Publications by authors named "Kaping Lee"

14 Publications

  • Page 1 of 1

A Cholesterol Homeostasis-Related Gene Signature Predicts Prognosis of Endometrial Cancer and Correlates With Immune Infiltration.

Front Genet 2021 1;12:763537. Epub 2021 Nov 1.

Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Endometrial cancer (EC) is one of the most common gynecological malignancies in women. Cholesterol metabolism has been confirmed to be closely related to tumor proliferation, invasion and metastasis. However, the correlation between cholesterol homeostasis-related genes and prognosis of EC remains unclear. EC patients from the Cancer Genome Atlas (TCGA) database were randomly divided into training cohort and test cohort. Transcriptome analysis, univariate survival analysis and LASSO Cox regression analysis were adopted to construct a cholesterol homeostasis-related gene signature from the training cohort. Subsequently, Kaplan-Meier (KM) plot, receiver operating characteristic (ROC) curve and principal component analysis (PCA) were utilized to verify the predictive performance of the gene signature in two cohorts. Additionally, enrichment analysis and immune infiltration analysis were performed on differentially expressed genes (DEGs) between two risk groups. Seven cholesterol homeostasis-related genes were selected to establish a gene signature. KM plot, ROC curve and PCA in two cohorts demonstrated that the gene signature was an efficient independent prognostic indicator. The enrichment analysis and immune infiltration analysis indicated that the high-risk group generally had lower immune infiltrating cells and immune function. We constructed and validated a cholesterol homeostasis-related gene signature to predict the prognosis of EC, which correlated to immune infiltration and expected to help the diagnosis and precision treatment of EC.
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http://dx.doi.org/10.3389/fgene.2021.763537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8591263PMC
November 2021

Miller-Payne Grading and 70-Gene Signature Are Associated With Prognosis of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Early-Stage Breast Cancer After Neoadjuvant Chemotherapy.

Front Oncol 2021 24;11:735670. Epub 2021 Sep 24.

Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Introduction: HR+/HER2- breast cancer (BC) has a much lower pathological complete response (pCR) rate to neoadjuvant chemotherapy (NAC). Therefore, to better stratify the relapse risk for HR+/HER2- non-pCR populations, it is essential to accurate identification new prognostic markers.

Materials And Methods: The study retrospectively analyzed 105 stage II-III patients who were diagnosed with HR+/HER2- BC and received NAC followed by breast and axilla surgery between 2013 and 2019 in Sun Yat-Sen University Cancer Center. The Miller-Payne (MP) grading system was used to evaluate pathological responses to NAC. The 70-gene signature was used to classify the prognosis signatures.

Results: Among the 105 patients, the study demonstrated that larger tumor size and lower progesterone receptor level at baseline and larger tumor size postoperative were statistically significantly associated with worse disease-free survival (DFS) ( = 0.004, = 0.021, and = 0.001, respectively). Among 54 patients who underwent the 70-gene assays, 26 (48.1%) had a low-risk signature; 28 (51.9%) patients had a high-risk signature. Patients with poor response (MP grades 1-2) were more likely to with a high-risk 70-gene signature than those with good response (MP grades 4-5). The final analysis showed that DFS was longer in the low-risk group than in the high-risk group [52.4 vs. 36.1 months of the median DFS, hazard ratio (HR) for recurrence, 0.29; 95% confidence interval (CI), 0.10-0.80; = 0.018]. DFS was longer in the good response (MP grades 3-4) group than in the poor response (MP grades 1-2) group (94.7% vs. 60% of the patients free from recurrence; HR, 0.16; 95% CI, 0.05-0.47; = 0.037). When stratified by MP grades combined with the 70-gene signature, subgroup analyses showed the good-response low-risk group with the best DFS, whereas the poor-response high-risk group showed the worst DFS ( = 0.048). Due to the short median follow-up time of 34.5 months (5.9-75.1 months), MP grades and the 70-gene signature did not show significant prognostic value for overall survival.

