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Keywords = Elacestrant

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23 pages, 2680 KiB  
Article
Novel Polymorphic Patterns for Elacestrant Dihydrochloride
by Zia Uddin Masum, P. Grant Spoors, Matt D. Burke and Vivek Gupta
Pharmaceutics 2025, 17(6), 745; https://doi.org/10.3390/pharmaceutics17060745 - 5 Jun 2025
Viewed by 915
Abstract
Objective: This study expands on the polymorphic characterization of elacestrant dihydrochloride, developed by Stemline Therapeutics and approved by the FDA in 2023. The article focuses on more extensive polymorphism screening using various methods and solvents to discover the new polymorphism forms of this [...] Read more.
Objective: This study expands on the polymorphic characterization of elacestrant dihydrochloride, developed by Stemline Therapeutics and approved by the FDA in 2023. The article focuses on more extensive polymorphism screening using various methods and solvents to discover the new polymorphism forms of this molecule, besides identifying three polymorphic forms in the previously published studies. Methods: The crystalline and amorphous elacestrant hydrochloride solubility was assessed, and crystals were formed, followed by polymorph screening using 40 non-conventional solvents via different techniques to obtain the new polymorphic forms. XRPD, NMR, DSC, TGA, IC, and HPLC were used for solid-state characterization. Results: Patterns A, B, C, D, E, F, and G, and previously published forms 1,3, were identified in multiple studies during the extensive polymorphism screening using various methods and numerous solvent systems. Solid state characterization and purity analysis were completed using different relevant instruments. After the characterization, it was found that Pattern A was the most stable, like the desired/most stable Form 1, but it had fewer crystals; Pattern B is like Form 3 but a unique XRPD pattern; Pattern D is degradant; Pattern C, E, F, and G are considered as the new pattern of elacestrant along with patterns A and B. Conclusions: With XRPD, six new patterns (A, B, C, E, F, G) were identified. Patterns A, C, and E are promising crystalline candidates for further analysis and scale-up. Full article
(This article belongs to the Section Physical Pharmacy and Formulation)
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10 pages, 4795 KiB  
Article
Highly Efficient and Sustainable HT@NC/Pd Catalysts for Suzuki Coupling and Their Application in Elacestrant Synthesis
by Jiajun He, Muwei Liu, Chao Chen, Guozhang Li, Kai Zheng and Chao Shen
Catalysts 2025, 15(4), 389; https://doi.org/10.3390/catal15040389 - 17 Apr 2025
Viewed by 482
Abstract
Mg-Al hydrotalcite (HT), comprising Mg2+ and Al3+ as layered hydroxide cations, was synthesized via a hydrothermal process at 200 °C. The HT was evaluated as a carrier, and subsequently, palladium was immobilized on the surface of the hydrotalcite (HT/NC), resulting in [...] Read more.
Mg-Al hydrotalcite (HT), comprising Mg2+ and Al3+ as layered hydroxide cations, was synthesized via a hydrothermal process at 200 °C. The HT was evaluated as a carrier, and subsequently, palladium was immobilized on the surface of the hydrotalcite (HT/NC), resulting in the development of an innovative biomass-based palladium catalyst. The catalyst underwent analysis by X-ray diffraction (XRD), scanning electron microscopy (SEM), and X-ray photoelectron spectroscopy (XPS). It exhibited remarkable catalytic efficiency and superior activity as a catalyst in the Suzuki–Miyaura coupling reaction in water. The catalyst was recyclable without a decline in activity and could be utilized more than 10 times, with exceptional yield. Furthermore, the commercially accessible anticancer drug Elacestrant can be readily produced using this protocol. Full article
(This article belongs to the Special Issue Sustainable Catalysis for Green Chemistry and Energy Transition)
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14 pages, 3031 KiB  
Article
Detection of ESR1 Mutations in Tissue and Liquid Biopsy with Novel Next-Generation Sequencing and Digital Droplet PCR Assays: Insights from Multi-Center Real Life Data of Almost 6000 Patients
by Srushti Borkar, Fenja Markus, Agnes Oetting, Stefanie Schmidt, Christine Vössing, David Horst, Markus Möbs, Elena I. Braicu, Frank Griesinger, Katja Horling, Katharina Tiemann, Lukas C. Heukamp, Eva-Maria Willing and Claudia Vollbrecht
Cancers 2025, 17(8), 1266; https://doi.org/10.3390/cancers17081266 - 9 Apr 2025
Viewed by 2741
Abstract
Background: ESR1 mutations are biomarkers in breast cancer patients who develop metastatic disease after endocrine therapy (ET). Recently, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved Elacestrant, a selective estrogen receptor degrader for patients harboring ESR1 mutations. This [...] Read more.
