Targeted degradation of activating estrogen receptor α ligand-binding domain mutations in human breast cancer

Gonzalez, Thomas L.; Hancock, Molly; Sun, Siqi; Gersch, Christina L.; Larios, José M.; David, Wadie; Hu, Jiantao; Hayes, Daniel F.; Wang, Shaomeng; Rae, James M.

doi:10.1007/s10549-020-05564-y

Cited by 50 publications

(29 citation statements)

References 37 publications

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“…Samples were analyzed in triplicate using a CFX96 Real-Time PCR detection system (Bio-Rad, Hercules, CA). All samples were normalized to GAPDH as previously described [23] and measured as fold change of PD-L1 expression from untreated MDA-MB-231 cells. All primers were diluted to a working concentration of 250nM.…”

Section: Pd-l1 Gene Expressionmentioning

confidence: 99%

PD-L1 Expression on Circulating Tumor Cells and Platelets in Patients with Metastatic Breast Cancer

Darga¹,

Dolce²,

Fang

et al. 2021

Preprint

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Background: Immune checkpoint inhibition (ICPi) is effective in several cancers. Expression of programmed death-ligand 1 (PD-L1) on circulating tumor or immune effector cells could provide insights into selection of patients for ICPi. Methods: Whole blood (WB) was collected at serial timepoints from metastatic breast cancer (MBC) patients and healthy donors for circulating tumor cell (CTC) and platelet PD-L1 analysis using the CellSearch® assay. CTC PD-L1 was considered positive if detected on at least 1% of the cells; platelet PD-L1 was considered positive if ≥100 platelets per CellSearch frame expressed PD-L1. Results: A total of 207 specimens from 124 MBC patients were collected. 52/124 (42%) samples at timepoint-1 (at or close to time of progressive disease) had ≥5 CTC/7.5ml WB. Of those, 21 (40%) had positive CTC PD-L1. In addition, platelet PD-L1 expression was observed in 35/124 (28%) at timepoint-1. Platelet PD-L1 was not detected in more than 70 specimens from 12 healthy donors. Platelet PD-L1 was associated with ≥5 CTC/7.5ml WB (p=0.0002), less likely in patients with higher red blood cell counts (OR=0.72, p<0.001) and a history of smoking tobacco (OR=0.76, p<0.001). Platelet PD-L1 staining was not associated with tumor marker status, recent procedures or treatments, platelet-affecting drugs, or CTC PD-L1 expression. Conclusion: PD-L1 expression was found in MBC patients on both CTC and platelets in an independent fashion. Inter-patient platelet PD-L1 expression was highly heterogeneous suggesting that it is a biological event associated with cancer in some but not all patients. Taken together, our data suggest that CTC and platelet PD-L1 expression could play a role in predicting which patients should receive ICPi and as a pharmacodynamics biomarker during treatment.

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Section: Pd-l1 Gene Expressionmentioning

confidence: 99%

PD-L1 Expression on Circulating Tumor Cells and Platelets in Patients with Metastatic Breast Cancer

Darga¹,

Dolce²,

Fang

et al. 2021

Preprint

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“…Compound ERD-148 is a novel orally bioavailable degrader of ERα. ERD-148 inhibited the growth of ER+ BC cells via specifically antagonizing the ERα receptor with comparable potency to FUL and marginal non-specific toxicity ( 105 ).. Bazedoxifene is a potent anti-estrogen agent that is clinically approved for hormone replacement therapy. Fanning et al.…”

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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“…PROTACs can be used to overcome drug resistance resulting from mutations of a protein of interest, such as PROTACs targeting mutated forms of BCR-ABL, 13 receptor tyrosine kinases, 14 estrogen receptor-α, 15 and Bruton tyrosine kinase. 16 PROTACs can overcome resistance to small-molecule inhibitors resulting from target upregulation by degrading the target; one such example is androgen receptor degraders, which have recently overcome resistance developed to the androgen receptor antagonist enzalutamide during prostate cancer treatment.…”

Section: Proteolysis-targeting Chimerasmentioning

confidence: 99%

Taking Aim at the Undruggable

Coleman

Rodón

2021

American Society of Clinical Oncology Educational Book

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The term “undruggable” is used to describe a protein that is not pharmacologically capable of being targeted; recently, however, substantial efforts have been made to turn these proteins into “druggable” targets. Thus, “difficult to drug” or “yet to be drugged” are perhaps more appropriate terms. In cancer, a number of elusive targets fall into this category, including transcription factors such as STAT3, TP53, and MYC. Pharmacologically targeting these intractable proteins is now a key challenge of modern drug development, requiring innovation and the development of new technologies. In this article, we discuss some of the recent technologic and pharmacologic advances that have underpinned the erosion of the concept of undruggability. We describe recent successes in drugging the undruggable RAS ( KRAS G12C and HRAS), and discuss the advances that have led to the validation of further targets previously believed to be undruggable, such as HIF-2α, BCL-2, MDM2, and MLL. Finally, we look to the future and describe important advances that are likely to have a major impact on targeting undruggable targets, such as the advent of proteolysis-targeting chimeras and protein-protein modulators, which are leading to considerable excitement surrounding the development of cancer targets.

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Targeted degradation of activating estrogen receptor α ligand-binding domain mutations in human breast cancer

Cited by 50 publications

References 37 publications

PD-L1 Expression on Circulating Tumor Cells and Platelets in Patients with Metastatic Breast Cancer

PD-L1 Expression on Circulating Tumor Cells and Platelets in Patients with Metastatic Breast Cancer

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

Taking Aim at the Undruggable

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