Conclusion: The study showed that analysis of MP grades combined with the 70-gene signature with residual NAC-resistant breast samples has a significant correlation with DFS.
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http://dx.doi.org/10.3389/fonc.2021.735670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498026PMC
September 2021

Clinical genomic profiling to identify actionable alterations for very early relapsed triple-negative breast cancer patients in the Chinese population.

Ann Med 2021 12;53(1):1358-1369

Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China.

Background: Triple-negative breast cancer (TNBC) represents about 19% of all breast cancer cases in the Chinese population. Lack of targeted therapy contributes to the poorer outcomes compared with other breast cancer subtypes. Comprehensive genomic profiling helps to explore the clinically relevant genomic alterations (CRGAs) and potential therapeutic targets in very-early-relapsed TNBC patients.

Methods: Formalin-fixed paraffin-embedded (FFPE) tumour tissue specimens from 23 patients with very-early-relapsed TNBC and 13 patients with disease-free survival (DFS) more than 36 months were tested by FoundationOne CDx (F1CDx) in 324 genes and select gene rearrangements, along with genomic signatures including microsatellite instability (MSI) and tumour mutational burden (TMB).

Results: In total, 137 CRGAs were detected in the 23 very-early-relapsed TNBC patients, averaging six alterations per sample. The mean TMB was 4 Muts/Mb, which was higher than that in non-recurrence patients, and is statistically significant. The top-ranked altered genes were TP53 (83%), PTEN (35%), RB1 (30%), PIK3CA (26%) and BRCA1 (22%). RB1 mutation carriers had shorter DFS. Notably, 100% of these patients had at least one CRGA, and 87% of patients had at least one actionable alteration. In pathway analysis, patients who carried a mutation in the cell cycle pathway were more likely to experience very early recurrence. Strikingly, we detected one patient with ERBB2 amplification and one patient with ERBB2 exon20 insertion, both of which were missed by immunohistochemistry (IHC). We also detected novel alterations of ROS1-EPHA7 fusion for the first time, which has not been reported in breast cancer before.

Conclusions: The comprehensive genomic profiling can identify novel treatment targets and address the limited options in TNBC patients. Therefore, incorporating F1CDx into TNBC may shed light on novel therapeutic opportunities for these very-early-relapsed TNBC patients.
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http://dx.doi.org/10.1080/07853890.2021.1966086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381897PMC
December 2021

CPSF4 promotes triple negative breast cancer metastasis by upregulating MDM4.

Signal Transduct Target Ther 2021 05 19;6(1):184. Epub 2021 May 19.

Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

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http://dx.doi.org/10.1038/s41392-021-00565-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131696PMC
May 2021

Safety, tolerability, and pharmacokinetics of BAT8001 in patients with HER2-positive breast cancer: An open-label, dose-escalation, phase I study.

Cancer Commun (Lond) 2021 02 2;41(2):171-182. Epub 2021 Feb 2.

Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, P. R. China.

Background: The introductions of anti- human epidermal growth factor receptor-2 (HER2) agents have significantly improved the treatment outcome of patients with HER2-positive breast cancer. BAT8001 is a novel antibody-drug conjugate targeting human epidermal growth factor receptor-2 (HER2)-expressing cells composed of a trastuzumab biosimilar linked to the drug-linker Batansine. This dose-escalation, phase I study was designed to assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of BAT8001 in patients with HER2-positive locally advanced or metastatic breast cancer.

Methods: This trial was conducted in subjects with histologically confirmed HER2-positive breast cancer (having evaluable lesions and an Eastern Cooperative Oncology Group performance status of 0 or 1) using a 3 + 3 design of escalating BAT8001 doses. Patients received BAT8001 intravenously in a 21-day cycle, with dose escalation in 5 cohorts: 1.2, 2.4, 3.6, 4.8, and 6.0 mg/kg. The primary objective was to evaluate the safety and tolerability of BAT8001. Preliminary activity of BAT8001 was also assessed as a secondary objective.

