Table 1 PDAC stroma-associated therapeutic targets
From: The role of stromal cancer-associated fibroblasts in pancreatic cancer
Drug | Target | Mechanism | Preclinical results | Clinical results | Author |
|---|---|---|---|---|---|
All-trans retinoic acid + gemcitabine | PDAC and stroma | CAF deactivation to quiescence with vitamin A storage capacity | Decrease in transcription factors in PDAC cells Increased markers of stromal quiescence Decrease in EMT | N/A | Carapuca et al. [50] |
SPARC overexpression + nab-paclitaxel | PDAC via stroma | Sequestration of drug by SPARC | 2.8× gemcitabine concentration within tumor | 50% reduction in PDAC cell proliferation Increase in endothelial proliferation | Von Hoff et al. [12] |
PEGPH20 + gemcitabine | Stroma | Stromal degradation by hyaluronidase | Significant depletion of hyaluronan 4× increase microvessel lumen diameter Increase in drug delivery to tumor within first 24 h | 7.2-month progression-free survival (PFS) and 12-month OS in tumors highly expressing hyaluronan Overall response rate of 25 and 67% in high HA tumors vs. 13% in standard therapy Minimal side effects | Hingorani et al. [52] |
Momelotinib, ruxulitinib + nab-paclitaxel or gemcitabine | JAK2 | JAK2 inhibition | Depletion of stroma Decreased PSC activation Diminished and altered collagen structures | OS 0.79 and PFS 0.72 hazard ratio (HR) ruxolitinib vs. placebo High inflammation subgroup: OS HR 0.47 vs. placebo Ruxolitinib failed phase III, momelotinib ongoing | Hurwitz et al. [53] Dawkins et al. Koh et al. Wormann et al. [33] |
SHH inhibitors | SHH | Decreased stroma expansion | Conflicting results | Conflicting results | Olive et al. [5] Kim et al. [54] Laheru et al. Dejesus-Acosta et al. |
Pasireotide | CAFs | Somatostatin analog | Reduced tumor growth Reduced chemoresistance | N/A | Duluc et al. [47] |