TABLE 2.
Selected therapeutic targets in the emerging and developing antitumor attempts
| Targets | Drugs | Biologic action | Target cells | Monotherapy or combinatorial therapies | Current status | Tumor types | Trial No. |
|---|---|---|---|---|---|---|---|
| Reprogram the TME | |||||||
| CSF‐1R | BLZ945 | Kinase inhibitor | Macrophages | Monotherapy or in combination with anti‐PD1 mAb (Spartalizumab) | Phase I/II ongoing | Advanced solid tumors | NCT02829723 |
| Pexidartinib | Kinase inhibitor | Macrophages | In combination with chemo‐radiotherapy (Temozolomide + RT) | Phase Ib/II completed | Glioblastoma | NCT01790503 | |
| CXCR1/2 | Reparixin | Allosteric inhibitor | Neutrophils | In combination with chemotherapy (Paclitaxel) | Phase II completed | Metastatic triple‐negative breast cancer | NCT02370238 |
| Hyaluronic acid | PEGPH20 | PEGylated enzyme | ECM | In combination with chemotherapy (Gemcitabine) | Phase I/II completed | Stage IV pancreatic cancer | NCT01453153 |
| Inhibit tumor angiogenesis | |||||||
| VEGF‐A | Bevacizumab | Anti‐VEGF mAb | Endothelial cells | In combination with standard chemotherapy (Taxanes, Gemcitabine, Capecitabine, or Vinorelbine) | Phase III completed | Metastatic breast cancer | NCT00281697 |
| VEGFR2 | Sorafenib | Kinase inhibitor | Endothelial cells | In combination with chemotherapy (Capecitabine) | Phase III completed | Advanced or metastatic HER2‐negative breast cancer | NCT01234337 |
| In combination with chemotherapy (Gemcitabine + Cisplatin) | Phase III completed | Advanced nonsquamous NSCLC | NCT00449033 | ||||
| Sunitinib | Kinase inhibitor | Endothelial cells | Monotherapy | Phase II/III ongoing | Glioblastoma | NCT03025893 | |
| Prevent PMN formation | |||||||
| CCR2 | MLN1202 | Anti‐CCR2 mAb | Macrophages | Monotherapy | Phase II completed | Metastatic cancer | NCT01015560 |
| CXCR4 | Plerixafor | CXCR4 antagonist | Hematopoietic progenitor cells | In combination with anti‐PD1 mAb (Cemiplimab) | Phase II ongoing | Metastatic pancreatic cancer | NCT04177810 |
| TGFβ | Fresolimumab | Anti‐TGFβ mAb | Fibroblasts | In combination with stereotactic ablative radiotherapy | Phase Ib/II ongoing | Stage IA/IB NSCLC | NCT02581787 |
| PDGFR | Imatinib | Kinase inhibitor | Fibroblasts; Endothelial cells | In combination with chemotherapy (Gemcitabine) | Phase II completed | Metastatic pancreatic cancer | NCT00161213 |
| Disrupt metabolic homeostasis | |||||||
| HIF‐1α | RO7070179 | ASO inhibitor | Tumor cells | Monotherapy | Phase I completed | HCC | NCT02564614 |
| Everolimus | mTOR inhibitor | Tumor cells, endothelial cells | In combination with chemotherapy (FOLFOX) and anti‐angiogenic therapy (Bevacizumab) | Phase I/II completed | Colorectal cancer | NCT01047293 | |
| EZN‐2968 | ASO inhibitor | Tumor cells | Monotherapy | Phase I completed | Advanced solid tumors | NCT01120288 | |
| Tirapazamine | Hypoxic cytotoxin | Hypoxic cancer cells | In combination with chemo‐radiation therapy (Cisplatin + 5‐fluorouracil + RT) | Phase II completed | Advanced squamous head and neck cancer | NCT00002774 | |
| Reboot antitumor immunity | |||||||
| CTLA4 | Ipilimumab | Anti‐CTLA4 mAb | T cells | In combination with anti‐PD1 mAb (Pembrolizumab) | Phase III ongoing | Stage IV, metastatic NSCLC | NCT03302234 |
| Monotherapy | Phase III completed | Metastatic melanoma | NCT01515189 | ||||
| Tremelimumab | Anti‐CTLA4 mAb | T cells | Monotherapy | Phase II completed | Colorectal cancer | NCT00313794 | |
| In combination with PARP inhibitor (Olaparib) | Phase I/II ongoing | Recurrent ovarian Cancer | NCT02571725 | ||||
| PD1 | Nivolumab | Anti‐PD1 mAb | T cells | In combination with anti‐CTLA4 mAb (Ipilimumab) | Phase III completed | Advanced melanoma | NCT03068455 |
| Pembrolizumab | Anti‐PD1 mAb | T cells | Monotherapy | Phase III completed | Advanced melanoma | NCT01866319 | |
| Monotherapy | Phase II completed | Metastatic high grade neuroendocrine tumors | NCT02939651 | ||||
| In combination with IDO1 inhibitor (Epacadostat) | Phase III completed | Cisplatin‐ineligible urothelial carcinoma | NCT03361865 | ||||
| In combination with chemotherapy (mFOLFOX6) | Phase II ongoing | Advanced colorectal cancer | NCT02375672 | ||||
| PD‐L1 | Atezolizumab | Anti‐PD‐L1 mAb | T cells | In combination with chemotherapy (Nab‐paclitaxel + Carboplatin) | Phase II ongoing | NSCLC | NCT02716038 |
| In combination with anti‐angiogenic therapy (Bevacizumab) | Phase III ongoing | Advanced or metastatic HCC | NCT03434379 | ||||
| In combination with chemo‐radiotherapy (Carboplatin + Paclitaxel + RT) | Phase II ongoing | NSCLC | NCT02525757 | ||||
| Durvalumab | Anti‐PD‐L1 mAb | T cells | In combination with MEK inhibitor (Trametinib) | Phase II ongoing | Microsatellite stable metastatic colon cancer | NCT03428126 | |
| After chemo‐radiotherapy | Phase II ongoing | Stage II‐IV rectal cancer | NCT03102047 | ||||
| In combination with anti‐CTLA4 mAb (Tremelimumab) | Phase II completed | Metastatic HER2 negative breast cancer | NCT02536794 | ||||
| In combination with anti‐CTLA4 mAb (Tremelimumab) and RT | Phase II ongoing | Invasive bladder cancer | NCT03702179 | ||||
ASO, antisense oligonucleotide; CCR2, C‐C motif chemokine receptor 2; CSF‐1R, colony‐stimulating factor‐1 receptor; CTLA4, cytotoxic T‐lymphocyte‐associated protein 4; CXCR, C‐X‐C motif chemokine receptor; ECM, extracellular matrix; IDO1, indoleamine 2,3 dioxygenase 1; HCC, hepatocellular carcinoma; HER2, human epidermal growth factor receptor 2; HIF‐1α, hypoxia inducible factor‐1 α; MEK, mitogen‐activated extracellular signal‐regulated kinase; mAb, monoclonal antibody; mTOR, mammalian target of rapamycin; NSCLC, non‐small cell lung cancer; PARP, poly ADP‐ribose polymerase; PD‐1, programmed cell death‐1; PDGFR, platelet‐derived growth factor receptor; PD‐L1, programmed cell death 1 ligand 1; RT, radiation therapy; RTK, receptor tyrosine kinase; TGFβ, transforming growth factor β; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.