Combination of Anastrozole with Fulvestrant in the Intratumoral Aromatase Xenograft Model

Macedo, Luciana F.; Sabnis, Gauri; Goloubeva, Olga; Brodie, Angela

doi:10.1158/0008-5472.can-07-6807

Cited by 85 publications

(61 citation statements)

References 43 publications

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“…Interestingly, a dose-dependent effect was not seen, and the optimal dose that resulted in disease stabilization in the breast cancer models seems to be 50 mg/kg, which is an effective dose range seen in in vivo models of other tumor types (11,12). It is noteworthy that, although letrozole has been reported to cause tumor regression (32), xenograft studies of the aromatase inhibitor anastrozole only achieved disease stabilization (33). Therefore, our observation that PTK/ZK failed to cause tumor regression does not exclude the in vivo aromatase inhibition capability of this drug in contributing to part of its overall in vivo profile.…”

Section: Discussionmentioning

confidence: 70%

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

Banerjee

A’Hern

Detre

et al. 2010

Clinical Cancer Research

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Purpose: Targeting vascular endothelial growth factor (VEGF) and estrogen receptor signaling pathways concomitantly may enhance benefit in estrogen receptor-positive breast cancer. We had shown previously that the VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 (PTK/ZK) is a competitive aromatase inhibitor in vitro. Here we investigated (a) whether PTK/ZK shows both antiangiogenic and antiaromatase inhibitory properties in vivo, and (b) whether the combination of PTK/ZK and letrozole is superior to letrozole alone.Experimental Design: Estrogen-dependent human breast cancer cells engineered to express aromatase (MCF7 AROM 1 and BT474 AROM) were used. Mice were treated with vehicle, PTK/ZK (25, 50, or 100 mg/kg), letrozole, or PTK/ZK in combination with letrozole.Results: In MCF7 AROM 1 tumors, all treatments induced growth suppression and were associated with a reduction in cell turnover index, a composite measurement of both proliferation and apoptosis. PTK/ZK significantly reduced vessel density. Whereas letrozole caused tumor regression, PTK/ZK stabilized tumor volumes. The growth suppressive and antiangiogenic effects of PTK/ZK were confirmed in BT474 AROM xenografts. The addition of PTK/ZK did not enhance the growth-suppressive effects of letrozole. However, PTK/ZK decreased progesterone receptor (PgR) and TFF1 expression and uterine weight, indicating that PTK/ZK decreases 17β-estradiol (E2) signaling in vivo.Conclusion: The VEGF receptor inhibitor PTK/ZK showed effects on E2-dependent gene expression consistent with aromatase inhibition as well as antiangiogenesis in xenograft models of breast cancer. The combination with letrozole was not superior to letrozole alone. Overall, these results provide further support for a potential therapeutic approach of dual inhibition of VEGF and E2 signaling using a single agent. Clin Cancer Res; 16(16); 4178-87. ©2010 AACR.

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Section: Discussionmentioning

confidence: 70%

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

Banerjee

A’Hern

Detre

et al. 2010

Clinical Cancer Research

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“…Furthermore, fulvestrant results in clinical benefits in ERBB2-overexpressing advanced breast cancers (Robertson et al 2010). Additionally, in model systems, treatment of breast cancer cells with the combination of fulvestrant and growth factor pathway inhibitors more significantly represses growth than either treatment alone, and prevents the development of endocrine resistance (Kunisue et al 2000;Gee et al 2003;Pietras et al 2003;Macedo et al 2008). Considering that ERa-and ERBB2-positive breast cancers are resistant to endocrine therapies targeting estrogen stimulation of ERa, such as aromatase inhibitors or selective ER modulators, our results provide a mechanistic understanding for this clinical observation.…”

Section: Discussionmentioning

confidence: 99%

Growth factor stimulation induces a distinct ERα cistrome underlying breast cancer endocrine resistance

Lupien¹,

Meyer²,

Bailey³

et al. 2010

Genes Dev.

161

165

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Estrogen receptor a (ERa) expression in breast cancer is predictive of response to endocrine therapy; however, resistance is common in ERa-positive tumors that overexpress the growth factor receptor ERBB2. Even in the absence of estrogen, ERa can be activated by growth factors, including the epidermal growth factor (EGF). EGF induces a transcriptional program distinct from estrogen; however, the mechanism of the stimulus-specific response is unknown. Here we show that the EGF-induced ERa genomic targets, its cistromes, are distinct from those induced by estrogen in a process dependent on the transcription factor AP-1. The EGF-induced ERa cistrome specifically regulates genes found overexpressed in ERBB2-positive human breast cancers. This provides a potential molecular explanation for the endocrine therapy resistance seen in ERa-positive breast cancers that overexpress ERBB2. These results suggest a central role for ERa in hormone-refractory breast tumors dependent on growth factor pathway activation and favors the development of therapeutic strategies completely antagonizing ERa, as opposed to blocking its estrogen responsiveness alone.[Keywords: ERBB2; breast cancer; cistrome; estrogen receptor; growth factors; transcription] Supplemental material is available at http://www.genesdev.org.

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“…All animal-handling procedures were approved by the Case Western Reserve University Institutional Animal Care and Use Committee and conformed to the standards of the US Public Health Service Policy on Humane Care and Use of Laboratory Animals. Drug administration was as described (Macedo et al, 2008) using a 1 mg/ml solution of anastrozole in 0.3% hydroxypropylcellulose and 0.9% NaCl. Mice in the treatment group (n 5 8) received a daily subcutaneous injection of 200 ml (200 mg) anastrozole, whereas animals in the control group (n 5 6) received a daily injection (200 ml) of the vehicle.…”

Section: Methodsmentioning

confidence: 99%

Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy

2015

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Cytochrome P450 CYP27A1 is the only enzyme in humans converting cholesterol to 27-hydroxycholesterol, an oxysterol of multiple functions, including tissue-specific modulation of estrogen and liver X receptors. Both receptors seem to mediate adverse effects of 27-hydroxycholesterol in breast cancer when the levels of this oxysterol are elevated. The present work assessed druggability of CYP27A1 as a potential antibreast cancer target. We selected 26 anticancer and noncancer medications, most approved by the Food and Drug Administration, and evaluated them first in vitro for inhibition of purified recombinant CYP27A1 and binding to the enzyme active site. Six strong CYP27A1 inhibitors/binders were identified. These were the two antibreast cancer pharmaceuticals anastrozole and fadrozole, antiprostate cancer drug bicalutamide, sedative dexmedetomidine, and two antifungals ravuconazole and posaconazole. Anastrozole was then tested in vivo on mice, which received subcutaneous drug injections for 1 week. Mouse plasma and hepatic 27-hydroxycholesterol levels were decreased 2.6-and 1.6-fold, respectively, whereas plasma and hepatic cholesterol content remained unchanged. Thus, pharmacologic CYP27A1 inhibition is possible in the whole body and individual organs, but does not negatively affect cholesterol elimination. Our results enhance the potential of CYP27A1 as an antibreast cancer target, could be of importance for the interpretation of Femara versus Anastrozole Clinical Evaluation Trial, and bring attention to posaconazole as a potential complementary anti-breast cancer medication. More medications on the US market may have unanticipated off-target inhibition of CYP27A1, and we propose strategies for their identification.

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Combination of Anastrozole with Fulvestrant in the Intratumoral Aromatase Xenograft Model

Abstract: Although the aromatase inhibitor anastrozole has been shown

Cited by 85 publications

References 43 publications

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

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

Growth factor stimulation induces a distinct ERα cistrome underlying breast cancer endocrine resistance

Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy

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