Table 1.
TUMOR MICROENVIRONMENT-TARGETED THERAPIES AND THEIR TARGETS
| class | Examples | current status |
|---|---|---|
| Heterotypic cell-signaling mediators | Infliximab (monoclonal antibody against TNFα), etanercept (soluble TNFα receptor) | Infliximab is approved in US for Crohn disease and ulcerative colitis (both predispose to colorectal cancer). Etanercept is approved in us for rheumatoid arthritis. Both are in clinical trials for efficacy in cancer |
| Nonsteroidal anti-inflammatory drugs (NSAIDs) | Aspirin | Large observational studies of hundreds of thousands of individuals have associated frequent aspirin use with significantly reduced incidence of colorectal cancer, in which cyclooxygenase 2 is often highly expressed. 1,2 |
| VEGF targeting therapies | Bevacizumab | Approval in the US for treatment of colorectal cancer in combination with 5-flourouracil |
| Aromatase inhibitors | Anastrazole, letrozole, exemesthane | Class has been shown to be more effective than tamoxifen at preventing recurrence after surgery for breast cancer in postmenopausal women, where aromatase in stromal cells plays a crucial role in biosynthesis of estrogen, which in turns promotes tumor growth in estrogen-positive tumors |
| Bisphosphonates | Zoledronic acid | Demonstrated utility in solid tumors metastasizing to bone. If treatment is started when bone loss due to multiple myeloma is first detected, zoledronic acid significantly reduces the incidence and delays the onset of skeletal complications. The drug achieves high local concentrations by binding to bone hydroxyapatite, leading to loss of osteoclasts and, consequently, an attenuation of bone resorption. |
| Cryptic peptide fractions of extracellular proteins that inhibit angiogenesis | Canstatin and tumstatin (from collagen IV), endostatin (from collagen XVIII), angiostatin (from plasminogen), restin (from collagen XV) | Collagen XVIII is located on chromosome 21. Individuals with down syndrome who bear three copies of this chromosome have 50% more serum endostatin, and experience epithelial malignancies at one tenth the rate of age-matched individuals of normal genotype. While endostatin has shown efficacy in preclinical models, the early results of clinical trials in human patients were not very encouraging. Nevertheless, anecdotal reports of a Chinese Phase III study using a modified endostatin are considerably more promising. |
1
E. Giovannucci et al., “Aspirin use and the risk for colorectal cancer and adenoma in male health professionals,” Ann Intern Med, 121:241–6, 1994.
2
M.J. thun et al., “Aspirin use and reduced risk of fatal colon cancer,” N Engl J Med, 325:1593–6, 1991
3
Y. sun et al., “Results of phase iii trial of Endostar (rh-endostatin, y-16) in advanced non-small cell lung cancer (NSCLC) patients,” Proc ASCO, 23:7138a, 2005.