Qing Cheng

Overview:

My research has been focusing on the development of methodologies and strategies to address the general question of human cancer heterogeneity and complexity, recognizing that clinical outcomes reflect a combination of contribution from the actual tumor but also the environment in which the tumor resides. By understanding who is at risk for recurrence, who is likely to respond to a given agent or regimen, and who is likely to exhibit an adverse event associated with a particular therapy, it will be possible to tailor therapeutic strategies to the characteristics of the individual patient as opposed to relying on the results of studies with heterogeneous populations of patients.

I made the original observation that gene copy number alterations (CNAs) in malignant cells can quantitatively affect gene function (Nat Genet 2005), and the contribution of this work to the field of cancer pharmacogenomics and personalized medicine was highly recognized by a "NEWS AND VIEWS" paper of Nature Genetics, in 2005. I demonstrated that clinical phenotypes can be affected by multiple forms of alterations (methylation, mutation, CNA) (Am J Hum Genet 2006), and genome-scan of CNAs followed by pathway analysis could uncover the novel gene interactions (Nat Med 2011). We developed a methodology that compiled a large collection of genomic data (Breast Cancer Res 2012) and demonstrated that uniquely characteristic of a clinical phenotype, such as dormancy, could be accessed using gene signature, a collection of multiple genetic alterations (Breast Cancer Res 2014).

Positions:

Associate Professor in Surgery

Surgery, Surgical Sciences
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2001

National University of Singapore (Singapore)

Postdoctoral Research Associate

St. Jude Children's Research Hospital

Grants:

Publications:

Multiplex immunohistochemistry/immunofluorescence (mIHC/IF) for PD-L1 testing in triple-negative breast cancer: a translational assay compared with conventional IHC.

BACKGROUND: Programmed death-ligand 1 (PD-L1) monoclonal antibody therapy has recently gained approval for treating metastatic triple-negative breast cancer (TNBC) -, in particular in the PD-L1+ patient subgroup of the recent IMpassion130 trial. The SP142 PD-L1 antibody clone was used as a predictive assay in this trial, but this clone was found to be an outlier in previous harmonisation studies in lung cancer. AIMS: To address the comparability of PD-L1 clones in TNBC, we evaluated the concordance between conventional immunohistochemistry (IHC) and multiplex immunohistochemistry/immunofluorescence (mIHC/IF) that allowed simultaneous quantification of three different PD-L1 antibodies (22C3, SP142 and SP263). METHODS: Our cohort comprised 25 TNBC cases, 12 non-small-cell lung carcinomas and 8 other cancers. EpCAM labelling was used to distinguish tumour cells from immune cells. RESULTS: Moderate-to-strong correlations in PD-L1 positivity were found between results obtained through mIHC/IF and IHC. Individual concordance rates in the study ranged from 67% to 100%, with Spearman's rank correlation coefficient values up to 0.88. CONCLUSIONS: mIHC/IF represents a promising tool in the era of cancer immunotherapy, as it can simultaneously detect and quantify PD-L1 labelling with multiple antibody clones, and allow accurate evaluation of tumour and immune cells. Clinicians and pathologists require this information to predict patient response to anti-PD-1/PD-L1 therapy. The adoption of this assay may represent a significant advance in the management of therapeutically challenging cancers. Further analysis and assay harmonisation are essential for translation to a routine diagnostic setting.
Authors
Yeong, J; Tan, T; Chow, ZL; Cheng, Q; Lee, B; Seet, A; Lim, JX; Lim, JCT; Ong, CCH; Thike, AA; Saraf, S; Tan, BYC; Poh, YC; Yee, S; Liu, J; Lim, E; Iqbal, J; Dent, R; Tan, PH
MLA Citation
Yeong, Joe, et al. “Multiplex immunohistochemistry/immunofluorescence (mIHC/IF) for PD-L1 testing in triple-negative breast cancer: a translational assay compared with conventional IHC.J Clin Pathol, vol. 73, no. 9, Sept. 2020, pp. 557–62. Pubmed, doi:10.1136/jclinpath-2019-206252.
URI
https://scholars.duke.edu/individual/pub1428122
PMID
31969377
Source
pubmed
Published In
J Clin Pathol
Volume
73
Published Date
Start Page
557
End Page
562
DOI
10.1136/jclinpath-2019-206252

