Table 1 Selected preclinical data for potential anti-metastatic therapies
From: A framework for the development of effective anti-metastatic agents
Agent | Target | Preclinical dataa |
|---|---|---|
Antibodies | ||
Anti-CCL2 | CCL2 (chemokine) | Prevented mobilization of myeloid cells from the bone marrow to colorectal liver metastases and thereby reduced metastasis177 |
Anti-BMP6 | BMP6 (TGFβ superfamily cytokine) | Reduced osteoblastic bone metastasis from prostate cancer178 |
Anti-PTHrP | PTHrP (hormone involved in bone vicious cycle) | Reduced liver and bone metastasis of melanoma179 |
Anti-N-cadherin | N-cadherin (mesenchymal cadherin) | Reduced prostate cancer muscle invasion and induced tumour cell apoptosis180 |
Anti-CD24 | CD24 (GPI-linked sialo-glycoprotein) | Reduced lung metastasis of bladder cancer181 |
Anti-CDCP1 | Protease cleavage site of CDCP1 | Prevented lung metastasis by inducing poly(ADP-ribose) polymerase-mediated cell death182 |
Anti-TSPAN8 | TSPAN8 (tumour-associated tetraspanin) | Reduced metastasis of epithelial ovarian cancer183 |
Anti-MT1-MMP | Membrane type 1 MMP | Reduced lung metastasis of melanoma184 |
Small-molecule inhibitors | ||
BL5923 | CCR1 (CCL9 and/or CCL15 chemokine signalling) | Inhibited liver metastasis of CRC by blocking recruitment of myeloid cells185 |
SD208 | TGFβ receptor 1 | Reduced melanoma and prostate bone metastasis and decreased progression of established lesions186,187 |
CCT129254 | Multiple kinases (including ROCK, PI3K and AKT) | Inhibited melanoma lung metastasis188 |
Zibotentan | Endothelin 1 | Prevented lung colonization by bladder cancer cells but had no effect on established metastases189 |
Debio 0719 | Lysophosphatidic acid receptor 1 (fibrosis) | Decreased lung and liver metastasis in breast cancer and induced tumour cell dormancy11 |
β-Aminopropionitrile | Lysyl oxidases | Prevented breast cancer metastasis but had no effect on existing lesions190 |
CCT365623 | Lysyl oxidases | Prevented metastasis of breast cancer191 |
CA-074 | Cathepsin B inhibitor | Prevention of bone metastasis and shrinkage of existing bone metastases in a breast cancer model192 |
Napabucasin | Unclear (STAT3 and cancer stem cell pathways) | Reduced metastasis of pancreatic and colon cancers193 |
HO-3867 | Unclear (STAT3 signalling and reversion of mutant p53 to a wild-type phenotype) | Reduced metastasis of ovarian cancer194 |
IRAK inhibitor and ginsenosides | IRAK1 | Reversed paclitaxel resistance and reduced metastasis of TNBC195 |
Bafetinib | LYN and BCR–ABL1 | Decreased liver metastasis in a breast cancer model196 |
KPT-6566 | PIN1 (prolyl isomerase that regulates proline-directed kinase signalling) | Decreased lung metastasis of TNBC197 |
SF2523 | Dual PI3K and BRD4 inhibitor (MYC-mediating factors) | Reduced regional colonic lymph node metastasis and shrank established metastases in pancreatic carcinoma model198 |
Nifuroxazide | Unclear (STAT3 signalling) | Inhibited lung and abdomen metastasis of CRC and shrank existing metastases199 |
AECHL-1 (triterpenoid) | Unclear (alters cytoskeletal dynamics and inhibits NF-κB-mediated MAPK activity) | Decreased lung metastasis of TNBC200 |
CCG-203971 | Unclear (inhibits the RHO–MRTF–SRF pathway) | Decreased lung metastasis in melanoma model201 |
Regorafenib | Multiple kinases (including angiogenic receptor tyrosine kinases) | Decreased lung metastasis of CRC (via activation of the protein tyrosine phosphatase SHP1) and shrank existing metastases202 |
GW3965 | Liver X receptors | Inhibited brain metastasis of melanoma and shrank existing lesions203 |
Low-dose paclitaxel | Tubulin | Decreased lung metastasis of cholangiocarcinoma (via reduced nuclear import of the calcium-binding protein S100A4)204 |
Selumetinib | MEK | Decreased lung metastasis of TNBC205 |
G2 | Fascin (actin-bundling protein) | Decreased lung metastases of breast cancer206 |
Zileuton | Arachidonate 5-lipoxygenase | Reduced spontaneous metastasis of MMTV-PyMT cells168 |
Peptides | ||
Bone metastasis-targeting peptide 78 | Endoplasmic reticulum chaperone BiP | Reduced outgrowth of established lung and bone micrometastases in an advanced-stage breast cancer model207 |
T22 | CXCR4 (SDF1 chemokine signalling) | Showed synergy with anti-CTLA-4 therapy in reducing the size of established melanoma metastases208 |
Ac-PhScN-NH2 | α5β1 integrin (fibronectin receptor) | Inhibited bone metastasis, disease progression and lung colonization in a breast cancer model and shrank established lesions209 |
Immunotherapies | ||
MTDH DNA vaccine | MTDH | Induced T cell responses and prevented lung metastasis in a breast cancer model210 |
LMP1 DNA vaccine | LMP1 viral antigen | Inhibited TC-1 lung metastasis in vivo via targeting of EBV LMPs211 |
Others | ||
Retinoic acid | Retinoic acid receptor (inhibits cell adhesion) | Inhibited melanoma lung metastasis by inhibiting tumour cell adhesion to the vascular endothelium and subendothelium212 |
IGF trap | IGF1R | Promoted apoptosis of colon and lung cancer cells in nascent liver metastases213 |
Ad.dcn (decorin-expressing oncolytic adenovirus) | Various (results in downregulation of MET, β-catenin and VEGFA) | Systemic delivery shrank established bone metastases of prostate cancer214 |
Cellax-DTX polymer (docetaxel–acetylated carboxymethylcellulose–PEG conjugate nanoparticles) | Tubulin (results in selective depletion of activated, cancer-associated fibroblasts) | Decreased development of pancreatic metastases215 |
N-acetylcysteine | Reactive oxygen species (antioxidant) | Inhibited liver metastasis of pancreatic cancer216 |
NM-NP-CFZ (neutrophil-mimicking-nanoparticles containing carfilzomib) | Inflammatory neutrophils | Prevented early lung metastases and shrank established metastases in mammary carcinoma models217 |
