Other Antiangiogenic Agents In Investigation

While bevacizumab has lead the efforts in antiangiogenesis studies, several other agents have shown promise in early clinical investigation. A second class of agents specifically targeting the VEGF receptor tyrosine kinase has seen a few compounds reach phase II trials with varying success. SU11248 (sunitinib, Sutent®, Pfizer, New York, NY), a multi-targeted tyrosine-kinase inhibitor which blocks not only the VEGF-receptors, but also platelet-derived growth factor receptor (PDGFR), c-kit and Flt-3, has recently been approved for the treatment of gastrointestinal stromal tumors and renal cell carcinoma. Since breast cancer has been shown to express several of these receptors, SU11248 should be effective in blocking several pathways regulating angiogenesis in breast carcinomas. In fact, precli-nical data support this notion (65) leading to a recently reported phase II trial where single agent SU11248 demonstrated activity in heavily pretreated patients with refractory metastatic breast cancer (66). Toxicity in this trial did prompt dose-reductions in several patients, and future studies should look to explore alternative dosing schedules in patients with less refractory disease.

The matrix metalloproteinase inhibitors are agents designed to block the action of naturally occurring enzymes whose overexpression in cancer leads to the degradation of the basement membrane and extracellular matrix, promoting conditions favorable for angiogenesis and metastasis (67). The ECOG performed a randomized, placebo-controlled, phase III trial looking at the use of marimastat, an oral MMPI, versus placebo in patients with metastatic breast cancer following first-line chemotherapy (68). This study (E2196) evaluated 190 patients with responding or stable disease following six to eight cycles of prior first-line treatment. The findings revealed no significant difference in median PFS or OS between the groups, and in fact higher plasma marimastat levels were associated with an increased risk of death in the treatment arm. Additional studies looking at MMPIs in other cancers have similarly failed to show any treatment benefit with these agents, and one agent (BAY12-9566) has even shown diminished survival in treated patients with pancreatic cancer (vs. gemcitabine) (69). Thus these agents have largely been abandoned in active clinical investigation.

Two-methoxyestradiol (2-ME), a naturally occurring metabolite of estradiol that disrupts microtubule function, has been shown to inhibit proliferating cells and inhibit angiogenesis in vitro. Human breast cancer cells have shown particular sensitivity to this agent, making it an intriguing choice for clinical study. In fact, pre-clinical studies with breast cancer xenografts in mice showed a 60% suppression in growth in these tumors after one month of treatment with 2-ME with minimal tox-icity (70). In addition, this same group showed that treatment with 2-ME could reduce VEGF-induced neovascularization by 54%. Studies combining 2-ME with other microtubule inhibitors (vinorelbine and paclitaxel) demonstrated superior tumor control in breast cancer xenografts in nude mice, with little additional tox-icity (71). Early clinical work with 2-ME in patients with metastatic breast cancer, both as a single-agent (72) or combined with docetaxel (73), showed a reasonable response rate with most patients tolerating the drug quite well. Further studies looking at a newer preparation of 2-ME are currently underway.

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