scholarly journals Antiestrogenic Effects of the Novel Sphingosine Kinase-2 Inhibitor ABC294640

Endocrinology ◽  
2010 ◽  
Vol 151 (11) ◽  
pp. 5124-5135 ◽  
Author(s):  
James W. Antoon ◽  
Martin D. White ◽  
William D. Meacham ◽  
Evelyn M. Slaughter ◽  
Shannon E. Muir ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Resistance ◽  
Sphingosine Kinase ◽  
Hek293 Cells ◽  
Sphingolipid Metabolism ◽  
Cancer Drug ◽  
The Novel ◽  
Er Positive ◽  
Cancer Tumor ◽  
Positive Breast Cancer

Alterations in sphingolipid metabolism have been shown to contribute to the development of endocrine resistance and breast cancer tumor survival. Sphingosine kinase (SK), in particular, is overexpressed in breast cancer and is a promising target for breast cancer drug development. In this study, we used the novel SK inhibitor ABC294640 as a tool to explore the relationship between SK and estrogen (E2) receptor (ER) signaling in breast cancer cells. Treatment with ABC294640 decreased E2-stimulated ERE-luciferase activity in both MCF-7 and ER-transfected HEK293 cells. Furthermore, the inhibitor reduced E2-mediated transcription of the ER-regulated genes progesterone receptor and SDF-1. Competitive receptor-binding assays revealed that ABC294640 binds in the antagonist ligand-binding domain of the ER, acting as a partial antagonist similar to tamoxifen. Finally, treatment with ABC294640 inhibited ER-positive breast cancer tumor formation in vivo. After 15 d of treatment with ABC294640, tumor volume was reduced by 68.4% (P < 0.05; n = 5) compared with control tumors, with no marked weight loss or illness. Taken together, these results provide strong evidence that this novel SK inhibitor, which had not previously been known to interact with E2 signaling pathways, has therapeutic potential in treating ER-positive breast cancer via inhibition of both SK and ER signaling.

HER2 FISH ratio cut-points and pathologic complete response (pCR), residual tumor (RT), HER2 status, and survival prediction in HER2-positive breast cancer (BC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22033-e22033
Author(s):  
R. S. Mehta ◽  
D. Jackson ◽  
T. Schubbert ◽  
D. Hsiang
Keyword(s):  
Breast Cancer ◽  
Pathologic Complete Response ◽  
Endocrine Resistance ◽  
Disease Free Survival ◽  
Survival Prediction ◽  
Her2 Positive ◽  
Cut Point ◽  
Her2 Positive Breast Cancer ◽  
Er Positive ◽  
Positive Breast Cancer

e22033 Background: We demonstrated that pCR is correlated with increasing HER2-FISH ratio, while disease-free survival (DFS) with pCR and ER-positivity in HER2-positive breast cancer treated with trastuzumab (SABCS 2008). It is known that quantitative HER2-FISH ratio correlates with ER levels and HER2-positivity imparts a higher grade in ER-positive BC. Collectively, we hypothesized that combined ER (≥10) and a HER2 ratio cut-point may subdivide HER2-positive BC into pCR predictive subtypes.Methods: Of the 80 HER2-positive (IHC3+/FISH+) BC, quantitative HER2 FISH ratio (widely spread over 1–18.3) and ER correlation was noted (r=0.34, p=0.002). Moreover, HER2 ratio (>4) correlated with higher Ki-67 (r= 0.5, p=0.01) and grade (p trend=0.05) in ER-positive subtype, inferring a biologic cut-point. Results: Of patients with stage I-IV BC treated neoadjuvantly (92% trastuzumab-based), pCR was 0% (0/13) in ER-positive-low-HER2 compared to 77% (10/13, p=0.0001), 75% (24/32, p<0.0001) and 37.5% (3/8, p=0.043) in ER-positive-high-HER2, ER-negative-high-HER2 and ER-negative-low-HER2, respectively. DFS was 100, 90, 80% and 60% (logrank-trend p<0.05) in these 4 subtypes (excluding stage IV), respectively, at a median follow-up of 38 months (range 6–72). In ER-negative subtypes, DFS was 97% and 29% (logrank p=0.0001) in patients with or without pCR; of the six with RT, 0% DFS was noted in four with HER2-negative/HER2-reduced (HER2-R) RT, compared to 100% in the two with unchanged HER2 (p=<0.05, logrank test). In ER-positive subtypes, DFS is 95% overall, and 100% in patients with RT; 7 of 10 tested RT were HER2- R. Conclusions: pCR is crucial and high in ER-negative-high-HER2 and is crucial (but low) in ER-negative-low-HER2-positive BC for improved outcome. Improved DFS is associated with high pCR in ER-positive-high-HER2 BC, but is independent of the low pCR in ER-positive-low-HER2-subtype. Thus, combined HER2 and ER offer improved prediction. In hypothesis generating analysis, HER2-R may underlie relapse in ER-negative subtypes (HER2-basal-transitional-residual), while it may be beneficial in ER-positive subtypes (luminal-B- A-transitional) by reducing HER2-pathway mediated endocrine resistance. [Table: see text]

