-	NCT01273805
		Gemcitabine	NCT01128296
		Gemcitabine + nab paclitacel	NCT01506973, NCT01978184
		Temuterkib	NCT04386057
		Radiation + capecitabine	NCT01494155
		Chlorphenesin carbamate + mFOLFIRINOX	NCT05083780
		Kinase inhibitors	NCT03825289, NCT05518110, NCT04132505
		Paricalcitol + gemcitabine + nab-paclitaxel	NCT04524702
		Paricalcitol + losartan	NCT05365893
		Leflunomide/bevacizumab	NCT06229340
		CPI-613 + 5-fluorouracil or gemcitabine	NCT05733000
		Paclitaxel protein bound gemcitabine + cisplatin	NCT04669197
2-DG	Glycolysis	Docetaxel	NCT00096707
CPI-613	PDH	mFOLFIRINOX	NCT01835041, NCT03504423
		Gemcitabine + nab-paclitaxel	NCT03435289
Metformin	OXPHOS: Complex I	-	NCT01971034
		Gemcitabine	NCT01210911, NCT02005419
		mFOLFOX-6	NCT01666730
		Stereotactic radiosurgery	NCT02153450
		Rapamycin	NCT02048384
		Gemcitabine + paclitaxel albumin-stabilized nanoparticle formulation	NCT02336087
		Everolimus + octreotide LAR	NCT02294006
IACS-010759	OXPHOS: Complex I	-	NCT03291938
Omeprazole	FASN	-	NCT04930991
Disulfiram	ALDH	Gemcitabine	NCT02671890
Simvastatin	HMG-CoA reductase	Gemcitabine	NCT00944463
		Valproic acid + gemcitabine/nab-paclitaxel-based regimens	NCT05821556
		Metformin + Digoxin	NCT03889795
		Digoxin + Gemcitabine	NCT06030622
		Standard chemotherapy	NCT06241352
Atorvastatin	HMG-CoA reductase	Evolocumab + Ezetimibe	NCT04862260
Opaganib	SK2	-	NCT01488513
Paricalcitol	Lipid metabolism	Liposomal irinotecan + 5-FU/LV	NCT03883919
		Pembrolizumab	NCT03331562
		Gemcitabine + nab-paclitaxel	NCT03520790
ERY-ASP	Asparagine	-	NCT01523808
		Gemcitabine/FOLFOX	NCT02195180, NCT03665441
Indoximod	IDO	Chemotherapy	NCT02077881
Epacadostat		Immunotherapy, chemotherapy + GVAX	NCT03006302, NCT03085914
PEG-ADI	Arginine metabolism	Gemcitabine + nab-paclitaxel	NCT02101580
SM-88	Mucin-1 synthesis	-	NCT04229004
		MPS	NCT03512756

ALDH: Aldehyde dehydrogenase; FASN: Fatty acid synthase; OXPHOS: Oxidative phosphorylation; IDO: Indoleamine 2,3-dioxygenase; PEG-ADI: Pegylated arginine deiminase.