A Phase I Study of LSZ102, an Oral Selective Estrogen Receptor Degrader, with or without Ribociclib or Alpelisib, in Patients with Estrogen Receptor–Positive Breast Cancer

Jhaveri, Komal; Juric, Dejan; Yap, Yoon Sim; Cresta, Sara; Layman, Rachel M.; Duhoux, François; Terret, C.; Takahashi, Shunji; Huober, Jens; Kundamal, Nicole; Sheng, Qing; Balbin, Alejandro; Ji, Yan; He, Wei; Crystal, Adam S.; Vita, Serena De; Curigliano, Giuseppe

doi:10.1158/1078-0432.ccr-21-1095

Cited by 29 publications

(25 citation statements)

References 32 publications

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“… 42 PROTAC and molecular glue are two major technologies that rely on the UPS for the degradation of protein of interest (POI), and will be the focus of our discussion (Table 1 ). Additionally, many PROTAC-based technologies, including selective androgen receptor degrader (SARD) 43 , 44 , Hydrophobic tagging (HyT), 45 – 47 TF-PROTAC, 48 dual-PROTAC, 49 and selective estrogen receptor degrader (SERD), 50 – 54 have recently emerged (Table 1 ).…”

Section: Targeted Protein Degradation Via Proteasomementioning

confidence: 99%

Targeted protein degradation: mechanisms, strategies and application

Zhao

Zhong

et al. 2022

Sig Transduct Target Ther

268

185

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Traditional drug discovery mainly focuses on direct regulation of protein activity. The development and application of protein activity modulators, particularly inhibitors, has been the mainstream in drug development. In recent years, PROteolysis TArgeting Chimeras (PROTAC) technology has emerged as one of the most promising approaches to remove specific disease-associated proteins by exploiting cells’ own destruction machinery. In addition to PROTAC, many different targeted protein degradation (TPD) strategies including, but not limited to, molecular glue, Lysosome-Targeting Chimaera (LYTAC), and Antibody-based PROTAC (AbTAC), are emerging. These technologies have not only greatly expanded the scope of TPD, but also provided fresh insights into drug discovery. Here, we summarize recent advances of major TPD technologies, discuss their potential applications, and hope to provide a prime for both biologists and chemists who are interested in this vibrant field.

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Section: Targeted Protein Degradation Via Proteasomementioning

confidence: 99%

Targeted protein degradation: mechanisms, strategies and application

Zhao

Zhong

et al. 2022

Sig Transduct Target Ther

268

185

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“…LSZ102 monotherapy was associated with high rates of gastrointestinal (GI) toxicities experienced: any grade nausea (61%) and diarrhea (55%). Notably, the toxicity profile did not significantly differ in the combination arms [53].…”

Section: Serds With Acrylic Acid Side Chainsmentioning

confidence: 90%

Accelerating drug development in breast cancer: New frontiers for ER inhibition

Ferraro¹,

Walsh²,

Tao³

et al. 2022

Cancer Treatment Reviews

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“…In one of the experimental arms, 43 patients with endocrine-resistant breast cancer were treated with LSZ102 plus alpelisib. Clinical activity was encouraging, with ORR and CBR measured at 7.0% (95% CI: 1.5–19.1) and 20.9% (95% CI: 10.0–36.0) respectively, with an estimated modest median PFS of 3.5 months, irrespective of PIK3CA mutation status [ 107 ].…”

Section: Future Perspectivesmentioning

confidence: 99%

Role of PI3K/Akt/mTOR pathway in mediating endocrine resistance: concept to clinic

Skolariki

D’Costa

Little

et al. 2022

Exploration of Targeted Anti-Tumor Therapy

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The majority of breast cancers express the estrogen receptor (ER) and for this group of patients, endocrine therapy is the cornerstone of systemic treatment. However, drug resistance is common and a focus for breast cancer preclinical and clinical research. Over the past 2 decades, the PI3K/Akt/mTOR axis has emerged as an important driver of treatment failure, and inhibitors of mTOR and PI3K are now licensed for the treatment of women with advanced ER-positive breast cancer who have relapsed on first-line hormonal therapy. This review presents the preclinical and clinical data that led to this new treatment paradigm and discusses future directions.

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A Phase I Study of LSZ102, an Oral Selective Estrogen Receptor Degrader, with or without Ribociclib or Alpelisib, in Patients with Estrogen Receptor–Positive Breast Cancer

Cited by 29 publications

References 32 publications

Targeted protein degradation: mechanisms, strategies and application

Targeted protein degradation: mechanisms, strategies and application

Accelerating drug development in breast cancer: New frontiers for ER inhibition

Role of PI3K/Akt/mTOR pathway in mediating endocrine resistance: concept to clinic

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