1000/1000
Hot
Most Recent
Cancer-associated fibroblasts (CAFs) are key components of the pancreatic tumor microenvironment, maintaining the extracellular matrix, while also being involved in intricate crosstalk with cancer cells and infiltrating immunocytes. Therefore, they are potential targets for developing therapeutic strategies against pancreatic ductal adenocarcinoma (PDAC). However, studies have demonstrated significant heterogeneity in CAFs with respect to their origins, spatial distribution, and functional phenotypes within the PDAC tumor microenvironment. Therefore, it is imperative to understand and delineate this heterogeneity prior to targeting CAFs for PDAC therapy.
S. No. | Target | Name of Therapeutic | Rationale Based on Pre-Clinical Studies | Current Status | ClinicalTrials.gov Identifier |
---|---|---|---|---|---|
1. | Hedgehog Pathway | IPI-926 | Inhibition of the Hedgehog Pathway, leading to reduced CAF activation |
Phase II was halted due to the early detection of a shorter median overall survival (OS) in the experimental arm, compared to the placebo arm. | NCT01130142 |
2. | Hedgehog Pathway | Vismodegib | The phase Ib/II randomized clinical trial, evaluating the addition of Vismodegib to gemcitabine, showed no treatment benefit for OS or progression free survival (PFS). |
NCT01195415 | |
3. | Hyaluronic acid | PEGPH20 | Depletion of stroma by PEGPH20, which may synergize with immunotherapy | Clinical trials failed to show any benefit. | NCT03634332 |
4. | Angiotensin receptor | Losartan | Attenuation of collagen and hyaluronan deposition by CAFs through inhibition of TGF-β signaling | Encouraging results in locally advanced PDAC | NCT03563248 |
5. | Lysyl oxidase like-2 (LOXL2) | Simtuzumab | Inhibition of matrix-remodeling enzyme Lysyl oxidase-like 2, an ECM remodeling enzyme | Study completed, and addition of Simtuzumab to gemcitabine did not improve clinical outcomes |
NCT01472198 |
6. | CXCL12-CXCR4 Axis | Olaptesed (NOX-A12) | Modulation of PDAC TME by reducing immunosuppressive factors, as CXCL12 secreted by iCAFs promotes tumorigenesis by reducing CD8 T cell infiltration | Clinical trial ongoing | NCT03168139 |
7. | CXCL12-CXCR4 Axis | BL-8040 CXCR4 Antagonist |
Clinical trial ongoing | NCT02826486 | |
8. | IL-6 | Siltuximab | Combination of IL-6 and PD-L1 blockade decreases tumor growth, improves survival, and leads to increased infiltration of effector CD8+ T cells | Clinical trial ongoing | NCT04191421 |
9. | Vitamin D receptor (VDR) | Paricalcitol (Vitamin D Receptor Agonist) | Modulating signaling in tumor microenvironment. CAFs highly express VDR, and treating them with Vitamin D can induce a quiescent phenotype |
Clinical trials ongoing | NCT03520790 |
NCT03300921 | |||||
NCT02754726 | |||||
10. | Vitamin D receptor (VDR) | Vitamin D3 | Clinical trials ongoing | NCT03472833 | |
11. | Stroma | All Trans Retinoic Acid (ATRA) | Inducing CAF quiescence and decreasing motility, leading to decreased tumor growth through decreased Wnt-β Catenin signaling | Clinical trials ongoing | NCT03307148 |
12. | IL-1R | Anakinra (IL-1R antagonist) |
By switching iCAF to a myCAF phenotype | Clinical trials ongoing | NCT02550327 |
CXC chemokine ligand 12 (CXCL12).