Table 3.
Strategies targeting PSCs in TME of PDAC.
| Strategies | Descriptions | Main results |
|---|---|---|
| Clinical studies | ||
| PEGPH20 | HA degradation | Phase Ib: Elevated OS and PFS in PDAC patients (99). |
| IPI-926 | Hedgehog pathway inhibitor | Phase II: Withdrawn for increased mortality (152). |
| Marimastat | MMP inhibitor | Phase II: No extra benefits were found in PDAC patients, compared to GEM alone (153). |
| ATRA | Retinoic acid derivatives | Phase Ib: Ongoing, no results released (154). |
| Cabiralizumab plus nivolumab | Target CSF1R | Phase Ia/Ib: no results published. NCT04191421 |
| Vitamin D3 | Target VDR | Phase III: no results published. NCT03472833, NCT03300921 |
| Paricalcitol | Target VDR | Phase II: no results published. NCT02754726 |
| Preclinical studies | ||
| IPI-926 | Hedgehog pathway inhibitor | Elevated vascular density and concentration of GEM in tumor of KPC mice (155). |
| AZD8542 | Hedgehog pathway inhibitor | Reduced tumor volume and metastasis in an orthotopic model of PDAC (156). |
| Metformin | Repurposed anti-diabetic drugs | Reduced PSC activation, tumor volume and increased GEM efficacy in an orthotopic mice of PDAC (157). |
| Minnelide | TGFβ signaling inhibitor | Reduced ECM production, increased vasculature, improved drug delivery in tumor in both spontaneous KPC mice and PDAC xenografts mice (158). |
| Calpeptin | Calpains inhibitor | Reduced PSC activation, decreased fibrosis, tumor volume in PDAC xenografts mice (159). |
| JQ1 & I-BET151 | BET inhibitors | Attenuated PSC activation and collagen I production in the mouse model of PDAC (160). |
| Genetical deletion of αSMA+ cells | αSMA+ cells | More aggressive tumors, increased hypoxia and EMT, reduced survival in transgenic PDAC mice (148). |
| Genetical deletion of SHH | SHH pathway | Undifferentiated malignancies, increased vascularity and proliferation in SHH-deleted PDAC mice (161). |
| PEGPH20 | HA degradation | Depleted HA, expanded blood vessels and increased chemotherapeutic drug delivery in tumor of PDAC mice (83). |
| Pirfenidone | TGFβ signaling inhibitor | Reduced PSC proliferation, collagen production; co-treatment with GEM reduced tumor growth and hepatic metastasis in PDAC mice (162). |
| Olmesartan | Ang II receptor 1 antagonists | Decreased PSC proliferation, αSMA expression, collagen I production, tumor growth in subcutaneous PDAC mice (163). |
| Losartan | Ang II receptor 1 antagonists | Decreased stress in solid tumors, improved vascular perfusion, increased chemotherapeutic delivery in PDAC mice (164). |
| ATRA | Retinoic acid derivatives | Decreased PSC migration, collagen synthesis, leading to an increased apoptosis of surrounding PSCs (151). |
| Calcipotriol | Vitamin D3 derivatives | Improved intratumoral concentration of drug, decreased tumor size, prolonged survival compared to GEM alone in KPC mice (137). |
| LXA4 | An endogenous bioactive lipid | Reduced PSC activation, fibrosis and tumor growth of in mouse model (150). |
| Fasudil | Rho-associated protein kinase inhibitor | Reduced PSC activation, decreased collagen deposition, increased GEM delivery, improved OS in PDAC mouse model (146). |
| AZ13381758 | CXCR2 inhibitor | Reduced collagen I/III, lowered metastasis, increased OS in PDAC mouse model (165). |
| AV3 | Integrin α5 inhibitor | Reduced desmoplasia, decompressed blood vasculature, improved GEM efficacy in patient-derived xenograft PDAC model (62). |
| AMD3100 | CXCR4 antagonist | Increased T cell infiltration, reduced tumor growth in PDAC mouse model (166). |
| AMG102 | HGF inhibitor | Reduced tumor volume and metastasis when treated together with GEM in orthotopic mice of PDAC (117). |
| CSF1 | Strong inducer of PSC deactivation | In mesenchymal PDAC, CSF1 deactivated PSCs thereby reducing the tumor-restraining effect of PSCs. |
| Exendin-4 | Glucagon-like peptide-1 receptor agonist | Decreased PSC proliferation and migration, reduced PCC migration, invasion and proliferation (167). |
| Resveratrol | Natural polyphenol with antioxidant and anticancer effects | Inhibited hypoxia-induced PSC activation, blocked PSCs–PCCs crosstalk, and decreased malignant progression of PDAC and stromal desmoplasia in a KPC mouse model (168). |
| ICG-001 | β-catenin/CBP inhibitor | Suppressed activation of PSCs and PSC-induced migration of PCCs (169). |
| XL888 | Hsp90 inhibitor | Reduced PSC activation and enhanced the efficacy of anti-PD-1 blockade in tumor bearing mice (170). |
| Curcumin | Turmeric polyphenol derivates of rhizomes of Curcuma longa | Reduced αSMA, type I collagen, and fibronectin and diminished PSC activation (171). |
| Emodin | Important component of Aloe vera | Reduced expression of αSMA, type I collagen, and fibronectin in PSCs and enhanced the efficacy of chemotherapeutic drugs for PDAC (172). |
| Pantoprazole | Proton pump inhibitor | Decreased collagen secretion from PSCs and proliferation of PCCs (173). |