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29/05/2018 10:45 am
Very good overview from:
Targeted Tumor Therapy Remixed—An Update on the Use of Small-Molecule Drugs in Combination Therapies http://www.mdpi.com/2072-6694/10/6/155/htm
| Principle/Substance Group | Molecular Target | Cancer Type/Ongoing Trials (Selection) |
|---|---|---|
| 1. Signaling/Kinase inhibitors | ||
| - RAF-MEK-MAPK pathway inhibitors | BRAFV600mut, MEK | MM (LOGIC-2), NSCLC, CRC |
| - PI3K pathway inhibitors | PI3K, AKT, mTOR, GSK3 | MM (LOGIC-2), advanced solid tumors |
| - Cell cycle kinase inhibitors | Cyclin-dependent kinases (CDK4/6) | MM (LOGIC-2), NSCLC, solid tumors |
| - Growth factor signaling inhibitors | Oncogenic receptor kinases | Advanced cancers (multikinase inhibitors) |
| - FGFR | MM (LOGIC-2), TNBC, NSCLC | |
| - MET kinase | MM (LOGIC-2), RC, NSCLC, lymphoma | |
| - EGFR | NSCLC, CRC | |
| - VEGFR, PDGFR, others | MM (NIPAWILMA) | |
| - JAK-STAT pathway inhibitors | Janus kinases (JAKs) | advanced solid tumors, NSCLC, lymphoma |
| - FAK inhibitors (FAKi) | Focal adhesion kinase (FAK) | CRC, NSCLC, combination ImT |
| 2. Apoptosis modulators | ||
| - BH3 mimetics, BCL-2/XL-inhibitors | Intrinsic cell death (NOXA, PUMA, BIM) | ALL (Venetoclax), n/f 1 (pre-clinical) |
| - SMAC mimetics | Inhibitor of apoptosis proteins (IAPs) | advanced solid tumors, NSCLC |
| - BCL-2 antisense oligonucleotides | Anti-apoptotic BCL-2 members | HM, MM (Oblimersen, withdrawn) |
| - p53 reactivation | Tumor suppressor p53, MDM2/4 | Advanced cancers, lymphoma, AML |
| - Death receptor activation | Death receptors (FAS, TRAIL/APO-2) | MM (DS-8273a), NSCLC, CRC |
| - Autophagy inhibitors | Autophagy pathways | CRC, HCC, advanced solid tumors |
| 3. DNA damage response inhibitors | ||
| - PI3K/PIKK (ATM/ATR) inhibitors | ATM and ATR kinases | Advanced solid tumors, lymphoma, CNS |
| - Checkpoint kinase inhibitors | CHK1 kinase, WEE kinase | tumors (phase 0–II), ChT/RT combinations |
| - PARP inhibitors | poly(ADP-ribose) polymerase (PARP) | OC, combination therapies |
| 4. Epigenetic drugs | ||
| - 5-Aza-(2-deoxy-)cytidine | DNA-methyl-transferases (DNMT1-3) | HM (MDS), MM |
| - HDAC inhibitors (HDACi) | Histone deacetylases (HDAC1-10) | HM, lymphoma, N/SCLC, MM |
| - EZH2 inhibitors | Polycomb repressive complex (PRC) 2 | Sarcoma, lymphoma, mesothelioma |
| - BET inhibitors | BET family of histone readers | Refractory HM (MDS, ALL), solid tumors |
| - DUB inhibitors | (Histone) deubiquitinases | n/f 1 |
| - si/miRNAs | microRNAs, lncRNAs, tumor mRNAs | withdrawn, only biomarker studies |
| 5. Telomerase inhibitors | ||
| - hTR antagonists/competitors | hTR nucleotide (TERC) | solid tumors, withdrawn (Imetelstat) |
| - hTERT inhibitors (Ti) | Telomerase reverse transcriptase (TERT) | withdrawn |
| 6. Redox drugs | ||
| - Dimethylfumarate (DMF) | BCL2, PARP1, NFκB-NRF2-KEAP1-axis | Lymphoma (CTL), CNS (pre-clinical) |
| - Antioxidants (Vitamins, NAC, others) | EMT, cytotoxicity reduction | NSCLC, CRC, solid tumors, lymphoma |
| 7. Metabolic drugs | ||
| - Metformin, Phenformin | mTOR, TCA cycle | MM, BC, OC, PC, advanced solid tumors |
| - PDK inhibitors (Dichloroacetate) | Pyruvate dehydrogenase kinase, Glycolysis | CNS tumors (completed), SCC |
| 8. Proteasome inhibitors | ||
| - Bortezomib, PS-341 | (Ubiquitin)-Proteasome pathway | Refractory solid tumors, HM |
| 9. Transdifferentiation inducers | ||
| - Retinoids (ATRA, Bexarotene) | Nuclear RAR and RXR receptors | HM, CNS, MM (pre-clinical) |
| - Unsaturated fatty acids | PPARγ, adipogenic differentiation pathways | CNS, MM (pre-clinical) |
| 10. Immunomodulators | ||
| - T cell receptor signaling enhancers | Ubiquitin ligases (CBL, ITCH, GRAIL, et al.) | n/f 1 |
| Adaptor proteins, kinases | ||
| - Kynurenine pathway inhibitors | Indoleamine 2,3-dioxygenase (IDO1) | MM (KEYNOTE-252/ECHO-301, halted) |
| 11. Others | ||
| - Matrix metalloprotease inhibitors | MMP, COL3 | Advanced solid tumors (completed) |
| - WNT/β-Catenin inhibitors | WNT ligand | WNT-driven tumors (MM, CRC, others) |
