Table 1.

Treating the tumor microenvironment: selected examples

Common name (trade name)	Company	Drug information
Endostatin (Endostar)	Simcere	Endostatin is a 20-kDa peptide fragment derived from the extracellular matrix protein collagen XVII125. Endostatin has a potent effect on endothelial cell proliferation and angiogenesis. It is currently used therapeutically (and in clinical studies) only in China under the trade name Endostar.
Bevacizumab (Avastin)	Genentech	In 2004, Avastin became the first FDA-approved angiogenesis inhibitor. It is a humanized monoclonal antibody with specific affinity for VEGF-A, thus inhibiting the signaling between the tumor and endothelial cells in the microenvironment126.
Sorafenib, BAY 43-9006 (Nexavar)	Bayer	Approved by the FDA in 2005, sorafenib is a small-molecule kinase inhibitor that inhibits many intracellular and extracellular kinases. Most affected are Raf kinase, VEGFR and PDGFR, thus resulting in multiple effects, such as reduced tumor growth and angiogenesis127.
MK-2461	Merck	MK-2461 is a small-molecule inhibitor of c-MET kinase, the receptor of the stromal-derived hepatocyte growth factor. c-MET activation has proliferative and antiapoptotic effects in the tumor cells but also stimulates endothelial cell–dependent angiogenesis128.
Zoledronate (Zometa)	Novartis	Zoledronate belongs to the bisphosphonate class of drugs. It is a small-molecule pyrophosphate analog that binds hydroxyapatite crystals and inhibits bone resorption by osteoclasts. It also inhibits the differentiation of myeloid cells, thus tumor-associated macrophages are also affected129,130.
Denosumab (Xgeva)	Amgen	Approved by the FDA in June of 2010, denosumab is a human antibody that binds human receptor activator of nuclear factor-κB ligand (RANKL). RANKL regulates osteoclastogenesis and is involved in pathways regulating osteoclastogenesis, tumor cell metastasis to bone and endothelial cell proliferation and apoptosis131,132.
Anastrazole (Armidex)	Novartis	Anastrazole is a third-generation inhibitor of aromatase, a cytochrome p450 complex present in the stromal fibroblasts. Aromatase catalyzes the conversion of androgens to estrogens, and the inhibitors are approved for the treatment of breast cancer in postmenopausal women.
AMD070	Genzyme	Currently in clinical trials, AMD070 belongs to a class of drugs that inhibit CXCR4. CXCR4 is specific for stromal-derived factor-1 ligand, which is predominantly expressed by fibroblasts and pericytes133.
DX2400	Dyax	In development, DX2400 is a new generation of MMP inhibitor, a human monoclonal antibody specific for MMP-14. Previous broad-spectrum MMP inhibitors were generally plagued by a lack of efficacy, and the majority of drug makers have since invested in other targets. However, since the end of the previous trials, much has been learned about MMPs, notably the need for drug specificity, as some MMPs are regarded as being protective, and others not. Thus, these newer inhibitors are being designed with specificity in mind134.
MK0822	Merck	MK0822 is an inhibitor of cathepsin K, a secreted protease involved in bone resorption. Similar to bisphosphonates, inhibitors of cathepsin K proteases may protect against bone loss induced by metastatic tumor cells135. Cathepsin inhibitors may be useful in other contexts, as well. In a preclinical animal model of pancreatic cancer, administration of a pancathepsin inhibitor, JPM-OEt, with cyclophosphamide led to a marked reduction in tumor burden136.
IPI-926	Infinity Pharmaceuticals	IPI-926 is a small-molecule inhibitor of the hedgehog pathway and is currently in phase 2 clinical trials. In a preclinical mouse model, inhibition of hedgehog signaling led to depletion of tumor-associated stromal tissue and enhanced delivery of gemcitibine.
TGF-β2 AP12009 (Trabedersen)	Antisense Pharma	Trabedersen is an antisense oligodeoxynucleotide with specificity for TGF-β2. It is currently in phase 1, 2 and 3 clinical trials and is being developed for the treatment of tumors that frequently express high levels of TGF-β2 (pancreatic carcinoma, melanoma and gliomas). Reductions in TGF-β2 in the tumor are likely to be profound, affecting both tumor and stromal cells (tumor cell growth, angiogenesis and immune response).
Celecoxib (Celebra)	Pfizer	Celecoxib is a specific inhibitor of cyclooxygenase-2 (COX-2). COX-2 is present in both tumor and associated stromal cells, and inhibitors of COX-2 can influence apoptosis, cell migration, proliferation and angiogenesis. Other anti-inflammatory drugs are also being tested clinically for their ability to alter the protumorigenic microenvironment in chronic inflammation137.
AVE1642	ImmunoGen/ Sanofi-Aventis	AVE1642, a humanized monoclonal antibody, is a specific antagonist of the insulin-like growth factor-1 receptor (IGF-1R). IGF-1 derived from bone marrow stroma promotes survival and growth of multiple myeloma cells. IGF-1R signaling also contributes to angiogenesis via its influence on hypoxia-inducible factor-1α and VEGF expression138.
BGJ398	Novartis	Currently in clinical trials, BGJ398 is a small-molecule inhibitor of fibroblast growth factor receptors (FGFRs). The ligands of these receptors, FGFs, are expressed by the activated fibroblasts of tumor stroma and have a protumorigenic effect.
Bortezomib, PS-341 (Velcade)	Millenium Pharmaceuticals	Bortezomib is an inhibitor of the 26S proteasome complex and is indicated for the treatment of relapsed multiple myeloma and mantle cell lymphoma. In addition to directly inhibiting the tumor cells, bortezomib interferes with multiple myeloma tumor and bone marrow stromal cell interactions, inhibiting cytokine signaling and angiogenesis139,140.
PG545	Progen	Currently being tested in a phase 1 clinical trial, PG545 is a heparan sulfate mimetic, designed to inhibit heparanase activity. Heparanase inhibitors prevent ECM remodeling and release of sequestered growth factors tethered to the heparan sulfate proteoglycans located near the surface of cells, thus affecting cell growth, metastasis and angiogenesis.
PEGPH20	Halozyme	PEGPH20 is a covalently modified form of hyaluronidase, which catalyzes the degradation of the extracellular matrix component hyaluronan. In preclinical animal models, PEGPH20 led to drastic reductions of the tumor interstitial fluid pressure, subsequently enhancing the delivery of coadministered drugs. PEGPH20 is currently in phase 1 clinical trials115.