Stroma-targeting strategies in pancreatic cancer: Past lessons, challenges and prospects

Table 1 Summary of stromal-targeting clinical trials in pancreatic cancer

Drug	Mechanism of action	Backbone therapy	Outcome
Targeting stroma-promoting pathways in PDAC cells
Saridegib (IPI-926)	SHH pathway inhibitor	Gemcitabine; mFOLFIRINOX	No improvement in OS or PFS (NCT01130142); No improvement in OS or PFS (NCT01383538)
Vismodegib	SHH pathway inhibitor	Gemcitabine; Gemcitabine + nab-paclitaxel	No improvement in OS or PFS (NCT01064622); No improvement in OS or PFS (NCT01088815)
Sonidegib	SHH pathway inhibitor (SMO receptor antagonist)	Gemcitabine; Gemcitabine + nab-Paclitaxel	No improvement in OS or PFS (NCT01487785); No improvement in OS or PFS (NCT02358161)
Galunisertib	TGF-β receptor inhibitor	Gemcitabine; Gemcitabine + Durvalumab	Ongoing trial (NCT01373164); Ongoing trial (NCT02734160)
Losartan	TGF-β ligand inhibitor	FOLFRINOX; Nivolumab + FOLFRINOX	Ongoing trial (NCT01821729); Ongoing trial (NCT03563248)
Defactinib	Focal Adhesion Kinase inhibitor	Gemcitabine + Pembrolizumab	Ongoing trial (NCT02546531)
Anakinra	IL-1 receptor inhibitor	GnP + Cisplatin	Ongoing trial (NCT02550327)
Targeting stroma-promoting pathways in CAFs
Pamrevlumab	Antibody against CTGF	Gemcitabine + nab-paclitaxel	Ongoing trial (NCT03941093)
Paricalcitol	Vitamin D agonist; Inactivation of PSC	GnP + Cisplatin; GnP + Hydroxychloroquine; 5FU/Leucovorin/liposomal Irinotecan; Pembrolizumab (2nd line)	Ongoing trial (NCT04054362); Ongoing trial (NCT04524702); Ongoing trial (NCT03883919); Ongoing trial (NCT03331562)
ATRA	Inactivation of PSC	Gemcitabine + nab-paclitaxel	Ongoing trial (NCT03307148)
Targeting ECM
PEGPH20	Hyaluronan degradation	Gemcitabine + nab-paclitaxel; mFOLFIRINOX	No improvement in OS or PFS (NCT02715804); Poor OS due to poor tolerance (NCT01959139)
Simtuzumab	Antibody against LOXL2	Gemcitabine	No improvement in OS (NCT01472198)
Cilengitide	Integrin inhibitor	Gemcitabine	No improvement in OS (ISRCTN13413322)
Marimastat	MMP inhibitor	Gemcitabine	No improvement in OS
Bay-12-9566	MMP inhibitor	Gemcitabine	No improvement in OS
Others
Halofunginone	PSC/CAF and SMAD2,3 inhibitor	-	Positive pre-clinical outcomes
Pirfenidone	Cell cycle inhibitor of CAF	-	Positive pre-clinical outcomes

SHH: Sonic hedgehog; OS: Overall survival; PFS: Progression free survival; SMO: Smoothened; TGF: Transforming growth factor; IL: Interleukin; GnP: Gemcitabine plus nab-paclitaxel; CTGF: Connective tissue growth factor; CAF: Cancer-associated fibroblasts; PSC: Pancreatic stellate cell; ECM: Extracellular matrix; LOXL2: Lysyl oxidase-like 2; MMP: Matrix metalloproteinases.