ROS1-fusion protein induces PD-L1 expression via MEK-ERK activation in non-small cell lung cancer

© 2020, © 2020 The Author(s). Published with license by Taylor & Francis Group, LLC. © 2020, © 2020 Zheng Liu, Kejia Zhao, Shiyou Wei, Chengwu Liu, Jiankang Zhou, Qiheng Gou, Xia Wu, Zhenyu Yang, Yanbo Yang, Yong Peng, Qing Cheng and Lunxu Liu. Introduction: Despite some of the oncogenic driver mutations that have been associated with increased expression of programmed death-ligand 1 (PD-L1), the correlation between PD-L1 expression and ROS1 fusion in NSCLC cells, especially for those with Crizotinib resistance has not been fully addressed. Materials and Methods: The expression of PD-L1 in 30 primary NSCLC tumors with/without ROS1-fusion protein was evaluated by immunohistochemical (IHC) analysis. To assess the correlation between ROS1 fusion and PD-L1 expression, we down-regulated ROS1 with RNA interference or specific inhibitor (Crizotinib) in ROS1-fusion positive NSCLC cell line HCC78; or up-regulate ROS1-fusion gene in an immortalized human bronchial epithelial cell line (HBE). Mouse xenograft models were also used to determine the effect of ROS1 expression on PD-L1 expression in vivo. Crizotinib-resistant cell line was generated for measuring the association between Crizotinib resistance and PD-L1 expression. Results: ROS1-rearrangement in primary NSCLC tumor was significantly associated with up-regulated PD-L1 expression. PD-L1 expression was significantly up-regulated in bronchial epithelial cells after forced expression of ROS1 fusion and was eliminated when HCC78 xenograft mouse models were treated with Crizotinib. We found PD-L1 expression was modulated by MEK-ERK pathway signaling in both parental and Crizotinib-resistant NSCLC cells with ROS1 fusion. Conclusions: The correlation between ROS1-fusion and PD-L1 overexpression suggested that PD-L1/PD-1 blockade could be the second-line treatment option for the Crizotinib-resistant NSCLC with ROS1 rearrangement.
Authors
Liu, Z; Zhao, K; Wei, S; Liu, C; Zhou, J; Gou, Q; Wu, X; Yang, Z; Yang, Y; Peng, Y; Cheng, Q; Liu, L
MLA Citation
Liu, Z., et al. “ROS1-fusion protein induces PD-L1 expression via MEK-ERK activation in non-small cell lung cancer.” Oncoimmunology, vol. 9, no. 1, Jan. 2020. Scopus, doi:10.1080/2162402X.2020.1758003.
URI
https://scholars.duke.edu/individual/pub1441297
Source
scopus
Published In
Oncoimmunology
Volume
9
Published Date
DOI
10.1080/2162402X.2020.1758003

An age-independent gene signature for monitoring acute rejection in kidney transplantation.

Acute rejection (AR) remains a significant problem that negatively impacts long-term renal allograft survival. Numerous therapies are used to prevent AR that differ by center and recipient age. This variability confounds diagnostic methods. Methods: To develop an age-independent gene signature for AR effective across a broad array of immunosuppressive regimens, we compiled kidney transplant biopsy (n=1091) and peripheral blood (n=392) gene expression profiles from 12 independent public datasets. After removing genes differentially expressed in pediatric and adult patients, we compared gene expression profiles from biopsy and peripheral blood samples of patients with AR to those who were stable (STA), using Mann-Whitney U Tests with validation in independent testing datasets. We confirmed this signature in pediatric and adult patients (42 AR and 47 STA) from our institutional biorepository. Results: We identified a novel age-independent gene network that identified AR from both kidney and blood samples. We developed a 90-probe set signature targeting 76 genes that differentiated AR from STA and found an 8 gene subset (DIP2C, ENOSF1, FBXO21, KCTD6, PDXDC1, REXO2, HLA-E, and RAB31) that was associated with AR. Conclusion: We used publicly available datasets to create a gene signature of AR that identified AR irrespective of immunosuppression regimen or recipient age. This study highlights a novel model to screen and validate biomarkers across multiple treatment regimens.
Authors
Shaw, BI; Cheng, DK; Acharya, CR; Ettenger, RB; Lyerly, HK; Cheng, Q; Kirk, AD; Chambers, ET
MLA Citation
Shaw, Brian I., et al. “An age-independent gene signature for monitoring acute rejection in kidney transplantation.Theranostics, vol. 10, no. 15, 2020, pp. 6977–86. Pubmed, doi:10.7150/thno.42110.
URI
https://scholars.duke.edu/individual/pub1447710
PMID
32550916
Source
pubmed
Published In
Theranostics
Volume
10
Published Date
Start Page
6977
End Page
6986
DOI
10.7150/thno.42110

Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer.

Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR+ luminal tumor cells and AR- neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR+ luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity.
Authors
Li, Y; He, Y; Butler, W; Xu, L; Chang, Y; Lei, K; Zhang, H; Zhou, Y; Gao, AC; Zhang, Q; Taylor, DG; Cheng, D; Farber-Katz, S; Karam, R; Landrith, T; Li, B; Wu, S; Hsuan, V; Yang, Q; Hu, H; Chen, X; Flowers, M; McCall, SJ; Lee, JK; Smith, BA; Park, JW; Goldstein, AS; Witte, ON; Wang, Q; Rettig, MB; Armstrong, AJ; Cheng, Q; Huang, J
MLA Citation
Li, Yanjing, et al. “Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer.Sci Transl Med, vol. 11, no. 521, Dec. 2019. Pubmed, doi:10.1126/scitranslmed.aax0428.
URI
https://scholars.duke.edu/individual/pub1423084
PMID
31801883
Source
pubmed
Published In
Sci Transl Med
Volume
11
Published Date
DOI
10.1126/scitranslmed.aax0428

Folate pathway gene expression differs in subtypes of acute lymphoblastic leukemia and influences methotrexate pharmacodynamics

The ability of leukemia cells to accumulate methotrexate polyglutamate (MTXPG) is an important determinant of the antileukemic effects of methotrexate (MTX). We measured in vivo MTXPG accumulation in leukemia cells from 101 children with acute lymphoblastic leukemia (ALL) and established that B-lineage ALL with either TEL-AML1 or E2A-PBX1 gene fusion, or T-lineage ALL, accumulates significantly lower MTXPG compared with B-lineage ALL without these genetic abnormalities or compared with hyperdiploid (fewer than 50 chromosomes) ALL. To elucidate mechanisms underlying these differences in MTXPG accumulation, we used oligonucleotide microarrays to analyze expression of 32 folate pathway genes in diagnostic leukemia cells from 197 children. This revealed ALL subtype-specific patterns of folate pathway gene expression that were significantly related to MTXPG accumulation. We found significantly lower expression of the reduced folate carrier (SLC19A1, an MTX uptake transporter) in E2A-PBX1 ALL, significantly higher expression of breast cancer resistance protein (ABCG2, an MTX efflux transporter) in TEL-AML1 ALL, and lower expression of FPGS (which catalyzes formation of MTXPG) in T-lineage ALL, consistent with lower MTXPG accumulation in these ALL subtypes. These findings reveal distinct mechanisms of subtype-specific differences in MTXPG accumulation and point to new strategies to overcome these potential causes of treatment failure in childhood ALL.
Authors
Kager, L; Cheok, M; Yang, W; Zaza, G; Cheng, Q; Panetta, JC; Pui, CH; Downing, JR; Relling, MV; Evans, WE
MLA Citation
Kager, L., et al. “Folate pathway gene expression differs in subtypes of acute lymphoblastic leukemia and influences methotrexate pharmacodynamics.” Journal of Clinical Investigation, vol. 115, no. 1, 2005, pp. 110–17. Scival, doi:10.1172/JCI200522477.
URI
https://scholars.duke.edu/individual/pub765075
Source
scival
Published In
Journal of Clinical Investigation
Volume
115
Published Date
Start Page
110
End Page
117
DOI
10.1172/JCI200522477