Table 2.
Clinical trials targeting cancer-associated fibroblasts.
| Target | Name | Drug and Biologic | Mechanism | Current Status | References |
|---|---|---|---|---|---|
| Inhibition of CAF activation | |||||
| FGFR | JNJ-42756493 | Small-molecule inhibitor | Promotes ECM depletion Prevents CAF activation |
Phase-I and phase-II trials ongoing | [93] |
| Hedgehog signaling pathway | JPI-926 (saridegib) and vismodegib |
Small-molecule inhibitor | Leads to ECM depletion via blocking the Hedgehog signaling pathway and targeting ECM-producing αSMA+ CAFs | Failed in phase-III trial | [92] |
| Inhibition of CAF activation and CAF action | |||||
| TGF-β | Various, including galunisertib | Both blocking Abs and small-molecule receptor inhibitors | Prevents CAF activation and immunosuppression | Phase-II and phase-III trials ongoing | [94,95] |
| Anjiotensin receptor II antagonist | Losartan | Small-molecule inhibitor | Decreases TGF-β activation in αSMA+ CAFs, leading to an increase in drug delivery and immunotherapy efficacy | Phase-III trial ongoing | [99] |
| Inhibition of CAF action | |||||
| CXCR4 | AMD3100 | Small-molecule inhibitor | Prevents signaling from CAFs to immune cells | CTs ongoing | [96] |
| ROCK | AT13148 | Small-molecule inhibitor | Reduces contractility | Phase-I trial completed | [100] |
| FAK | Defactinib | Small-molecule inhibitor | Reduces downstream signaling of integrins | Clinical trials ongoing | [92] |
| LOXL2 | Simtuzumab | Blocking Ab | Anticrosslinking | Preclinical and fibrosis trials ongoing | [102] |
| CTGF | FG-3019 | Blocking Ab | Blocks binding to receptors, including integrins | Early-phase clinical trials ongoing | [101] |
| Hyaluronic acid | PEGPH20 | Pegylated enzyme | Degrades ECM to increase access and efficacy of anticancer treatments and immunotherapies | Failed in phase-III trial | [97,98] |
| FAP-express cells | Various, including PT630 and RO6874281 | Blocking Abs, molecular radiotherapy, inhibitors or an Ab-IL-2 fusion | Blocks FAB CAF function, promoting T-cell function | Phase-I and phase-II trials under way | [105] |
| CAF normalization | |||||
| Vitamin A metabolism | ATRA minnelide |
Vitamin A metabolite | Transdifferentiates aHSCs into qHSCs | Clinical trials ongoing | [106] |
| Vitamin D receptor | Calcipotriol | Small-molecule agonist | Transdifferentiates aHSCs into qHSCs | Clinical trials ongoing | [107] |