TABLE I.
Newer Therapies for Pancreatic Cancer and Their Molecular Targets
| Treatment target | Drug description | Mechanism of action |
|---|---|---|
| 1 Fas-FasL interaction | Synthetic phosphodiester oligodeoxynucleotide | Modulate Fas-FasL expression |
| Antibodies and antisense oligonucleotide | Decrease FasL | |
| 2 Death receptors | TRAIL (TNF related apoptosis inducing ligand) and its structural modifications | Bind and activate DR4 and DR5 receptors |
| RO5458640 (humanized monoclonal antibody) | Inhibit binding of TWEAK (TNF-like weak inducer of apoptosis) ligand to its receptor (Fn14) | |
| Mapatumumab, Conatumumab/AMG 655 | Agonistic DR4/DR5 antibody | |
| 3 Bcl-2 family of proteins | Antisense oligonucleotides | Inhibit overexpression of Bcl-2 and BclXL. |
| Small molecule inhibitors (Gossypol-AT101, TW-37, PPARγ-inactive TZD derivatives, Apogossypolone, ABT 737, Obatoclax, ABT 199) | Inhibit the interaction of various anti-apoptotic Bcl-2 members to pro-apoptotic members increasing the activity of latter. BH3 mimetics | |
| 4 Inhibitor of apoptosis proteins (IAPs) | SMAC mimetics (JP 1201, TL32711 (Birinapant), LCL161, SM-164,) | Inhibit IAPs after binding to their BIR3 domain |
| Antisense oligonucleotides (AEG 35156, Embelin, Xantag) | Functional depletion of XIAP | |
| 5 Survivin | YM 155 (sepantronium bromide) | Transcriptional repressor |
| Antisense oligonucleotides (ISIS23722, EZO-3042), siRNAs | Functional depletion of survivin | |
| Hsp90 inhibitors (shepherdin, AICAR) | Interfere with survivin folding and stability | |
| 6 Caspases | Gambogic acid and its derivatives (MX-2167) | Directly activate caspase-3 |
| Reolysin (human reovirus) | Target transformed KRAS cancer cells and activate caspase-4 | |
| 7 EGFR/Ras/Raf/MAPK | EGFR inhibitors Tyrosine kinase inhibitors (Erlotinib, Geftinib) | Interfere with ATP binding site of EGFR tyrosine kinase |
| Monoclonal antibodies (Cetuximab, Matuzumab, Trastuzumab) | Inhibit EGF ligand binding to EGFR | |
| Farnesyl transferase inhibitors (Tipifarnib, Lonafarnib) | Inhibit isoprenylation of KRAS | |
| 8 PI3K/Akt/mTOR | Natural compounds (curcumin, triptolide, resveratrol) | Possible transcriptional inhibition. |
| HIV protease inhibitors (Nelfinavir), Metformin | Inhibit activation of Akt | |
| mTOR inhibitors (Everolimus, Ridaforolimus, Temsirolimus) | Bind to FKBP12 and inhibit mTOR | |
| 9 NF-κB | Natural compounds (triptolide, luteolin, curcumin, EGCG) | Possible transcriptional inhibition |
| IKK inhibitors (BAY-11–7082, BAY-11–7085) | Prevent degradation of IκB | |
| Proteasome inhibitors (bortezomib) | Prevent degradation of IκBα by inhibiting 20S proteasome. | |
| DNA binding inhibitor (SN-50) | Inhibit NF-κB nuclear translocation | |
| 10 HDAC | Class I inhibitors (Depsipeptide) | Bind to zinc containing catalytic domain of HDACs |
| Class I and II inhibitors (Vorinostat, panabinostat, abexinostat, valproic acid) |