Results: Between March 2017 to May 2018, 29 HER2-positive breast cancer patients were enrolled. The observed dose-limiting toxicities were grade 4 thrombocytopenia and grade 3 elevated transaminase. The maximum tolerated dose was determined to be 3.6 mg/kg. Grade 3 or greater adverse events (AEs) occurred in 14 (48.3%) of 29 patients, including thrombocytopenia in 12 (41.4%) patients, aspartate aminotransferase increased in 4 (13.8%) patients, γ-glutamyl transferase increased in 2 (6.9%) patients, alanine aminotransferase increased in 2 (6.9%) patients, diarrhea in 2 (6.9%) patients. Objective response was observed in 12 (41.4%; 95% confidence interval [CI] = 23.5%-61.1%) and disease control (including patients achieving objective response and stable disease) was observed in 24 (82.8%; 95% CI = 64.2%-94.2%) patients.

Conclusions: BAT8001 demonstrated favorable safety profiles, with promising anti-tumor activity in patients with HER2-positive locally advanced or metastatic breast cancer. BAT8001 has the potential to provide a new therapeutic option in patients with metastatic HER2-positive breast cancer.
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http://dx.doi.org/10.1002/cac2.12135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896747PMC
February 2021

Identification and characterization of critical genes associated with tamoxifen resistance in breast cancer.

PeerJ 2020 4;8:e10468. Epub 2020 Dec 4.

Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Background: Tamoxifen resistance in breast cancer is an unsolved problem in clinical practice. The aim of this study was to determine the potential mechanisms of tamoxifen resistance through bioinformatics analysis.

Methods: Gene expression profiles of tamoxifen-resistant MCF-7/TR and MCF-7 cells were acquired from the Gene Expression Omnibus dataset GSE26459, and differentially expressed genes (DEGs) were detected with R software. We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses using Database for Annotation, Visualization and Integrated Discovery. A protein-protein interaction (PPI) network was generated, and we analyzed hub genes in the network with the Search Tool for the Retrieval of Interacting Genes database. Finally, we used siRNAs to silence the target genes and conducted the MTS assay.

Results: We identified 865 DEGs, 399 of which were upregulated. GO analysis indicated that most genes are related to telomere organization, extracellular exosomes, and binding-related items for protein heterodimerization. PPI network construction revealed that the top 10 hub genes-, and -might be associated with tamoxifen resistance. Consistently, RT-qPCR analysis indicated that the expression of these 10 genes was increased in MCF-7/TR cells comparing with MCF-7 cells. Four hub genes ( and ) were related to overall survival in patients who accepted tamoxifen. In addition, knockdown of HSPH1 by siRNA may lead to reduced growth of MCF-7/TR cell with a trend close to significance ( = 0.07), indicating that upregulation of HSPH1 may play a role in tamoxifen resistance.

Conclusion: This study revealed a number of critical hub genes that might serve as therapeutic targets in breast cancer resistant to tamoxifen and provided potential directions for uncovering the mechanisms of tamoxifen resistance.
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http://dx.doi.org/10.7717/peerj.10468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720728PMC
December 2020

Axis Contributes to Tumor Progression and Malignant Phenotypes in Bladder Cancer.

Front Oncol 2020 7;10:568015. Epub 2020 Oct 7.

Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Abnormal expression or mutation of RNA splicing proteins are widely observed in human cancers. Here, we identified poly(U) binding splicing factor 60 () as one of the most differentially expressed genes out of 97 RNA splicing proteins between normal and bladder cancer tissues by bioinformatics analysis of TCGA bladder cancer expression data. The expression of was significantly higher in tumor tissues, while high expression was associated with malignant phenotypes of bladder cancer and shorter survival time. Moreover, we identified aurora kinase A () as a new downstream target of in bladder cancer cells. knockdown significantly inhibited cell viability and colony formation capacity in bladder cancer cells, whereas overexpression reversed this inhibition effect. Overexpression of significantly promoted cell viability and colony formation in bladder cancer cells, while treatment with specific inhibitor reversed this promotive effect. Mechanistically, specifically bound to the promoter, thereby activating its transcription and expression. Furthermore, we showed that there was a significant positive correlation between and expression in bladder cancer tissues, and and expression contributed to tumor progression and malignant phenotypes in the patients with bladder cancer. Collectively, these results indicate that the axis plays a key role in regulating tumorigenesis and progression of bladder cancer, and may be a potential prognostic biomarker and therapeutic target for bladder cancer patients.
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http://dx.doi.org/10.3389/fonc.2020.568015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576680PMC
October 2020

ClC-3/SGK1 regulatory axis enhances the olaparib-induced antitumor effect in human stomach adenocarcinoma.

Cell Death Dis 2020 10 22;11(10):898. Epub 2020 Oct 22.

Department of Clinical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.

Currently, only a few available targeted drugs are considered to be effective in stomach adenocarcinoma (STAD) treatment. The PARP inhibitor olaparib is a molecularly targeted drug that continues to be investigated in BRCA-mutated tumors. However, in tumors without BRCA gene mutations, particularly in STAD, the effect and molecular mechanism of olaparib are unclear, which largely restricts the use of olaparib in STAD treatment. In this study, the in vitro results showed that olaparib specifically inhibited cell growth and migration, exerting antitumor effect in STAD cell lines. In addition, a ClC-3/SGK1 regulatory axis was identified and validated in STAD cells. We then found that the down-regulation of ClC-3/SGK1 axis attenuated olaparib-induced cell growth and migration inhibition. On the contrary, the up-regulation of ClC-3/SGK1 axis enhanced olaparib-induced cell growth and migration inhibition, and the enhancement effect could be attenuated by SGK1 knockdown. Consistently, the whole-cell recorded chloride current activated by olaparib presented the same variation trend. Next, the clinical data showed that ClC-3 and SGK1 were highly expressed in human STAD tissues and positively correlated (r = 0.276, P = 0.009). Furthermore, high protein expression of both ClC-3 (P = 0.030) and SGK1 (P = 0.006) was associated with poor survival rate in STAD patients, and positive correlations between ClC-3/SGK1 and their downstream molecules in STAD tissues were demonstrated via the GEPIA datasets. Finally, our results suggested that olaparib inhibited the PI3K/AKT pathway in STAD cells, and up-regulation of ClC-3/SGK1 axis enhanced olaparib-induced PI3K/AKT pathway inhibition. The animal experiments indicated that olaparib also exerted antitumor effect in vivo. Altogether, our findings illustrate that olaparib exerts antitumor effect in human STAD, and ClC-3/SGK1 regulatory axis enhances the olaparib-induced antitumor effect. Up-regulation of the ClC-3/SGK1 axis may provide promising therapeutic potential for the clinical application of olaparib in STAD treatment.
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http://dx.doi.org/10.1038/s41419-020-03107-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583252PMC
October 2020

Metronomic chemotherapy of cyclophosphamide plus methotrexate for advanced breast cancer: Real-world data analyses and experience of one center.

Cancer Commun (Lond) 2020 05 11;40(5):222-233. Epub 2020 May 11.

Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China.

Background: Real-world data of the CM regimen [cyclophosphamide (CTX) plus methotrexate (MTX)] in metronomic pattern for advanced breast cancer is limited to small-sample or retrospective studies. This study was aimed to determine the effectiveness and safety of CM regimen in treating advanced breast cancer and to identify which patients are most likely to benefit from metronomic CM regimen.

