Table 1. Preclinical studies of BCBM.
Studies are arranged chronologically. The target(s) for each study is mentioned as well as the method of inhibiting/activating the target. Targeting methods that represent therapies presently suitable for clinical translation are italicized. The preclinical model used as well as outcome observed is included. Unless stated otherwise, the studies used human derived breast cancer cell lines implanted into immunodeficient mice. Studies with the potential for translation into treatment trials in the clinic are noted in bold in the comments section. Studies addressing enhanced drug delivery are also noted in the comments section.
| Target | Targeting Method | Cell lines/Delivery | Outcome | Comments | References |
|---|---|---|---|---|---|
| Human epidermal growth factor receptor 2 (HER2) | Trastuzumab | MCF-7-HER2 / Intracranial injection of athymic rat | Increased survival | Direct intracerebral microinfusion. | Grossi PM et al. 2003 |
| Vascular Endothelial Growth Factor Receptor (VEGFR) | PTK787/Z 222584 (RTK inhibitor) | MDA-231-BR3 / Intracarotid | Decreased BM / No survival benefit | Brain-seeking clones express more VEGF-A. | Kim LS et al. 2004 |
| Matrix-metalloproteinase 2 (MMP-2) | TIMP2 | ENU1564 rat mammary adenocarcinoma cells / Intraventricular | Decreased BM | TIMP2 expression decreases primary tumor growth as well. | Mendes O et al. 2007 |
| Immunostimulatory CpG | CpG oligodeoxynucleotides (ODN) | EMT6 murine mammary carcinoma cells / Intracranial injection of CpG-ODN challenged mice | Decreased BM | Induction of protective immunity in the brain. No beneficial effect on established BM | Xiong Z et al. 2008 |
| Histone deacetylase (HDAC) | Vorinostat | MDA-MB-231-BR / Intracranial | Decreased BM / Increased survival | Combination of Vorinostat with radiotherapy conveys better survival and further decreased BM when compared to monotherapy. Treatment study | Baschnagel A et al. 2009 |
| ST6GALNAC5 (Sialyltransferase) | shRNA | MDA-MB-231-BR, CN34-BrM2c / Intracarotid | Decreased BM / Increased survival | ST6GALNAC5 expression enhances adhesion to brain endothelial cells and promotes passage through the BBB. Addition of cetuximab (anti-EGFR antibody) further reduces BM. Increased expression in BM clinical tissue. | Bos PD et al. 2009 |
| Integrin αvβ3 | Plasmid-mediated expression of αvβ3 mutant (non-activated) | MDA-MB-435 / Intracranial | Decreased BM | Tumor cell integrin αvβ3 activation increases angiogenesis and decreases hypoxia. | Lorger M et al. 2009 |
| HDAC | Vorinostat | MDA-MB-231-BR / Intracardiac | Decreased BM | No significant decrease in BM observed when treatment is delayed to 18 days post-injection | Palmieri D et al. 2009 |
| Phosphodiesterase 5 (PDE5) / HER2 | Vardenafil (PDE5 inhibitor) / trastuzumab | BT-474 / Intracranial | Increased survival | PDE5 inhibition increases trastuzumab delivery in brain. Treatment study | Hu J et al. 2010 |
| Caveolin-1 and Signal transducer and activator of transcription 3 (Stat3) | Suppressor Of Cytokine Signaling 1 (SOCS1) expression | MDA-MB-231-BR / Intracarotid | Decreased BM | SOCS-1 regulates Stat3 expression. Stat3 regulates Caveolin-1 expression. Increased pStat3 and decreased caveolin-1 expression in BM clinical tissue. | Chiu WT et al. 2011 |
| Proto-oncogene B-Raf | Pazopanib | MDA-MB-231-BR-HER2 and MCF7- HER2-BR3 / Intracardiac | Decreased BM | Pazopanib does not alter vasculature. | Gril B et al. 2011 |
| Notch1 | shRNA or DAPT (gamma secretase inhibitor) | CD44hi_CD24lo_MDA-MB-231-BR / Intracardiac | Decreased BM | DAPT effective in treating established BM lesions (14 days post injection). | McGowan PM et al. 2011 |
| Polo-like kinase 1 (Plk1) | GSK461364A | MDA-MB-231-BR/ Intracardiac injection | Decreased BM / Increased survival | GSK461364A sensitizes cells to radiation. Delayed delivery of GSK461364A (13 days) also promotes survival. Increased expression in BM clinical tissue. Treatment study | Qian Y et al. 2011 |
| Heparinase | MicroRNA-1258 | MDA-MB-231-BR3 / Intracardiac | Decreased BM | Effect of miR-1258 partly rescued by Heparinase overexpression. Increased Heparinase and decreased miRNA- 1258 expression in BM clinical tissue. | Zhang L et al. 2011 |
| Microtubules | TPI-287 | MDA-MB-231-BR / Intracardiac | Decreased BM | No significant decrease in BM observed when treatment delayed to 18 days post-injection | Fitzgerald DP et al. 2012 |
