Targeting Tumor Microenvironment for Cancer Therapy
Abstract
:1. Introduction
2. Targeting the Tumor Microenvironment
2.1. Targeting the Extracellular Matrix
2.2. Targeting Hypoxia and Acidosis
2.3. Avoiding Neovascularization—Targeting Endothelial Cells and Pericytes
2.4. Targeting Immune System
2.4.1. Inhibiting Macrophages Recruitment and Differentiation
2.4.2. Targeting Chronic Inflammation
2.4.3. Activating Anti-Tumoral Activity of Immune System
2.5. Targeting Cancer-Associated Fibroblasts
2.6. Targeting Exosomes
3. The Case of Combined Therapies
4. Nanomedicines
5. Models for the Study of TME
6. Conclusions and Outlook
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ANGPT | Angiopoietin |
ARG1 | Arginase 1 |
CAFs | Cancer-associated fibroblasts |
CSC | Cancer stem cell |
CSF | Colony stimulating factor |
CTLA-4 | Cytotoxic T-lymphocyte-associated protein 4 |
ECM | Extracellular matrix |
EGF | Epidermal growth factor |
EMT | Epithelial-to-mesenchymal transition |
EPR | Enhanced permeability and retention |
FAP | Fibroblast activation protein |
FGF | Fibroblast growth factor |
FRβ | Targeted-folate-receptor beta |
GM-CSF | Granulocyte-macrophage colony stimulating factor |
HGF | Hepatocyte growth factor |
HIF-1 | Hypoxia-induced factor-1 |
IL | Interleukin |
IFN | Interferon |
iNOS | Inducible nitric oxide synthase |
MCTS | Multicellular tumor spheroids |
MDR | Multidrug resistance |
MDSCs | Myeloid-derived suppressive cells |
MMPs | Matrix metalloproteinases |
MT | Malignant transition |
NSCLC | Non-small cell lung cancer |
NK | Natural killer |
NKT | Natural killer T |
PD-1 | Programmed death 1 receptor |
PDMS | Polymethylsiloxane |
PlGF | Placental growth factor |
PDGF | Platelet-derived growth factor |
PHD-2 | Prolyl-hydroxylase enzyme-2 |
TAM | Tumor-associated macrophage |
TCDEs | Tumor cells derived exosomes |
TME | Tumor microenvironment |
TGF | Transforming growth factor |
TNF | Tumor necrosis factor |
Treg | Regulatory T cells |
VEGF | Vascular endothelial growth factor |
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VEGF 1/VEGFR 2 Targeting Therapeutic Agent | Therapeutic Strategy | Cancer Type | Clinical Trial Reference (Phase) |
---|---|---|---|
Bevacizumab (Apatinib) | Bevacizumab (anti-VEGF) in a chemotherapeutic cocktail with 5-Fu, Folinic acid, Panitumumab and intra-arterial vs. intravenous Oxaliplatin | Colorectal neoplasms | NCT02885753 (3) |
Cisplatin with Etoposide vs. Cisplatin, Etoposide and Bevacizumab | Small cell lung cancer | NCT03100955 (3) | |
Bevacizumab vs. placebo | Thyroid cancer | NCT03048877 (3) | |
Bevacizumab as second line treatment | Intrahepatic Cholangiocarcinoma | NCT03251443 (3) | |
LY01008 and Bevacizumab | LY01008 (anti-VEGF antibody) with Carboplatin/Paclitaxel vs. Bevacizumab with Carboplatin/Paclitaxel | Non-small cell lung cancer | NCT03533127 (3) |
Cediranib | Olaparib (PARP inhibitor) with Cediranib (VEGF-A inhibitor) or Olaparib alone | Ovarian cancer | NCT03278717 (3) |
Ramucirumab (LY3009806) | Ramucirumab (anti-VEGFR) with Paclitaxel vs. Placebo with Paclitaxel | Gastric adenocarcinoma | NCT02898077 (3) |
Aflibercept | Injection of Aflibercept (anti-VEGF) vs. placebo injection | Ocular melanoma | NCT03172299 (3) |
