The Vascular Endothelial Growth Factor Receptor Inhibitor PTK787/ZK222584 Inhibits Aromatase

Abstract

Endocrine therapy is well established for the treatment of breast cancer, and antiangiogenic agents are showing considerable promise. Targeting the vascular endothelial growth factor (VEGF) and estrogen receptor (ER) signaling pathways concomitantly may provide enhanced therapeutic benefit in ER-positive breast cancer. Therefore, the effects of the VEGF receptor (VEGFR) tyrosine kinase inhibitor PTK787/ZK222584 (PTK/ZK) were investigated using human breast cancer cell lines engineered to express aromatase. As expected in this system, estrogen (E2) or androstenedione induced a proliferative response and increased ER-mediated transcription in ER-positive cell lines expressing aromatase. However, surprisingly, in the presence of androstenedione, PTK/ZK suppressed both the androstenedione-stimulated proliferation and ERmediated transcription. PTK/ZK alone and in the presence of E2 had no observable effect on proliferation or ER-mediated transcription. These effects result from PTK/ZK having previously unrecognized antiaromatase activity and PTK/ZK being a competitive aromatase inhibitor. Computer-assisted molecular modeling showed that PTK/ZK could potentially bind directly to aromatase. The demonstration that PTK/ZK inhibits aromatase and VEGFR indicates that agents crossinhibiting two important classes of targets in breast cancer could be developed. [Cancer Res 2009;69(11):4716-23]

Biological Evidence for Dual Antiangiogenic-Antiaromatase Activity of the VEGFR Inhibitor PTK787/ZK222584In vivo

“…Finally, the xenograft models provided opportunities to investigate whether there was evidence for the novel antiaromatase activity in vitro holding true in vivo (14). The level of circulating E2 in the ovariectomized, athymic mice was too low to be reliably detected.…”

“…MCF7 AROM 1 [ER+ HER2-] and BT474 AROM [ER+ HER2+] breast cancer cells were generated as previously described (14,15). Cell lines were cultured in phenol red containing RPMI medium containing 10% fetal bovine serum, 10 μg/mL insulin, 2 mmol/L glutamine, and 1 mg/mL G418.…”

“…Having established that PTK/ZK inhibits angiogenesis in an ER-positive breast cancer model, we next addressed whether the novel in vitro antiaromatase activity we had identified (14) was sufficient to suppress E2-dependent effects in vivo. The plasma levels of E2 were too low to be reliably detected in this model and therefore the level of PgR was measured as a marker of estrogenic stimulation (24).…”

“…We recently showed that PTK/ ZK also significantly inhibits aromatase in vitro (14). This "multitargeting" activity could potentially contribute to the antitumor effect of PTK/ZK.…”

Regulation of Angiogenesis in Human Cancer via Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2)

“…But in several phase II trials, results were disappointing, albeit providing a good security profile (Fury et al 2007). Other additional inhibitors of the VEGFR-2 tyrosine kinase are currently being examined in clinical trials, such as PTK 787, ZD6474, and CP547632 which have been selected on the basis of relatively selective inhibition of the VEGFR-2 ATP binding site (Ansiaux et al 2009;Banerjee et al 2009;Beebe et al 2003). SCC-S2, a novel antiapoptotic molecule, has shown to decrease the proliferation and tumorigenicity of MDA-MB-435 human breast cancer cells (Kumar et al 2004).…”