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RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models.

Garner F, Shomali M, Paquin D, Lyttle CR, Hattersley G - Anticancer Drugs (2015)

Bottom Line: Importantly, RAD1901 produced a robust and profound inhibition of tumor growth in MCF-7 xenograft models.In an intracranial MCF-7 model, RAD1901-treated animals survived longer than those treated with either control or fulvestrant, suggesting the potential benefit of RAD1901 in the treatment of ER-positive breast cancer that has metastasized to the brain.Finally, RAD1901 preserved ovariectomy-induced bone loss and prevented the uterotropic effects of E2, suggesting that it may act selectively as an agonist in bone but as an antagonist in breast and uterine tissues.

View Article: PubMed Central - PubMed

Affiliation: aRadius Health Inc., Waltham bPfizer, Andover, Massachusetts, USA.

ABSTRACT
Agents that inhibit estrogen production, such as aromatase inhibitors or those that directly block estrogen receptor (ER) activity, such as selective estrogen receptor modulators and selective estrogen receptor degraders, are routinely used in the treatment of ER-positive breast cancers. However, although initial treatment with these agents is often successful, many women eventually relapse with drug-resistant breast cancers. To overcome some of the challenges associated with current endocrine therapies and to combat the development of resistance, there is a need for more durable and more effective ER-targeted therapies. Here we describe and characterize a novel, orally bioavailable small-molecule selective estrogen receptor degrader, RAD1901, and evaluate its therapeutic potential for the treatment of breast cancer. RAD1901 selectively binds to and degrades the ER and is a potent antagonist of ER-positive breast cancer cell proliferation. Importantly, RAD1901 produced a robust and profound inhibition of tumor growth in MCF-7 xenograft models. In an intracranial MCF-7 model, RAD1901-treated animals survived longer than those treated with either control or fulvestrant, suggesting the potential benefit of RAD1901 in the treatment of ER-positive breast cancer that has metastasized to the brain. Finally, RAD1901 preserved ovariectomy-induced bone loss and prevented the uterotropic effects of E2, suggesting that it may act selectively as an agonist in bone but as an antagonist in breast and uterine tissues. RAD1901 is currently under clinical study in postmenopausal women with ER-positive advanced breast cancer.

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Dose-dependent inhibition of tumor growth by RAD1901 in an MCF-7 mouse xenograft model. Female nude mice were implanted with 1×107 MCF-7 cells subcutaneously in the right flank. Fourteen days after implantation, tumor volumes were recorded and treatment was initiated with vehicle, tamoxifen (1 mg/animal every other day), fulvestrant (0.5 mg/animal daily), or RAD1901 (0.3, 1, 3, 10, 30, 60, 90, and 120 mg/kg daily). Tumor volume was evaluated twice per week until the study endpoint. (a) Mean tumor volumes over time for daily doses of 0.3, 1, 3, 10, 30, 60 mg/kg RAD1901, tamoxifen, and fulvestrant. (b) Box and whisker plots show the day 40 tumor volume by group. The box represents the 25th through 75th percentiles of observations, the line represents the mean of the observations, and the whiskers represent the extreme observations. (c) Mean tumor volumes over time for daily doses of 60, 90, and 120 mg/kg RAD1901, tamoxifen, and fulvestrant. (d) Tumor volumes from individual animals at day 42, with the mean percent change detailed for each group.
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Figure 3: Dose-dependent inhibition of tumor growth by RAD1901 in an MCF-7 mouse xenograft model. Female nude mice were implanted with 1×107 MCF-7 cells subcutaneously in the right flank. Fourteen days after implantation, tumor volumes were recorded and treatment was initiated with vehicle, tamoxifen (1 mg/animal every other day), fulvestrant (0.5 mg/animal daily), or RAD1901 (0.3, 1, 3, 10, 30, 60, 90, and 120 mg/kg daily). Tumor volume was evaluated twice per week until the study endpoint. (a) Mean tumor volumes over time for daily doses of 0.3, 1, 3, 10, 30, 60 mg/kg RAD1901, tamoxifen, and fulvestrant. (b) Box and whisker plots show the day 40 tumor volume by group. The box represents the 25th through 75th percentiles of observations, the line represents the mean of the observations, and the whiskers represent the extreme observations. (c) Mean tumor volumes over time for daily doses of 60, 90, and 120 mg/kg RAD1901, tamoxifen, and fulvestrant. (d) Tumor volumes from individual animals at day 42, with the mean percent change detailed for each group.

Mentions: The antitumor effects of RAD1901 were characterized using an MCF-7 xenograft model in mice supplemented with E2 to stimulate tumor growth. RAD1901 inhibited tumor growth in a dose-dependent manner (Fig. 3). Significant TGI responses were seen at doses of 30 and 60 mg/kg RAD1901, with TGI at day 40 being 66% (P<0.05) and 88% (P<0.001), respectively. These were comparable to the TGI observed for tamoxifen and fulvestrant, which on day 40 were 86 and 88%, respectively (Fig. 3a). RAD1901 was well tolerated, with no adverse effect on body weight.


RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models.