Everolimus (RAD001) | Everolimus (m-TOR inhibitor) alone | Renal cell carcinoma | NCT01206764 (4) |
Therapeutic Agent | Therapeutic Agent Description | Cancer Type | Clinical Trial Reference (Phase) |
---|---|---|---|
Pexidartinib (PLX3397) | CSF-1R 1 inhibitor | Advanced solid tumors Giant cell tumor Melanoma Pancreatic/Colorectal cancer Gastrointestinal stromal cancer Advanced solid tumors Gastric cancer | NCT02734433 (-) NCT02371369 (3) NCT02975700 (1/2) NCT02777710 (1) NCT03158103 (1) NCT01525602 (1) NCT03694977 (2) |
ARRY-382 | CSF-1R inhibitor | Advanced solid tumors | NCT02880371 (2) |
BLZ945 | CSF-1R inhibitor | Advanced solid tumors | NCT02829723 (1/2) |
JNJ-40346527 | CSF-1R inhibitor | Prostate cancer | NCT03177460 (1) |
Emactuzumab | CSF-1R antibody | Squamous cell carcinoma | NCT03708224 (2) |
DCC-3014 | CSF-1R inhibitor | Advanced malignant neoplasm | NCT03069469 (1) |
Chiauranib | Tyrosine kinase inhibitor | Ovarian cancer Small Cell Lung cancer Hepatocellular carcinoma | NCT03166891 (1) NCT03216343 (1) NCT03245190 (1) |
IMC-CS4 (LY3022855) | CSF-1R blocking agent | Pancreatic cancer Melanoma | NCT03153410 (1) NCT03101254 (1/2) |
Cabiralizumab (FPA008) | CSF-1R antibody | Pancreatic cancer Melanoma/Non-small cell lung cancer/Renal cell carcinoma Resectable biliary tract cancer | NCT03697564 (2) NCT03502330 (1) NCT03768531 (2) |
SNDX-6352 (UCB6352) | CSF-1R antibody | Advanced malignant neoplasm | NCT03238027 (1) |
PD 0360324 | CSF-1 antibody | Ovarian cancer | NCT02948101 (2) |
Nilotinib | Tyrosine kinase inhibitor | Malignant solid neoplasms Soft tissue sarcoma | NCT02029001 (2) NCT03784014 (3) |
Lacnotuzumab (MCS110) | CSF-1 antibody | Melanoma | NCT03455764 (1/2) |
Therapeutic Agent | Therapeutic Strategy | Cancer Type | Clinical Trial Reference (Phase) |
---|---|---|---|
Anakinra (Kineret) | Combined with Nab-paclitaxel, Gemcitabine, Cisplatin | Pancreatic cancer | NCT02550327 (1) |
Alone | Multiple myeloma | NCT03233776 (2) | |
Canakinumab (Ilaris) | Alone | 1 NSCLC | NCT03447769 (3) |
Chemotherapeutic cocktail with or without Canakinumab | NSCLC | NCT03631199 (3) | |
Possible use of Canakinumab with Spartalizumab and LAG525 | 2 TNBC | NCT03742349 (1) | |
Docetaxel with Canakinumab vs. Docetaxel with placebo | NSCLC | NCT03626545 (3) | |
Possible use with PDR001 | Colorectal cancer/TNBC/NSCLC | NCT02900664 (1) | |
Possible use with PDR001, cisplatin, pemetrexed and carboplatin | NSCLC | NCT03064854 (1) | |
Possible use with PDR001 | Melanoma | NCT03484923 (2) |
Therapeutic Strategy | Cancer Type | Phase | Clinical Trial Reference |
---|---|---|---|
HLX10 (anti-PD-1 1) + HLX04 (anti-VEGF 2) | Solid tumor | 1 | NCT03757936 |
SHR-1210 (anti-PD-1) with Bevacizumab (anti-VEGFR) | Gastric and hepatocellular cancer | 1/2 | NCT02942329 |
Atezolizumab (anti-PD-L1) with Bevacizumab (anti-VEGF) | Digestive, respiratory and intrathoracic organs tumors | 2 | NCT03074513 |
Atezolizumab (PD-L1 inhibitor), Bevacizumab (anti-VEGF) and Cobimetinib (MEK 3 inhibitor) | Ovarian and fallopian tube cancer and peritoneal carcinoma | 2 | NCT03363867 |
PLD 4 with Atezolizumab (PD-L1 inhibitor) vs. PLD with Bevacizumab (anti-VEGF) and Atezolizumab vs. PLD with Bevacizumab | Ovarian, fallopian tube and peritoneal carcinoma | 2/3 | NCT02839707 |
