Seviteronel, a Novel CYP17 Lyase Inhibitor and Androgen Receptor Antagonist, Radiosensitizes AR-Positive Triple Negative Breast Cancer Cells

Michmerhuizen, Anna R.; Chandler, Benjamin C.; Olsen, Eric; Wilder-Romans, Kari; Moubadder, Leah; Liu, Meilan; Pesch, Andrea M.; Zhang, Amanda; Ritter, Cassandra L.; Ward, Shannon; Santola, Alyssa; Nyati, Shyam; Rae, James M.; Hayes, Daniel F.; Feng, Felix Y.; Spratt, Daniel E.; Wahl, Daniel R.; Eisner, Joel R.; Pierce, Lori J.; Speers, Corey

doi:10.3389/fendo.2020.00035

Cited by 26 publications

(29 citation statements)

References 44 publications

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“…Inhibition of AR with enzalutamide results in increased radiosensitization of AR+ breast cancer cells through the inhibition of AR-activated DNA-PKcs-mediated repair 100 . Similar results were observed with seviteronel, the dual CYP17 inhibitor and AR antagonist 101 , however the differences in the mechanisms of radiosensitization with these agents need to be further assessed.…”

Section: Combination Therapies Ar + Radiation Therapysupporting

confidence: 54%

“…Recent data in breast cancer suggest that loss of AR signaling through knockdown or pharmacologic inhibition with enzalutamide or seviteronel results in increased sensitivity to ionizing radiation 100,101 . In addition, AR mRNA levels correlate with survival following radiation treatment, and AR is important for regulating the DNA damage response in AR+ breast cancer cell lines 102 .…”

Section: Breast Cancermentioning

confidence: 99%

“…Breast cancer. The AR has been shown to be a potential mediator of radioresistance and a target for the radiosensitization of AR+ TNBC [100][101][102]200 . Inhibition of AR with enzalutamide results in increased radiosensitization of AR+ breast cancer cells through the inhibition of AR-activated DNA-PKcs-mediated repair 100 .…”

Section: Combination Therapies Ar + Radiation Therapymentioning

confidence: 99%

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ARe we there yet? Understanding androgen receptor signaling in breast cancer

et al. 2020

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The role of androgen receptor (AR) activation and expression is well understood in prostate cancer. In breast cancer, expression and activation of AR is increasingly recognized for its role in cancer development and its importance in promoting cell growth in the presence or absence of estrogen. As both prostate and breast cancers often share a reliance on nuclear hormone signaling, there is increasing appreciation of the overlap between activated cellular pathways in these cancers in response to androgen signaling. Targeting of the androgen receptor as a monotherapy or in combination with other conventional therapies has proven to be an effective clinical strategy for the treatment of patients with prostate cancer, and these therapeutic strategies are increasingly being investigated in breast cancer. This overlap suggests that targeting androgens and AR signaling in other cancer types may also be effective. This manuscript will review the role of AR in various cellular processes that promote tumorigenesis and metastasis, first in prostate cancer and then in breast cancer, as well as discuss ongoing efforts to target AR for the more effective treatment and prevention of cancer, especially breast cancer.

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Section: Combination Therapies Ar + Radiation Therapysupporting

confidence: 54%

Section: Breast Cancermentioning

confidence: 99%

Section: Combination Therapies Ar + Radiation Therapymentioning

confidence: 99%

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ARe we there yet? Understanding androgen receptor signaling in breast cancer

et al. 2020

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“…More than that, AR inhibition with enzalutamide was shown to be an inductor of radiation sensitivity in AR-positive TNBC cell lines, proposing AR inhibition as an effective radiosensitization strategy [ 85 ]. Additionally, seviteronel, a CYP17 lyase inhibitor, which therefore inhibits synthesis of androgens and estrogens [ 86 ] and also acts as a competitive antagonist of AR [ 87 ], has showed a unique mechanism of radiosensitization compared to enzalutamide [ 88 ].…”

Section: Androgen Receptors As a Therapeutic Targetmentioning

confidence: 99%

Clinical Implications of Androgen-Positive Triple-Negative Breast Cancer

Brumec

Sobočan

Takač

et al. 2021

Cancers

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This review summarizes the recent findings of a vast array of studies conducted on androgen receptor-positive triple-negative breast cancer (AR-positive TNBC) to provide a better understanding of this specific breast cancer subgroup. AR expression is correlated with higher age, lower histological grade, lower proliferation index Ki-67, spiculated masses, and calcifications on mammography. Studies investigating the correlation between AR expression and lymph node metastasis are highly discordant. In addition, results regarding prognosis are highly contradictory. AR antagonists are a promising novel therapeutic approach in AR-positive TNBC. However, AR signaling pathways should be more investigated in order to understand the influence of AR expression on TNBC more thoroughly.

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“…It is a FDA-approved anthelmintic agent to treat tapeworms, which is known to inhibit cell growth in vitro and tumor growth in vivo in TNBC studies [ 74 ]. Niclosamide was identified as an inhibitor of BCSCs owing to a high-throughput drug screening [ 76 ]. It reverses EMT and inhibits the stem-like phenotype in cancer cells suggesting that it may reverse cisplatin resistance [ 74 ].…”

Section: Drug Repurposing For Tnbcmentioning

confidence: 99%

Drug Repurposing for Triple-Negative Breast Cancer

Ávalos-Moreno

López-Tejada

Blaya-Cánovas

et al. 2020

JPM

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Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer which presents a high rate of relapse, metastasis, and mortality. Nowadays, the absence of approved specific targeted therapies to eradicate TNBC remains one of the main challenges in clinical practice. Drug discovery is a long and costly process that can be dramatically improved by drug repurposing, which identifies new uses for existing drugs, both approved and investigational. Drug repositioning benefits from improvements in computational methods related to chemoinformatics, genomics, and systems biology. To the best of our knowledge, we propose a novel and inclusive classification of those approaches whereby drug repurposing can be achieved in silico: structure-based, transcriptional signatures-based, biological networks-based, and data-mining-based drug repositioning. This review specially emphasizes the most relevant research, both at preclinical and clinical settings, aimed at repurposing pre-existing drugs to treat TNBC on the basis of molecular mechanisms and signaling pathways such as androgen receptor, adrenergic receptor, STAT3, nitric oxide synthase, or AXL. Finally, because of the ability and relevance of cancer stem cells (CSCs) to drive tumor aggressiveness and poor clinical outcome, we also focus on those molecules repurposed to specifically target this cell population to tackle recurrence and metastases associated with the progression of TNBC.

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Seviteronel, a Novel CYP17 Lyase Inhibitor and Androgen Receptor Antagonist, Radiosensitizes AR-Positive Triple Negative Breast Cancer Cells

Cited by 26 publications

References 44 publications

ARe we there yet? Understanding androgen receptor signaling in breast cancer

ARe we there yet? Understanding androgen receptor signaling in breast cancer

Clinical Implications of Androgen-Positive Triple-Negative Breast Cancer

Drug Repurposing for Triple-Negative Breast Cancer

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