| Pigment epithelium-derived factor (PEDF) | Plasmid-mediated expression. | MDA-MB-231-BR or murine 4T1-BR / Intracranial or intracardiac | Decreased BM | PEDF previously identified in gene array with human BM tissue. PEDF promotes neuronal survival around BM lesion. PDEF is downregulated in BM clinical tissue. | Fitzgerald DP et al. 2012 |
| HER2 and VEGFR2 | Anti-VEGFR2 (DC101), lapatinib and trastuzumab | BT-474 / Intracranial | Decreased BM / Increased survival | First targeted therapy combination. Treatment study | Kodack D et al. 2012 |
| Met Proto-oncogene (c-Met) | shRNA | MDA-MB-435 / Intracranial | Decreased BM | Survival benefit in intra-internal carotid artery injection model. Increased expression in BM clinical tissue. | Lee SJ et al. 2012 |
| MMP-1 | shRNA | MDA-MB-231-BR and -BR3 / Intracardiac | Decreased BM | Also effective in lung metastasis model. | Liu H et al. 2012 |
| Neurotrophin-3 (NT-3) | shRNA | MDA-MB-361, BCM2 BRainG2 / Intracranial | Decreased BM | NT3 expression decreases microglia activation and increases HER2 expression. Increased expression in BM clinical tissue. | Louie E et al. 2012 |
| Phosphatidylinositide 3-kinase (PI3K) | BKM-120 | Rag2−/−;Il2rg−/− mice / MDA-MB-453, BT-474 / Intravenous and intramammary | Decreased BM | Spontaneous brain metastasis model. Model further recapitulates multi-organ metastasis. | Nanni P et al. 2012 |
| αB-crystallin | shRNA | GILM2 and MDA-MB-231 / Intramammary | Decreased BM | Spontaneous brain metastasis model. αB-crystallin knockdown does not reduce primary tumor growth. Increased expression in BM clinical tissue. | Malin D et al. 2013 |
| Chemotherapy | HA–paclitaxel nanoconjugate | MDA-MB-231-BR / Intracardiac | Increased survival | HA conjugate increases delivery of Paclitaxel into the brain by bypassing p-glycoprotein mediated efflux. | Mittapalli RK et al. 2013 |
| Epidermal growth factor receptor (EGFR) / HER2 | TAK-285 (dual inhibitor) | BT-474 / Intracranial | Decreased BM | Evades efflux mechanism since not a p-glycoprotein substrate. Treatment study | Nakayama A et al. 2013 |
| Bone morphogenetic protein 2 (BMP-2) | shRNA | MDA-MB-231BR / Intracranial | Decreased BM | BMP-2 promotes differentiation of NPCs into astrocytes. Expressed in BM clinical tissue. | Neman J et al. 2013 |
| Kruppel-like factor 4 (KLF4) | miR-7 (regulates expression of the stem cell protein KLF4) | CD24−_CD44+_ESA+ CTCs from 231BrM / Intracardiac | Decreased BM / Increased survival | High KLF4 expression is inversely correlated with brain metastasis-free survival. miR-7 is downregulated and KLF4 upregulated in BM clinical tissue. | Okuda H et al. 2013 |
| Insulin-like growth factor 1 receptor (IGF-1R) | shRNA | MDA-MB-231BR / Intracarotid | Increased survival | Picropodophyllin used to block IGF-IR in vitro but not in vivo. | Saldana SM et al. 2013 |
| Proto-oncogene tyrosine kinase Src (c-Src) | Saracatinib with lapatinib | BT-474-BR and MDA-MB-231-BR / Intracarotid | Decreased BM and Increased survival | Monotherapy does not significantly decrease BM. Effective on established BM. Increased expression in BM clinical tissue. Treatment study | Zhang S et al. 2013 |
| Angiopoietin-2 (Ang-2) | Trebananib | 4T1-BRM5 murine mammary carcinoma cells / Mammary fat pad | Decreased BM | Spontaneous brain metastasis. Trebananib improves BBB integrity. Ang-2 is secreted by endothelial cells. | Avraham HK et al. 2014 |
| Fructose-1,6-bisphosphatase isozyme 2 (FBP-2) | shRNA | 4T1 murine mammary carcinoma cells and MDA-MB-31Br3 / Intracranial | Decreased BM / Increased survival | Knockdown of FBP2 does not reduce primary tumor growth. Highlights microenvironment-specific regulation of tumor metabolism. | Chen J et al. 2014 |
| Cathepsin S | shRNA, and VBY-999 | MDA-MB-231-Br-M PyMT-BrM / Intracardiac | Decreased BM | Both stromal and tumor derived Cathepsin blocked for effect. VBY-999 not effective on established brain metastases. Increased expression in BM clinical tissue. | Sevenich L et al. 2014 |
| Serpins and L1 neural cell adhesion molecule (L1CAM) | shRNA | MDA-MB-231-BrM2 / Intracarotid | Decreased BM / Increased survival | SERPINs also mediate survival of brain metastatic lung cancer cell lines. L1CAM is a major vessel co-option molecule. Increased expression in BM clinical tissue. | Valiente M et al. 2014 |
BM, brain metastases; BBB, blood-brain barrier