Sintilimab (anti-PD-1) with IBI305 (anti-VEGF), Pemetrexed and Cisplatin vs. Sintilimab with IBI305 and Pemetrexed vs. Pemetrexed and Cisplatin | Non-squamous non-small cell lung cancer | 3 | NCT03802240 |
Bevacizumab (anti-VEGF) with Carboplatin and Pemetrexed vs. Bevacizumab with Atezolizumab (anti-PD-1), Carboplatin and Pemetrexed | Pleural mesothelioma malignant advanced | 3 | NCT03762018 |
Tyrosine Kinase Inhibitor | Inhibited Tyrosine Kinases | Therapeutic Strategy/Objective | Cancer Type | Phase | Clinical Trial Reference |
---|---|---|---|---|---|
Sitravatinib (MGCD516) | c-Met, AXL, MER, VEGFR 1, PDGFR 2, DDR2, TRK 3, Eph 4 | Dosage and clinical activity of Sitravatinib | Advanced cancer | 1/1b | NCT02219711 |
Sitravatinib with Nivolumab (Opdivo, anti-PD-1 5) | Renal cell cancer | 1/2 | NCT03015740 | ||
Axitinib (AG-013736) | VEGFR1-3, c-KIT, PDGFR | Avelumab (anti-PD-1) with Axitinib | Non-small cell lung or urothelial cancer | 2 | NCT03472560 |
Sandostatin LAR with Axitinib vs. with placebo | Neuroendocrine tumors | 2/3 | NCT01744249 | ||
Cabozantinib | c-Met, VEGFR | Nivolumab (anti-PD-1) vs. Nivolumab with Cabozantinib | Renal cell carcinoma | 3 | NCT03793166 |
Lenvatinib | VEGFR1-3 | Lenvatinib with Pembrolizumab (anti-PD-1) vs. Paclitaxel or Doxorubicin | Endometrial neoplasms | 3 | NCT03517449 |
Culture Model | Composition | Major Advantages | Major Disadvantages | References |
---|---|---|---|---|
Tumor tissue explants | Tumor collected from a biopsy and placed on a collagen matrix | Maintenance of tumor architecture | Difficulty on maintaining the culture for more than 3 weeks | Reviewed in [183,189,190,191,192] |
Organoid cultures from tissue explants | Long-lasting culture | Poorly resembles TME 1 and disease progression | ||
“Tumor on a chip” | co-cultures of tumor cells with other cell types to organs | TME 1 reproduction with the movement of biological fluids | Size limited | Reviewed in [193,194,195,196,197,198,199,200] |
Multicellular Tumor Spheroids (MCTS) | Spheroids composed by mono- or co-culture aggregates | TME 1 reproduction | Fail in reproducing ECM architecture | Reviewed in [184,189,191,192,201] |
Spheroids composed by mono- or co-cultures on a scaffold | TME 1 reproduction ECM 2 architecture reproduction | Low reproducibility Cost |
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Roma-Rodrigues, C.; Mendes, R.; Baptista, P.V.; Fernandes, A.R. Targeting Tumor Microenvironment for Cancer Therapy. Int. J. Mol. Sci. 2019, 20, 840. https://doi.org/10.3390/ijms20040840
Roma-Rodrigues C, Mendes R, Baptista PV, Fernandes AR. Targeting Tumor Microenvironment for Cancer Therapy. International Journal of Molecular Sciences. 2019; 20(4):840. https://doi.org/10.3390/ijms20040840
Chicago/Turabian StyleRoma-Rodrigues, Catarina, Rita Mendes, Pedro V. Baptista, and Alexandra R. Fernandes. 2019. "Targeting Tumor Microenvironment for Cancer Therapy" International Journal of Molecular Sciences 20, no. 4: 840. https://doi.org/10.3390/ijms20040840
APA StyleRoma-Rodrigues, C., Mendes, R., Baptista, P. V., & Fernandes, A. R. (2019). Targeting Tumor Microenvironment for Cancer Therapy. International Journal of Molecular Sciences, 20(4), 840. https://doi.org/10.3390/ijms20040840