Tumor Biology
In cancer selectin adhesion receptors present on endothelia, platelets, and leukocytes facilitate metastasis through binding to glycoprotein ligands on circulating tumor cells. The ligands contain characteristic sugars, such as sialyl Lewis X (sLeX), that are over-expressed on the surface of tumor cells and their expression correlates directly with metastatic efficiency and mortality. Thus, the development of a pharmacological approach to inhibit sLeX could improve patient survival. Towards this goal, we have prepared synthetic disaccharides related in structure to sLeX. One compound, acetylated GlcNAcb3Galb-O-NM (ZP103) inhibits sLeX expression on tumor cells. Treatment of colon carcinoma and murine melanoma with ZP103 reduces tumor cell adhesion to purified selectins, activated endothelial cells, and platelets and prevents experimental pulmonary metastasis (Fuster et al. 2003). Subcutaneous administration of the compound in mice also reduced spontaneous metastasis from subcutaneously implanted tumors, suggesting that ZP103 might have anti-metastatic activity in humans (Brown et al. 2006). This compound is now in development in collaboration with Zacharon Pharmaceuticals, Inc. Analogs are being made in the lab and a strategy for developing related compounds is under investigation.
We have also developed high throughput methods to identify small molecule antagonists of heparan sulfate function. One of the compounds discovered in this way is bis-2-methyl-4-amino-quinolyl-6-carbamide, also known as surfen. Fluorescence-based titrations indicate that surfen binds to glycosaminoglycans and neutralizes the anti-Factor Xa activity of heparin-antithrombin complexes. Addition of surfen to cultured cells blocks binding and signaling mediated by FGF2, which depends on formation of ternary complexes of FGF, FGF receptors and cell surface heparan sulfate. 
Furthermore, surfen blocks cell adhesion to the heparin-binding Hep-II domain of fibronectin and prevents infection by Herpes simplex virus dependent on glycoprotein D binding to cell surface heparan sulfate. Surfen also blocks both FGF and VEGF mediated endothelial sprouting in Matrigel. These findings demonstrate the feasibility of identifying small molecule antagonists of glycosaminoglycans. Compounds like surfen may prove useful for inhibiting tumor growth and tumor angiogenesis.
Another approach to this problem is to target cells for death by exploiting proteoglycans expressed on the cell surface (Elson-Schwab et al. 2007). Incollaboration with Yitzhak Tor, we have tested analogs of aminoglycosides in which the amino groups were converted to guanidinium groups. A derivative of the aminoglycoside antibiotic neomycin can carry large (>300 kDa) bioactive molecules across cell membranes. Delivery occurs at nanomolar transporter concentrations and under these conditions depends entirely on cell surface heparan sulfate proteoglycans. Conjugation of guanidino-neomycin to the plant toxin saporin, a ribosome-inactivating agent, results in proteoglycan-dependent cell toxicity. The high selectivity of guanidino-neomycin for heparan sulfate suggests the possibility of exploiting differences in proteoglycan compositions to target delivery to different cell types.
Other relevant reading:
- Fuster MM, Esko JD. The sweet and sour of cancer: glycans as novel therapeutic targets. Nat Rev Cancer. 2005 Jul;5(7):526-42.
- Fuster MM, Wang L, Castagnola J, Sikora L, Reddi K, Lee PH, Radek KA, Schuksz M, Bishop JR, Gallo RL, Sriramarao P, Esko JD. Genetic alteration of endothelial heparan sulfate selectively inhibits tumor angiogenesis. J Cell Biol. 2007 May 7;177(3):539-49.
- Brown JR, Crawford BE, Esko JD. Glycan antagonists and inhibitors: a fount for drug discovery. Crit Rev Biochem Mol Biol. 2007 Nov-Dec;42(6):481-515