Table 2.
Clinical strategies to modulate CAF activation in the TME for anticancer therapeutic intervention.
| Drug/compound | Cancer type | Mechanism | Clinical stage | Reference(s) |
|---|---|---|---|---|
| Blocking CAF activation | Relevant life cycle stages: CAF priming, CAF maturation and mature CAF | |||
| Y-27632, Fasudil (HA-1077) | PDAC | Inhibits Rho/ROCK pathway | Preclinical | 100 |
| NT157 | Colorectal | Targets STAT3 and IGF-1R pathways | Preclinical | 101 |
| Targeting the CAF hyperproliferative phenotype | Relevant life cycle stages: CAF maturation and mature CAF | |||
| Tranilast | Lymphoma, lung | Anti-fibrotic agent that suppresses proliferation and TGF-β release | Preclinical | 102 |
| Pirfenidone | Pancreatic, NSCLC | Anti-fibrotic agent that suppresses proliferation and downregulates TGF-β, PDGF and collagen synthesis | Phase 1 (NCT03177291) | 103 |
| Targeting mature CAF function | Relevant life cycle stages: CAF maturation and mature CAF | |||
| Metformin | Ovarian | Inhibits IL-6 secretion by suppressing NF-κB signalling | Preclinical | 105 |
| Imatinib | Cervical | Blocks PDGF receptors | Preclinical | 106 |
| Sonidegib (LDE225) | Triple-negative breast | Inhibits Hedgehog signalling through SMO inhibitor | Phase 1 (NCT02027376) | 109 |
| Val-boroPro (Talabostat) | Colorectal | Inhibits FAP enzymatic activity | Phase 2 | 119 |
| Pasireotide (SOM230 analogue) | PDAC | Inhibits mTOR/4E-BP1 protein synthesis pathway | Phase 1 (NCT01385956) | 120 |
| Losartan | Breast | Decreased collagen I synthesis | Preclinical | 121 |
| AMD3100 | Gastric | Inhibits CXCL12/CXCR4 signalling | Preclinical | 122 |
| Inactivating the CAF phenotype | Relevant life cycle stages: mature CAF, senescent CAF and CAF inactivation | |||
| AC1MMYR2 | Breast, glioblastoma and gastric | Inhibits microRNA-21 maturation via NF-κB/miR-21/VHL axis | Preclinical | 123 |
| Dasatinib | Lung | Inhibits PDGFR | Preclinical | 124 |
| Vitamin D receptor ligand (Calcipotriol) | PDAC | Binds to master transcriptional regulator of CAFs | Preclinical (NCT02030860) | 97 |
| All-trans-retinoic acid | PDAC | Biomechanical reprogramming through an ATRA-dependent downregulation of actomyosin contractility via the RARβ/MLC2 pathway | Phase 1 (STAR_PAC: NCT03307148) | 125 |
| Ruxolitinib | Head and neck, lung and breast | Inhibits JAK/STAT pathway and DNA methyltransferase activity | Phase 2 (NCT03153982) | 60 |
| Minnelide | PDAC | Suppresses TGF-β signalling pathway | Preclinical | 107 |
| Depleting the CAF population | Relevant life cycle stages: mature CAF, senescent CAF and CAF inactivation | |||
| aFAP-PE38 | Breast | Immunotoxin that binds to FAP | Preclinical | 108 |
| Navitoclax (ABT-263) | Cholangiocarcinoma | BH3 mimetic that initiates cell death by inhibiting Bcl-2 proteins | Preclinical | 95 |
ATRA all-trans-retinoic acid, BH3 Bcl-2 homology domain 3, CAF cancer-associated fibroblast, CXCL12 CXC motif ligand 12, CXCR4 CXC motif chemokine receptor 4, IGF-1R insulin-like growth factor type 1 receptor, IL-6 interleukin-6, FAP fibroblast activation protein, JAK Janus kinase, MLC2 myosin light chain 2, mTOR mammalian target of rapamycin, NF-κB nuclear factor κB, NSCLC non-small-cell lung cancer, PDAC pancreatic ductal adenocarcinoma, PDGF platelet-derived growth factor, RARβ retinoid acid receptor β, ROCK Rho kinase, SMO smoothened, STAT3 signal transducer and activator of transcription 3, TGF-β transforming growth factor-β, VHL von Hippel–Lindau