Key players in pancreatic cancer-stroma interaction: Cancer-associated fibroblasts, endothelial and inflammatory cells

Table 1 Important clinical trials describing drugs that target components of the pancreatic cancer stroma

Clinical trial	Target	Drug	Results
Bramhall et al[138], 2002	ECM	Marimastat: MMP inhibitor	No survival advantage was found in patients receiving marimastat in combination with gemcitabine compared to patients receiving gemcitabine alone
Moore et al[137], 2003	ECM	Bay 12-9566: MMP inhibitor	Phase III trial was closed early because Bay12-9566 treatment was inferior to gemcitabine treatment
Strimpakos et al[141], 2013	ECM	PEGPH20: degradation of hyaluronan	Phase Ib trial of PEGPH20 administration in combination with gemcitabine showed no significant toxicity. Phase II trials are warranted
Lutz et al[217], 2011; Laheru et al[218], 2008	Immune cells	GVAX: GM-CSF-based immunotherapy	Phase II trial showed that GM-CSF-based immunotherapy was a safe immunotherapeutic approach in combination with chemoradiation therapy. Phase II, multicentre trials are warranted
Royal et al[192], 2010	Immune cells	Ipilimumab: CTLA-4 inhibitor	Phase II trial of administration of ipilimumab did not show an acceptable response as a single-agent therapy
Le et al[219], 2013	Immune cells	Ipilimumab + GVAX	Phase Ib trial of ipilimumab in combination with GVAX demonstrated an improvement in overall survival compared to patients receiving ipilimumab alone. Phase II trials are warranted
Brahmer et al[194], 2012	Immune cells	BMS-936559: PDL1 inhibitor	Phase I trial found no objective response in PC patients receiving BMS-936559 treatment
Beatty et al[168], 2013	Immune cells	CP-870893: CD40 agonist	Phase I trial showed that CP-870,893 was well-tolerated in combination with gemcitabine in patients with advanced PDAC, and immune activation was observed. Phase II trials are warranted
Ko et al[98], 2015	Stromal depletion	IPI-926 (saridegib): hedgehog inhibitor	Phase Ib trial administered IPI-926 in combination with FOLFIRINOX. The study was closed early because a separate trial documented that the patients experienced a shorter median survival
Kindler et al[210], 2010	Angiogenesis	Bevacizumab: VEGF-A inhibitor	Phase III trial of bevacizumab in combination with gemcitabine did not improve overall survival compared to patients receiving gemcitabine alone
Kindler et al[211], 2011	Angiogenesis	Axitinib: inhibitor of VEGF receptors 1, 2 and 3	Phase III trial of axitinib in combination with gemcitabine did not improve overall survival compared to patients receiving gemcitabine alone

ECM: Extracellular matrix; MMPs: Matrix metalloproteinases; VEGF: Vascular endothelial growth factor; PC: Pancreatic cancer; PDAC: Pancreatic ductal adenocarcinoma.