Methods: Patients with advanced breast cancer who received the metronomic CM regimen at least once between January 2009 and February 2019 in Sun Yat-sen University Cancer Center were included. Clinicopathological characteristics were collected. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier estimates. Characteristics between patients with PFS < 6 months and ≥6 months were compared using the Chi-square test. Univariate and multivariate Cox regression model was used to estimate the prognostic factors for PFS and OS.

Results: A total of 186 patients were included. The median age and follow-up were 49 years and 13.3 months, respectively. Over 50% of the patients were estrogen receptor/progesterone receptor-positive, and 60.8% had been heavily treated (≥3 lines). The objective response rate was 3.8%, the disease control rate at 12 weeks was 41.4%, and the clinical benefit rate at 24 weeks was 31.2% (58/186). The median PFS was 4.0 months [95% confidence interval (CI): 3.6-4.7 months], the median duration of clinical benefit was 9.5 months (95% CI: 8.2-10.8 months), and the median OS was 26.8 months (95% CI: 20.9-37.7 months). Multivariate analysis for PFS revealed the CM regimen as maintenance therapy and no liver metastasis as favorable prognostic factors. Furthermore, patients without liver metastasis were more likely to have a PFS over 6 months than those with liver involvement (P = 0.022). Liver, lymph node, and brain metastases were unfavorable prognostic factors for OS. The CM regimen was well-tolerated without newly reported adverse events.

Conclusions: The CM regimen was effective in selected patients. In clinical practice, it would be better used as maintenance therapy and in patients without liver metastasis. Further follow-up investigation should be performed to examine its effect when used in combination with other treatments and determine predictive biomarkers.
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http://dx.doi.org/10.1002/cac2.12029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238669PMC
May 2020

Administration of Lapatinib with Food Increases Its Plasma Concentration in Chinese Patients with Metastatic Breast Cancer: A Prospective Phase II Study.

Oncologist 2020 09 14;25(9):e1286-e1291. Epub 2020 Feb 14.

Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.

Lessons Learned: Administration of lapatinib with food significantly increased its plasma concentration in Chinese patients with metastatic breast cancer. There were no serious adverse events during the study and no significant differences in lapatinib-related adverse events between the fasted and fed states.

Background: Lapatinib, a small molecular reversible dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth receptor 2 (HER2), was approved for use in combination with capecitabine to treat metastatic HER2-positive breast cancer. Administration of lapatinib in the fasted state was recommended; however, our preliminary phase II trial data showed that administration of lapatinib with food increased its concentration.

Methods: This study was a single-center, open-label, and prospective self-controlled clinical study. Ten Chinese patients with metastatic breast cancer were enrolled from June 2017 to April 2018. They were required to receive lapatinib plus physician's choice of chemotherapy. Patients were required to take lapatinib orally on an empty stomach continually for 10 days, and then take lapatinib with food continually for the next 10 days. Plasma concentration was measured by liquid chromatography on the 9th and 10th day of each state.

Results: Area under the concentration-time curve (AUC) of the fasted state and the fed state was 21.23 ± 8.91 mg*h/L (coefficient of variation (CV)% 42%) and 60.60 ± 16.64 mg*h/L (CV% 27%), respectively. The mean plasma concentration in the fasted state was 0.88 ± 0.39 mg/L (CV% 45%), and that in the fed state was 2.53 ± 0.77 mg/L (CV% 30%). Compared with taking lapatinib on an empty stomach, receiving lapatinib with food significantly increased the plasma concentration of lapatinib (Wilcoxon match-paired test, p = .005). In addition, there were no serious adverse events during the study or significant difference in lapatinib-related adverse events between the two states.

Conclusion: Our study shows that receiving lapatinib with food can increase its plasma concentration with no significantly increased drug-related toxicity. We suggest that a larger-sample-size clinical trial is needed to fully understand the effect of administration of lapatinib with food.
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http://dx.doi.org/10.1634/theoncologist.2020-0044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485350PMC
September 2020

Bicalutamide plus Aromatase Inhibitor in Patients with Estrogen Receptor-Positive/Androgen Receptor-Positive Advanced Breast Cancer.