Background: ESR1 mutations are biomarkers in breast cancer patients who develop metastatic disease after endocrine therapy (ET). Recently, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved Elacestrant, a selective estrogen receptor degrader for patients harboring ESR1 mutations. This has necessitated the establishment of reliable and sensitive NGS- or PCR-based assays to detect these ESR1 resistance mutations in liquid biopsy samples. Methods: We evaluated NGS results of a pan-cancer cohort of almost 6000 patients from two major German institutes of pathology, to show that the occurrence of ESR1 mutations is extremely rare (<1%) in ET-naïve patients. This suggests that ESR1 mutations arise almost exclusively under the pressure of ET. Therefore, we designed a breast cancer-specific hybrid capture-based NGS liquid biopsy assay covering 12 breast cancer-related genes, including ESR1, PIK3CA, AKT1, ERBB2, BRCA1/2, and TP53. We validated the HS2-Mamma-LIQ assay extensively using reference material to detect mutations to 0.1% variant allele frequency (VAF) and compared the performance to a commercially available ESR1 ddPCR assay. Results: We show the results of routine diagnostic analysis of the first consecutive 354 patients with activating ESR1 mutations rate of 43%, with 20% of patients harboring co-mutations in PIK3CA and other genes underlining the relevance of tumor heterogeneity. Our study highlights liquid biopsy as a preferred approach for monitoring ESR1 mutations in breast cancer patients by showing cases where NGS analysis suggests complex tumor heterogeneity with multiple ESR1 as well as PIK3CA mutations at different VAFs. Conclusions: Our findings not only corroborate prior research concerning the rarity of these mutations in unselected patients but also emphasize the importance of robust and broad molecular assays rather than single gene assays in their detection and characterization in the diagnostic setting. Advantages of different approaches are discussed to address the current clinical need. Full article
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16 pages, 3142 KiB  
Article
Effect of Tasurgratinib as an Orally Available FGFR1–3 Inhibitor on Resistance to a CDK4/6 Inhibitor and Endocrine Therapy in ER+/HER2 Breast Cancer Preclinical Models
by Satoshi Kawano, Sayo Fukushima, Kyoko Nishibata, Ryu Gejima and Saori Watanabe Miyano
Cancers 2025, 17(7), 1084; https://doi.org/10.3390/cancers17071084 - 24 Mar 2025
Viewed by 731
Abstract
Background: Fibroblast growth factor (FGF) signaling plays a crucial role in several cellular functions in cancer cells. Tasurgratinib, formerly known as E7090, is an orally available FGF receptor (FGFR)1–3 selective inhibitor. Here, we present the effects of tasurgratinib on the resistance to CDK4/6 [...] Read more.
Background: Fibroblast growth factor (FGF) signaling plays a crucial role in several cellular functions in cancer cells. Tasurgratinib, formerly known as E7090, is an orally available FGF receptor (FGFR)1–3 selective inhibitor. Here, we present the effects of tasurgratinib on the resistance to CDK4/6 inhibitors and endocrine therapy (ET) in a preclinical model. Methods: Estrogen receptor (ER)+ breast cancer (BC) patient-derived xenograft (PDX) models harboring ESR1 wild-type or ESR1 mutation were used as animal models. An in vitro cell proliferation assay of ER+ BC cell lines treated with fulvestrant or palbociclib + fulvestrant was conducted in the presence of FGF2 and FGF10, with or without tasurgratinib. Results: Among five ER+ BC PDX models, OD-BRE-0438 and OD-BRE-0704 showed higher sensitivities to tasurgratinib with prior palbociclib + fulvestrant than without it. In these models, palbociclib + fulvestrant treatment upregulated the expression of several FGF ligand mRNAs. In vitro, FGF2 and FGF10 decreased the sensitivity to both fulvestrant and palbociclib + fulvestrant, which was restored by co-treatment with tasurgratinib. Consistently, fulvestrant + tasurgratinib and elacestrant + tasurgratinib showed antitumor activity in ER+ BC PDX models harboring ESR1 wild-type and ESR1 mutation, respectively. In these models, fulvestrant or elacestrant upregulated the expression of several FGF ligand mRNAs. Conclusions: FGF signaling plays a role in resistance to CDK4/6 inhibitors and ET in ER+ BC. Tasurgratinib has the potential to exhibit significant antitumor activity in combination with ET against ER+ BC via FGF signaling inhibition. These findings indicate the therapeutic potential of tasurgratinib in treating ER+ BC. Full article
(This article belongs to the Special Issue New Insights into Targeted Drugs for Breast Cancer (Volume II))
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73 pages, 2038 KiB  
Review
The Diversity of Liquid Biopsies and Their Potential in Breast Cancer Management
by Corinna Keup, Rainer Kimmig and Sabine Kasimir-Bauer
Cancers 2023, 15(22), 5463; https://doi.org/10.3390/cancers15225463 - 17 Nov 2023
Cited by 12 | Viewed by 3853
Abstract
Analyzing blood as a so-called liquid biopsy in breast cancer (BC) patients has the potential to adapt therapy management. Circulating tumor cells (CTCs), extracellular vesicles (EVs), cell-free DNA (cfDNA) and other blood components mirror the tumoral heterogeneity and could support a range of [...] Read more.
