Table 3.
Recent studies targeting cellular pathways in pediatric acute leukemia (ClinilTrial.gov and Pubmed, accessed 12/31/2014)
| Class | Target | Name | Mechanism | Studies in pediatric acute leukemia |
|---|---|---|---|---|
| Tyrosine | BCR-ABL | Imatinib | Abl kinase inhibitor | 84-86, N00287105, NT01491763, NCT 01883219 |
| Dasatinib | Dual Src and Abl kinase inhibitor, penetrates CSF | NCT00720109, NCT01004497, NCT01460160 | ||
| Nilotinib | Inhibits imatinib resistant BCR-ABL mutations (not T351I), c-Kit, PDGFR | N01844764, NCT001219740, NCT01077544 | ||
| FLT3 | Midostaurin | Multikinase inhibitor for FLT3, PKC, VEGFR, PDGFR, c-Kit | NCT00866281 (completed), NCT00977782 (completed) | |
| Quizartinib | Inhibits Class III TK including FLT3, CSF1R, c-Kit, PDGFR | NCT01411267 (completed) | ||
| Lestaurtinib | Inhibits autophosphorylation of FLT3 | NCT00557193 (not recruiting), NCT00469859 (not recruiting) | ||
| Sorafenib | Inhibits FLT-ITD, RAF, VEGFR | NCT01371981, NCT01445080 (completed), NCT00908167, NCT02270788 | ||
| Crenolanib | Inhibits FLT3, PDGFRα | NCT02270788 | ||
| JAK | Ruxolitinib | Inhibits JAK1 and 2 | NCT01164163 (completed), NCT01251965 (not recruiting) | |
| Serine/Thre onine kinase | mTOR | Sirolimus | Binds to FKBP-12 to generate a complex to inhibit mTOR | NCT01658007, NCT00874562 (not recruiting) |
| Everolimus | Derivative of the natural macrocyclic lactone sirolimus | NCT01523977 | ||
| Temsirolimus | Derivative of rapamycin | NCT01403415 (not recruiting) | ||
| AKT | MK2206 | Binds to AKT and inhibit PI3K/AKT signaling pathway | NCT01231919 (completed) | |
| Aurora Kinase | Alisertib | Aurora kinase A inhibitor | NCT01154816 (completed) | |
| AT9283 | Multikinase inhibitor: Aurora Kinase A, B, JAK, BCR-ABL | NCT01431664 (completed) | ||
| Polo-like Kinase | Volasertib | Competitive inhibitor of Polo-like kinase 1 | NCT01971476 | |
| Epigenetics | DNMTs | Azacitidine | Nucleoside analog causes DNA hypomethylation | NCT01861002 (completed), NCT01995578, NCT01700673 |
| Decitabine | Nucleoside analog causes DNA hypomethylation | NCT02264873, NCT01853228, NCT01177540 | ||
| HDACi | Panobinostat | Binds to and inhibits histone deacetylase | NCT01321346 | |
| Vorinostat | Binds to and inhibits histone deacetylase | 87 | ||
| FR901228 | NCT00090531963 (completed) | |||
| DNMT + HDACi | Decitabine + Vorinostat or AR-42 | See above | 88, NCT01483690, NCT01798901 | |
| DOT | EPZ-5676 | Inhibits protein methyltransferase DOT1L | NCT02141828 | |
| Protein Degradation | Proteasome | Bortezomib | Reversible inhibitor of proteasome | 89-91, NCT02112916, NCT01371981 |
| Carfilzomib | Irreversible inhibitor of proteasome | NCT02303821 | ||
| NOTCH | Ysecretase | PF-03084014 | Blocks proteolytic activation of NOTCH receptor | NCT00878189 (not recruiting) |
| BMS-906024 | Pan NOTCH inhibitor | NCT01363817 | ||
| Cellular trafficking | Exportin 1 (XPO1) | Selinexor (KPT-330) | Selective inhibitor of nuclear export XPO1 | NCT02212561, NCT02091245 |
| DNA repair | PARP | BMN-673 | Inhibits DNA repair and cause apoptosis | NCT02116777 |
CSF, cerebrospinal fluid; DNMT, DNA methyltransferase; HDACi, histone deacetylase inhibitor