Oncologist 2020 01 21;25(1):21-e15. Epub 2019 Aug 21.

Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China.

Lessons Learned: Studies targeting the androgen receptor (AR) signaling pathway in aromatase inhibitor (AI)-resistant breast cancer are limited. Bicalutamide, one of the commonly used AR inhibitors in prostate cancer, in combination with AI, did not show synergistic activity in patients with estrogen receptor-positive and AI-resistant disease in this phase II, single-arm study. The clinical benefit rate and objective response rate at 6 months were 16.7% and 0%, respectively, and the study was terminated after the first stage.

Background: Endocrine resistance is a major problem in clinical practice. Studies have shown that androgen receptor (AR) signaling activation may be one of the mechanisms, and targeting AR showed some promising results in AR-positive triple-negative breast cancer. The aim of this study was to assess the efficacy and safety of bicalutamide plus another aromatase inhibitor in patients with nonsteroidal aromatase inhibitor (AI) or steroidal AI resistance and estrogen receptor (ER)-positive and AR-positive advanced breast cancer.

Methods: A Simon's two-stage, phase II, single-arm study was conducted. We assumed the clinical benefit rate (CBR) of 40% would be significant in clinical practice. In this case, if ≥4 patients of the 19 patients in the first stage benefited from treatment, the CBR would achieve the assumed endpoint. If fewer than four patients benefited from treatment in the first stage, the trial would be terminated. All patients received bicalutamide 50 mg per day orally plus another aromatase inhibitor. The primary outcome was CBR; secondary outcomes included objective response rate (ORR), progression-free survival (PFS), and tolerability.

Results: A total of 19 patients enrolled in the first stage, and 18 patients met all criteria for analysis. The trial terminated according to protocol after the first stage. After a median follow-up of 14 months, the CBR at 6 months was 16.7% (3/18); no patients with partial or complete response were observed. The median PFS was 2.7 months. Bicalutamide in combination with AI was well tolerated.

Conclusion: Bicalutamide in combination with another AI did not show synergistic activity in patients with ER-positive breast cancer and AI resistance. Results suggest that no more large-sample clinical trials should be conducted in this population for overcoming endocrine resistance.
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http://dx.doi.org/10.1634/theoncologist.2019-0564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964139PMC
January 2020

Panobinostat (LBH589) inhibits Wnt/β-catenin signaling pathway via upregulating APCL expression in breast cancer.

Cell Signal 2019 07 14;59:62-75. Epub 2019 Mar 14.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. Electronic address:

Breast cancer is the most common malignant disease among women worldwide and the novel therapeutic agents are urgently needed. Panobinostat (LBH589), a pan-HDACs inhibitor, has shown promising anti-tumor effect in recent years. However, the targets of this compound are largely unclear because of its low selectivity. In consideration of the transcription promoting activity of panobinostat, we speculated that specific tumor suppressor genes might be upregulated after panobinostat treatment. In this study, we verified the inhibition effect of panobinostat in different subtypes of breast cancer cells in vivo and in vitro. We found that panobinostat suppressed proliferation, migration as well as invasion, and induced apoptosis in both TNBC and non-TNBC cells. Consistently, panobinostat inhibited breast cancer growth and metastasis in mouse models. Mechanistically, we found APCL transcription and expression was significantly upregulated in panobinostat treated cells by RNA microarray analysis, while knockdown of APCL resulted in reduced sensitivity to panobinostat in breast cancer cells. APCL is a wnt/β-catenin pathway regulator that promotes β-catenin ubiquitylation and degradation. We found that panobinostat inhibited β-catenin expression by increasing its ubiquitylation and thus reducing its half-life. In addition, the expression of β-catenin activated targets including c-Jun, c-Myc, Cyclin D1 and CD44 were also decreased by panobinostat treatment in breast cancer cells. These results suggested that panobinostat inhibited tumor growth and metastasis via upregulating APCL expression in breast cancer cells, which was a novel and crucial mechanism of panobinostat.
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http://dx.doi.org/10.1016/j.cellsig.2019.03.014DOI Listing
July 2019

CDK4/6 inhibitor palbociclib enhances the effect of pyrotinib in HER2-positive breast cancer.