scholarly journals TIMELESS regulates sphingolipid metabolism and tumor cell growth through Sp1/ACER2/S1P axis in ER-positive breast cancer

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Shan Zhang ◽  
Peiqi Huang ◽  
Huijuan Dai ◽  
Qing Li ◽  
Lipeng Hu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Growth ◽  
Cancer Patients ◽  
Mitochondrial Respiration ◽  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Sphingolipid Metabolism ◽  
Breast Cancer Patients ◽  
Er Positive ◽  
Positive Breast Cancer

Abstract Breast cancer is one of the most common female malignant cancers. Biorhythm disorder largely increases the risk of breast cancer. We aimed to investigate the biological functions and molecular mechanisms of circadian gene TIMELESS circadian regulator (TIM) in estrogen receptor (ER)-positive breast cancer and provide a new therapeutic target for breast cancer patients. Here, we explored that the expression of TIM was elevated in breast cancer, and high expression of TIM in cancer tissues was associated with poor prognosis, especially in the ER-positive breast cancer patients. In addition, we found that TIM promoted cell proliferation and enhanced mitochondrial respiration. TIM interacted with specificity protein 1 (Sp1) which contributes to upregulate the expression of alkaline ceramidase 2 (ACER2). Moreover, ACER2 is responsible for TIM-mediated promotive effects of cell growth and mitochondrial respiration. Collectively, our research unveiled a novel function of TIM in sphingolipid metabolism through interaction with Sp1. It provides a new theoretical explanation for the pathogenesis of breast cancer, and targeting TIM may serve as a potential therapeutic target for ER-positive breast cancer.

scholarly journals ER-positive breast cancer cells are poised for RET-mediated endocrine resistance

PLoS ONE ◽  
2018 ◽  
Vol 13 (4) ◽  
pp. e0194023 ◽  
Author(s):  
Sachi Horibata ◽  
Edward J. Rice ◽  
Chinatsu Mukai ◽  
Brooke A. Marks ◽  
Kelly Sams ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Endocrine Resistance ◽  
Er Positive ◽  
Positive Breast Cancer

Open label, phase II trial of neoadjuvant TAK-228 plus tamoxifen in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor type 2 (HER2)-negative breast cancer-ANETT.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 584-584
Author(s):  
Emre Koca ◽  
Polly Ann Niravath ◽  
Joe Ensor ◽  
Tejal Amar Patel ◽  
Xiaoxian Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Phase Ii Trial ◽  
Endocrine Resistance ◽  
Newly Diagnosed ◽  
Open Label ◽  
Hormone Receptor Positive ◽  
Open Label Phase ◽  
Er Positive ◽  
Positive Breast Cancer

