Table 1.
Select agents targeting leukemia stem cell and microenvironment
| Molecular Target | Targeting Agent | Study in AML |
|---|---|---|
| Leukemia Stem Cell | ||
| Survival pathways | ||
| NF-ĸB | Parthenolide, bortezomib | Preclinical, phase I-III |
| PI3K/Akt/mTOR | BKM120, CAL-101, MK-2206, perifosine, GSK21110183, sirolimus, temsirolimus, deferolimus, everolimus, BEZ235, OSI-207 |
Preclinical, phase I-II |
| Self-renewal pathways | ||
| Wnt/β-catenin | CWP232291, PRI-724 | Phase I-II |
| Hedgehog | PF-04449913, LDE225 | Phase I-II |
| Mitochondrial targets | ||
| Bcl-2 | Oblimersen sodium, obatoclax, ABT-737, ABT-199 | Preclinical, Phase I-III |
| Mitochondrial translation | Tigecycline | Preclinical, Phase I |
| Cell surface antigen | ||
| CD123 | CSL362, SL-401 (IL-3-diphteria toxin), *CAR T cells, MGD006 (*DART CD123, CD3) |
Preclinical, Phase I-II |
| CLL-1 | mAB, nanoparticle-daunorubicin | Preclinical |
| CD25 | Basiliximab, Daclizumab, denileukin diftitox immunotoxin |
Preclinical, Phase I-II |
| CD47 | mAb, SIRPa Fc fusion protein | Preclinical |
| CD33 | Gemtuzumab ozogamicin, SGN-CD33A, 225-AcLintuzumab, AMG-330 (CD3, CD33 *BITE Ab), *CAR T cells |
Preclinical, Phase I-III |
| Bone marrow microenvironment | ||
| Adhesion, homing | ||
| CXCR4/SDF-1 | BMS-936564, BL-8040, plerixafor; NOX-A12 (SDF-1) | Preclinical, phase I-II |
| VLA-4 | natalizumab | Preclinical |
| CD44 | mAb | Preclinical |
| MUC1-C | peptide inhibitor GO-203 | Preclinical |
| Hypoxia | ||
| HIF-1a | ehinomycin | Preclinical |
| VEGF | bevacizumab, lenalidomide, sunitinib, sorafenib | Preclinical, Phase I-III |
| Hypoxia-activated prodrugs | PR-104, TH-302 | Preclinical, Phase I |
*
CAR (Chimeric Antigen Receptor) T cells; BITE Ab (Bispecific T cell Engager Ab); DART (Dual Affinity Retargeting Molecule)