GLL398, an oral selective estrogen receptor degrader (SERD), blocks tumor growth in xenograft breast cancer models

Guo, Shanchun; Zhang, Changde; Mottamal, Madhusoodanan; Hossain, Ahamed; Liu, Jiawang; Wang, Guangdi

doi:10.1007/s10549-020-05558-w

Cited by 10 publications

(8 citation statements)

References 35 publications

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“…Although FUL has displayed clinical benefit in ABC patients despite its inconvenience and poor bioavailability of intramuscular injections, the drug-resistant phenotypes of the ESR1 mutants underline the need to develop more potent SERDs/SERMs that are also orally bioavailable ( 102 ). GLL398, a boron-modified GW5638 analog, has shown superior ER degrading efficacy and oral bioavailability ( 103 , 104 ). Compound ERD-148 is a novel orally bioavailable degrader of ERα.…”

Section: Pre-clinical Studies On Novel Serds/sermsmentioning

confidence: 99%

Detection of ESR1 Mutations Based on Liquid Biopsy in Estrogen Receptor-Positive Metastatic Breast Cancer: Clinical Impacts and Prospects

et al. 2020

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Endocrine therapy is the main treatment option for estrogen receptor-positive (ER+) breast cancer (BC). Compared with other clinical subtypes, ER+ BC patients usually have a more favorable prognosis. However, almost all ER+ BCpatients develop endocrine resistance and disease progression eventually. A large number of studies based on liquid biopsy suggest that ESR1 mutations may play a key role in this process. For patients with ER+ metastatic BC (MBC), ESR1 is an important prognostic factor and may associate with the resistance to endocrine therapy, like aromatase inhibitors. The advances of sequencing technologies allow us to conduct longitudinal monitoring of disease and unveil the clinical implications of each ESR1 sub-clone in ER+ MBC. Moreover, since the ESR1-related endocrine resistance has not been fully addressed by existing agents, more potent cornerstone drugs should be developed as soon as possible. Herein, we reviewed the recent progress of detecting ESR1 mutations based on liquid biopsy and different sequencing technologies in ER+ MBC and discussed its clinical impacts and prospects.

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Section: Pre-clinical Studies On Novel Serds/sermsmentioning

confidence: 99%

Detection of ESR1 Mutations Based on Liquid Biopsy in Estrogen Receptor-Positive Metastatic Breast Cancer: Clinical Impacts and Prospects

et al. 2020

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“…42 Preclinical studies have suggested that oral SERDs exhibit comparable rates of inhibition with fulvestrant in ER1 breast cancer cell lines and have also shown clinical activity in ER1 breast cancer xenograft models. [43][44][45][46] Although several studies are ongoing with these compounds in the metastatic setting, some preliminary studies have been reported that provide proof of concept.…”

Section: Future Directionsmentioning

confidence: 99%

Clinical Review on the Management of Hormone Receptor–Positive Metastatic Breast Cancer

McAndrew

Finn

2022

JCO Oncology Practice

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The natural history of hormone receptor–positive breast cancer tends to be more favorable than other subtypes such as human epidermal growth factor receptor 2–amplified and triple-negative. In addition, the natural dependence on steroid hormone signaling has allowed for therapeutic targeting of this pathway and significant improvements in survival while maintaining quality of life: the two main goals in management of the disease. The sequential use of endocrine agents including the selective estrogen receptor modulators (tamoxifen), aromatase inhibitors (letrozole, anastrozole, and exemestane) and the selective estrogen receptor degrader fulvestrant has been the backbone of management for years. In the past decade, the introduction of molecularly targeted agents against intracellular targets such as mammalian target of rapamycin (everolimus), cyclin-dependent kinases 4 and 6 (palbociclib, ribociclib, and abemaciclib), and phosphatidylinositol 3-kinase (alpelisib) has offered patients effective nonchemotherapy-based options, which are improving outcomes. Although knowledge gaps still exist in regard to the optimal sequencing of these new regimens, they have expanded our repertoire of options for patients and have shifted the need for cytotoxic chemotherapy and its associated complications to later lines. Still, formatting a plan for these patients includes taking into account traditional prognostic factors such as menopausal status, previous treatments, disease-free interval for those patients with early breast cancer that has recurred, and tumor burden. To assist in developing this treatment plan, we will review the current data with systemic agents in the management of these patients.

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“…In addition to tamoxifen and fulvestrant, bazidoxifen (a SERM) is shown to inhibit both the ERα and ERβ, degrade ERα, decrease Cyclin D1 level, and therefore it holds greater potential in inhibiting tumor progression in ER-positive, endocrine-resistant cell lines (Lewis-Wambi et al, 2011). On the other hand, Fulvestrant-resistant tumors with ESR1 mutations, orally administrable drugs, such as AZD9496, GNE-149, GLL398, GDC-0810, and G1T48 are developed (Andreano et al, 2020;Guo et al, 2020;Lai et al, 2015;Liang et al, 2020;Weir et al, 2016). In epithelial ovarian cancer (EOC) combinatorial treatment of fulvestrant plus a Src inhibitor (saracatinib) together lowered the production of cyclin E, cdk 2, and increased p27 levels thereby repressing cell growth (Simpkins et al, 2012).…”

Section: Er-targeted Small Molecule Therapeutics and Clinical Studiesmentioning

confidence: 99%

Targeting steroid hormone receptors for anti‐cancer therapy—A review on small molecules and nanotherapeutic approaches

Mahadik

Bhattacharya

Padmanabhan

et al. 2021

WIREs Nanomed Nanobiotechnol

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The steroid hormone receptors (SHRs) among nuclear hormone receptors (NHRs) are steroid ligand-dependent transcription factors that play important roles in the regulation of transcription of genes promoted via hormone responsive elements in our genome. Aberrant expression patterns and contextspecific regulation of these receptors in cancer, have been routinely reported by multiple research groups. These gave an window of opportunity to target those receptors in the context of developing novel, targeted anticancer therapeutics. Besides the development of a plethora of SHR-targeting synthetic ligands and the availability of their natural, hormonal ligands, development of many SHR-targeted, anticancer nano-delivery systems and theranostics, especially based on small molecules, have been reported. It is intriguing to realize that these cytoplasmic receptors have become a hot target for cancer selective delivery. This is in spite of the fact that these receptors do not fall in the category of conventional, targetable cell surface bound or transmembrane receptors that enjoy over-expression status. Glucocorticoid receptor (GR) is one such exciting SHR that in spite of it being expressed ubiquitously in all cells, we discovered it to behave differently in cancer cells, thus making it a truly druggable target for treating cancer. This review selectively accumulates the knowledge generated in the field of SHR-targeting as a major focus for cancer treatment with various anticancer small molecules and nanotherapeutics on progesterone receptor, mineralocorticoid receptor, and androgen receptor while selectively emphasizing on GR and estrogen receptor. This review also briefly highlights lipid-modification strategy to convert ligands into SHRtargeted cancer nanotherapeutics.

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GLL398, an oral selective estrogen receptor degrader (SERD), blocks tumor growth in xenograft breast cancer models

Cited by 10 publications

References 35 publications

Detection of ESR1 Mutations Based on Liquid Biopsy in Estrogen Receptor-Positive Metastatic Breast Cancer: Clinical Impacts and Prospects

Detection of ESR1 Mutations Based on Liquid Biopsy in Estrogen Receptor-Positive Metastatic Breast Cancer: Clinical Impacts and Prospects

Clinical Review on the Management of Hormone Receptor–Positive Metastatic Breast Cancer

Targeting steroid hormone receptors for anti‐cancer therapy—A review on small molecules and nanotherapeutic approaches

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