Cancer Lett 2019 04 21;447:130-140. Epub 2019 Jan 21.

Sun Yat-Sen University Cancer Center, The State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, PR China. Electronic address:

Human epidermal growth factor receptor 2 (HER2) is amplified in about 20% breast cancers. Treat of HER2 positive breast cancers has been greatly promoted in last few years, but the accompany HER2 blockade has hindered the therapeutic effect. Pyrotinib is a pan-HER kinase inhibitor that suppresses signaling through the RAS/RAF/MEK/MAPK and PI3K/AKT pathways. Palbociclib is a CDK4/6 inhibitor that inhibits cell cycle progression and cancer cell proliferation in ER+ breast cancers. We hypothesized that the combination of pan-HER kinase inhibitors and CDK4/6 inhibitors would show synergistic antitumor activity in vivo in vitro. Our data show that a combination of palbociclib and pyrotinib was highly synergistic in inhibiting cancer proliferation and colony formation. The combined treatment also induced significant decreases in pAKT and pHER3 activation, induced G0-G1 cell cycle arrest, and increased rates of apoptosis. In the xenograft model, the combination treatment demonstrated greater antitumor activity than either agent alone, with no apparent increase in toxicity. Our results offer a preclinical rationale clinical investigation of the effectiveness of a combination treatment of palbociclib with pyrotinib for breast cancer treatment.
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http://dx.doi.org/10.1016/j.canlet.2019.01.005DOI Listing
April 2019

Clinical value of circulating mutations for patients with metastatic breast cancer: a meta-analysis.

Cancer Manag Res 2018 14;10:2573-2580. Epub 2018 Aug 14.

Sun Yat-Sen University Cancer Center, The State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People's Republic of China,

Background: The clinical implication of plasma ESR1 mutations in the estrogen receptor (ER)-positive metastatic breast cancer (MBC) patients who had progressed after prior aromatase inhibitor (AI)-based therapy remains controversial. We conducted the first meta-analysis to investigate the prognostic significance and predictive role of plasma ESR1 mutations in MBC patients with prior exposure to AI therapy.

Materials And Methods: We searched PubMed, Embase, and Cochrane Library databases for eligible studies. Meta-analysis was conducted to calculate combined hazard ratios (HRs) with 95% CIs for progression-free survival (PFS) and overall survival (OS). Subgroup and sensitivity analyses were also performed.

Results: This study enrolled a total of 1,530 patients with ER-positive MBC cases from six articles, including 429 ESR1 mutation carriers (28.04%). Meta-analysis demonstrated that plasma ESR1 mutation carriers had significantly worse PFS (HR: 1.40, 95% CI: 1.17-1.66; <0.0001) and OS (HR: 1.65, 95% CI: 1.36-2.01; <0.0001) compared to wild-type ESR1. Subgroup analysis showed that plasma ESR1 mutations were associated with shorter PFS after AI-based treatment, but were not significantly predictive of outcome on fulvestrant-containing therapy (HR: 1.26, 95% CI: 0.98-1.62; =0.077). As for different ESR1 mutations, D538G mutation implied significantly worse PFS (HR: 1.50, 95% CI: 1.18-1.91; =0.01), while Y537S mutation was not correlated with PFS (HR: 1.65, 95% CI: 0.87-1.73; =0.134).

Conclusion: The meta-analysis indicated that plasma ESR1 mutation assessment may have prognostic significance and clinical value in guiding further endocrine therapy choice in ER+ MBC patients who received prior AI therapy.
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http://dx.doi.org/10.2147/CMAR.S173193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097501PMC
August 2018
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