584 Background: Neoadjuvant endocrine therapy is standard care for women with hormone receptor-positive breast cancer. However, both primary and acquired endocrine resistance is not uncommon, thereby limiting efficacy. [1] The PI3K-Akt-mTOR pathway is a major mediator of endocrine resistance. [2,3] Therefore, we determined the efficacy and safety of the mTORC1/2 inhibitor TAK-228 in combination with tamoxifen in neoadjuvant setting. Methods: In this single-arm, open-label phase II trial, newly diagnosed patients with stage I−III ER-positive, HER2-negative breast cancer received TAK-228 (30 mg weekly) and tamoxifen (20 mg daily) for 16 weeks until 2-4 weeks prior to surgery. The primary endpoint was the change in Ki67 after 6 weeks. Secondary endpoints included pathological complete response rate (pCR), preoperative endocrine prognostic index (PEPI) score, and safety. Results: Of the 28 patients enrolled in the study, 3 were excluded due to non-compliance. Mean patient age was 51.7 years. Most patients had stage I or II disease (12 [43%] each); 4 (14%) had stage III disease. Mean Ki67 was significantly lowered from baseline to Week 6 (17.2% vs. 15.2%, p = 0.0023). Interestingly, mean Ki67 increased to 20.1% from baseline to the time of surgery. This may have been due to a rebound effect, as TAK-228 was discontinued 2-4 weeks prior to surgery. Tumor size also significantly decreased from baseline to surgery, with a median decrease of 0.75 centimeters (p < 0.0001). PEPI score was intermediate risk (score 1−3) in 6 patients and high risk group (score ≥4) in 15 patients. No patients achieved a PEPI score of 0 and no pCR was achieved. Overall, the combination was well tolerated, the most common side effects were nausea (72%), vomiting (72%), fatigue (72%), mucositis (45%), and headache (45%). The any Grade 3 AE rate was 7.7%. Conclusions: The TAK-228 and tamoxifen combination was found to be an effective neoadjuvant strategy with a favorable safety profile in newly diagnosed patients with hormone receptor-positive breast cancer. Further molecular analysis (PI3K-Akt-mTOR pathway) are pending and will be presented. Clinical trial information: NCT02988986.

scholarly journals Targeted Therapies Overcoming Endocrine Resistance in Hormone Receptor-Positive Breast Cancer

Breast Care ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. 168-172 ◽  
Author(s):  
Katrin Almstedt ◽  
Marcus Schmidt
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Hormone Receptor ◽  
Endocrine Resistance ◽  
Endocrine Treatment ◽  
Breast Cancer Patients ◽  
Hormone Receptor Positive ◽  
Study Results ◽  
Er Positive ◽  
Positive Breast Cancer

Breast cancer is a heterogeneous disease with different molecular subtypes. Most tumours are hormone receptor positive (luminal subtype) with potential endocrine responsiveness. Endocrine therapy is commonly used in these patients. Disease progression caused by endocrine resistance represents a significant challenge in the treatment of breast cancer. To understand the mechanisms of resistance of long-term oestrogen-deprived breast cancer cells, it is important to focus on cross-talk between steroid receptor signalling and other growth factor receptors and intracellular pathways. (Pre-)clinical trials showed that co-targeting these pathways can restore endocrine sensitivity. The focus of the current review is on the intracellular PI3K/AKT/mTOR signalling pathway and cyclin-dependant kinases (CDKs) in oestrogen receptor (ER)-positive breast cancer. Study results clearly show that both inhibition of the PI3K/AKT/mTOR pathway and CDK4/6 are promising ways to improve the efficacy of endocrine treatment in ER-positive breast cancer patients with comparably few side effects. Further clinical trials are needed to identify the patient population who would benefit most from a dual inhibition.

scholarly journals ER and PI3K Independently Modulate Endocrine Resistance in ER-Positive Breast Cancer: Figure 1.

2011 ◽  
Vol 1 (4) ◽  
pp. 287-288 ◽  
Author(s):  
Brian A. Van Tine ◽  
Robert J. Crowder ◽  
Matthew J. Ellis
Keyword(s):  
Breast Cancer ◽  
Endocrine Resistance ◽  
Er Positive ◽  
Positive Breast Cancer
Sign in / Sign up

Export Citation Format

Share Document