Analyzing blood as a so-called liquid biopsy in breast cancer (BC) patients has the potential to adapt therapy management. Circulating tumor cells (CTCs), extracellular vesicles (EVs), cell-free DNA (cfDNA) and other blood components mirror the tumoral heterogeneity and could support a range of clinical decisions. Multi-cancer early detection tests utilizing blood are advancing but are not part of any clinical routine yet. Liquid biopsy analysis in the course of neoadjuvant therapy has potential for therapy (de)escalation.Minimal residual disease detection via serial cfDNA analysis is currently on its way. The prognostic value of blood analytes in early and metastatic BC is undisputable, but the value of these prognostic biomarkers for clinical management is controversial. An interventional trial confirmed a significant outcome benefit when therapy was changed in case of newly emerging cfDNA mutations under treatment and thus showed the clinical utility of cfDNA analysis for therapy monitoring. The analysis of PIK3CA or ESR1 variants in plasma of metastatic BC patients to prescribe targeted therapy with alpesilib or elacestrant has already arrived in clinical practice with FDA-approved tests available and is recommended by ASCO. The translation of more liquid biopsy applications into clinical practice is still pending due to a lack of knowledge of the analytes’ biology, lack of standards and difficulties in proving clinical utility. Full article
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20 pages, 716 KiB  
Review
Filling the Gap after CDK4/6 Inhibitors: Novel Endocrine and Biologic Treatment Options for Metastatic Hormone Receptor Positive Breast Cancer
by Abhenil Mittal, Consolacion Molto Valiente, Faris Tamimi, Ilana Schlam, Sarah Sammons, Sara M. Tolaney and Paolo Tarantino
Cancers 2023, 15(7), 2015; https://doi.org/10.3390/cancers15072015 - 28 Mar 2023
Cited by 30 | Viewed by 12573
Abstract
The rise of cyclin-dependent kinase (CDK)4/6 inhibitors has rapidly reshaped treatment algorithms for hormone receptor (HR)-positive metastatic breast cancer, with endocrine treatment (ET) plus a CDK4/6-inhibitor currently representing the standard of care in the first line setting. However, treatment selection for those patients [...] Read more.
The rise of cyclin-dependent kinase (CDK)4/6 inhibitors has rapidly reshaped treatment algorithms for hormone receptor (HR)-positive metastatic breast cancer, with endocrine treatment (ET) plus a CDK4/6-inhibitor currently representing the standard of care in the first line setting. However, treatment selection for those patients experiencing progression while on ET + CDK4/6-inhibitors remains challenging due to the suboptimal activity or significant toxicities of the currently available options. There is also a paucity of data regarding the efficacy of older regimens, such as everolimus + exemestane, post-CDK4/6 inhibition. In this setting of high unmet need, several clinical trials of novel drugs have recently reported encouraging results: the addition of the AKT-inhibitor capivasertib to fulvestrant demonstrated a significant improvement in progression-free survival (PFS); the oral selective estrogen receptor degrader (SERD) elacestrant prolonged PFS compared to traditional ET in a phase 3 trial, particularly among patients with detectable ESR1 mutations; finally, PARP inhibitors are available treatment options for patients with pathogenic BRCA1/2 germline mutations. Overall, a plethora of novel endocrine and biologic treatment options are finally filling the gap between first-line ET and later line chemotherapy. In this review article, we recapitulate the activity of these novel treatment options and their potential role in future treatment algorithms. Full article
(This article belongs to the Section Cancer Therapy)
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