Table 1.
Current cancer-associated fibroblast clinical trial activity
| Target | Name | Drug or biologic | Mechanism | Current status |
|---|---|---|---|---|
| Interference with CAF activation | ||||
| FGFR | JNJ-42756493 | Small-molecule inhibitor | Prevents CAF activation | Phase I and phase II trials under way170 |
| Hedgehog | IPI-926 (saridegib) and vismodegib | Small-molecule inhibitor | Reduces CAF activation | Clinical trials ongoing; some reported lack of efficacy169,171 |
| Interference with CAF activation and CAF action | ||||
| TGFβ | Various, including galunisertib | Both blocking Abs and small-molecule receptor inhibitors | Prevents CAF activation and immunosuppression | Phase I, phase II and phase III trials under way172,173 |
| Angiotensin receptor | Losartan | Small-molecule inhibitor | Reduces collagen and hyaluronan levels | Phase II trial completed; randomized trial ongoing174,175 |
| Interference with CAF action | ||||
| CXCR4 | AMD3100 | Small-molecule inhibitor | Prevents signalling from CAFs to immune cells | Clinical trials ongoing176 |
| ROCK | AT13148 | Small-molecule inhibitor | Reduces contractility | Phase I trial completed177 |
| FAK | Defactinib (VS-6063, PF-04554878) | Small-molecule inhibitor | Reduces signalling downstream of integrins | Clinical trials ongoing178 |
| LOXL2 | Simtuzumab (GS 6624) | Blocking Ab | Anticrosslinking | Preclinical and fibrosis trials179 |
| CTGF | FG-3019 | Blocking Ab | Blocks binding to receptors, including integrins | Early-phase clinical trials ongoing |
| Hyaluronic acid | PEGPH20 (PVHA) | Pegylated enzyme | ECM degradation to increase the access and efficacy of cytotoxic therapies and immunotherapies | Phase III trial complete, awaiting final analysis180,181 |
| FAP-expressing cells | Various, including PT630 and RO6874281 | Blocking Abs (sibrotuzumab I (ref.182), molecular radiotherapy, inhibitors (PT630) or an Ab–IL-2 fusion (RO6874281) | Blocks FAP+ CAF function, promoting T cell function | Phase I and phase II trials under way183 |
| CAF normalization | ||||
| Vitamin A metabolism | ATRA | Vitamin A metabolite | ‘Normalizes’ stellate cells | Clinical trials ongoing184,185 |
| Vitamin D receptor | Paricalcitol | Small-molecule agonist | ‘Normalizes’ stellate cells | Clinical trial started186 |
Ab, antibody; ATRA, all-trans retinoic acid; CAF, cancer-associated fibroblast; CTGF, connective tissue growth factor; CXCR4, CXC-chemokine receptor 4; ECM, extracellular matrix; FAK, focal adhesion kinase; FAP, fibroblast activation protein; FGFR, fibroblast growth factor receptor; IL-2, interleukin-2; LOXL2, lysyl oxidase-like 2; ROCK, RHO kinase; TGFβ, transforming growth factor-β.