Garner F, Shomali M, Paquin D, Lyttle CR, Hattersley G - Anticancer Drugs (2015)

Dose-dependent inhibition of tumor growth by RAD1901 in an MCF-7 mouse xenograft model. Female nude mice were implanted with 1×107 MCF-7 cells subcutaneously in the right flank. Fourteen days after implantation, tumor volumes were recorded and treatment was initiated with vehicle, tamoxifen (1 mg/animal every other day), fulvestrant (0.5 mg/animal daily), or RAD1901 (0.3, 1, 3, 10, 30, 60, 90, and 120 mg/kg daily). Tumor volume was evaluated twice per week until the study endpoint. (a) Mean tumor volumes over time for daily doses of 0.3, 1, 3, 10, 30, 60 mg/kg RAD1901, tamoxifen, and fulvestrant. (b) Box and whisker plots show the day 40 tumor volume by group. The box represents the 25th through 75th percentiles of observations, the line represents the mean of the observations, and the whiskers represent the extreme observations. (c) Mean tumor volumes over time for daily doses of 60, 90, and 120 mg/kg RAD1901, tamoxifen, and fulvestrant. (d) Tumor volumes from individual animals at day 42, with the mean percent change detailed for each group.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4560273&req=5

Figure 3: Dose-dependent inhibition of tumor growth by RAD1901 in an MCF-7 mouse xenograft model. Female nude mice were implanted with 1×107 MCF-7 cells subcutaneously in the right flank. Fourteen days after implantation, tumor volumes were recorded and treatment was initiated with vehicle, tamoxifen (1 mg/animal every other day), fulvestrant (0.5 mg/animal daily), or RAD1901 (0.3, 1, 3, 10, 30, 60, 90, and 120 mg/kg daily). Tumor volume was evaluated twice per week until the study endpoint. (a) Mean tumor volumes over time for daily doses of 0.3, 1, 3, 10, 30, 60 mg/kg RAD1901, tamoxifen, and fulvestrant. (b) Box and whisker plots show the day 40 tumor volume by group. The box represents the 25th through 75th percentiles of observations, the line represents the mean of the observations, and the whiskers represent the extreme observations. (c) Mean tumor volumes over time for daily doses of 60, 90, and 120 mg/kg RAD1901, tamoxifen, and fulvestrant. (d) Tumor volumes from individual animals at day 42, with the mean percent change detailed for each group.
Mentions: The antitumor effects of RAD1901 were characterized using an MCF-7 xenograft model in mice supplemented with E2 to stimulate tumor growth. RAD1901 inhibited tumor growth in a dose-dependent manner (Fig. 3). Significant TGI responses were seen at doses of 30 and 60 mg/kg RAD1901, with TGI at day 40 being 66% (P<0.05) and 88% (P<0.001), respectively. These were comparable to the TGI observed for tamoxifen and fulvestrant, which on day 40 were 86 and 88%, respectively (Fig. 3a). RAD1901 was well tolerated, with no adverse effect on body weight.

Bottom Line: Importantly, RAD1901 produced a robust and profound inhibition of tumor growth in MCF-7 xenograft models.In an intracranial MCF-7 model, RAD1901-treated animals survived longer than those treated with either control or fulvestrant, suggesting the potential benefit of RAD1901 in the treatment of ER-positive breast cancer that has metastasized to the brain.Finally, RAD1901 preserved ovariectomy-induced bone loss and prevented the uterotropic effects of E2, suggesting that it may act selectively as an agonist in bone but as an antagonist in breast and uterine tissues.

View Article: PubMed Central - PubMed

Affiliation: aRadius Health Inc., Waltham bPfizer, Andover, Massachusetts, USA.

ABSTRACT
Agents that inhibit estrogen production, such as aromatase inhibitors or those that directly block estrogen receptor (ER) activity, such as selective estrogen receptor modulators and selective estrogen receptor degraders, are routinely used in the treatment of ER-positive breast cancers. However, although initial treatment with these agents is often successful, many women eventually relapse with drug-resistant breast cancers. To overcome some of the challenges associated with current endocrine therapies and to combat the development of resistance, there is a need for more durable and more effective ER-targeted therapies. Here we describe and characterize a novel, orally bioavailable small-molecule selective estrogen receptor degrader, RAD1901, and evaluate its therapeutic potential for the treatment of breast cancer. RAD1901 selectively binds to and degrades the ER and is a potent antagonist of ER-positive breast cancer cell proliferation. Importantly, RAD1901 produced a robust and profound inhibition of tumor growth in MCF-7 xenograft models. In an intracranial MCF-7 model, RAD1901-treated animals survived longer than those treated with either control or fulvestrant, suggesting the potential benefit of RAD1901 in the treatment of ER-positive breast cancer that has metastasized to the brain. Finally, RAD1901 preserved ovariectomy-induced bone loss and prevented the uterotropic effects of E2, suggesting that it may act selectively as an agonist in bone but as an antagonist in breast and uterine tissues. RAD1901 is currently under clinical study in postmenopausal women with ER-positive advanced breast cancer.

Show MeSH
Related in: MedlinePlus