Gao Zhang

Positions:

Assistant Professor in Neurosurgery

Neurosurgery
School of Medicine

Assistant Professor in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2012

University of Pennsylvania

Post Doctoral Fellow

The Wistar Institute

Staff Scientist

The Wistar Institute

Grants:

ATRX Mutations in Determining Immunity Against Glioma

Administered By
Neurosurgery, Neuro-Oncology
Awarded By
Brain Tumor Research Charity
Role
Investigator
Start Date
End Date

6-Thio-Deoxyguanosine: A novel telomerase-mediated therapy for oligodendroglioma linking cell-intrinsic DNA damage to immune activation

Administered By
Neurosurgery
Awarded By
Oligo Nation
Role
Co-Principal Investigator
Start Date
End Date

Publications:

Neural Crest-Like Stem Cell Transcriptome Analysis Identifies LPAR1 in Melanoma Progression and Therapy Resistance.

Metastatic melanoma is challenging to clinically address. Although standard-of-care targeted therapy has high response rates in patients with BRAF-mutant melanoma, therapy relapse occurs in most cases. Intrinsically resistant melanoma cells drive therapy resistance and display molecular and biologic properties akin to neural crest-like stem cells (NCLSC) including high invasiveness, plasticity, and self-renewal capacity. The shared transcriptional programs and vulnerabilities between NCLSCs and cancer cells remains poorly understood. Here, we identify a developmental LPAR1-axis critical for NCLSC viability and melanoma cell survival. LPAR1 activity increased during progression and following acquisition of therapeutic resistance. Notably, genetic inhibition of LPAR1 potentiated BRAFi ± MEKi efficacy and ablated melanoma migration and invasion. Our data define LPAR1 as a new therapeutic target in melanoma and highlights the promise of dissecting stem cell-like pathways hijacked by tumor cells. SIGNIFICANCE: This study identifies an LPAR1-axis critical for melanoma invasion and intrinsic/acquired therapy resistance.
Authors
Liu, J; Rebecca, VW; Kossenkov, AV; Connelly, T; Liu, Q; Gutierrez, A; Xiao, M; Li, L; Zhang, G; Samarkina, A; Zayasbazan, D; Zhang, J; Cheng, C; Wei, Z; Alicea, GM; Fukunaga-Kalabis, M; Krepler, C; Aza-Blanc, P; Yang, C-C; Delvadia, B; Tong, C; Huang, Y; Delvadia, M; Morias, AS; Sproesser, K; Brafford, P; Wang, JX; Beqiri, M; Somasundaram, R; Vultur, A; Hristova, DM; Wu, LW; Lu, Y; Mills, GB; Xu, W; Karakousis, GC; Xu, X; Schuchter, LM; Mitchell, TC; Amaravadi, RK; Kwong, LN; Frederick, DT; Boland, GM; Salvino, JM; Speicher, DW; Flaherty, KT; Ronai, ZA; Herlyn, M
MLA Citation
Liu, Jianglan, et al. “Neural Crest-Like Stem Cell Transcriptome Analysis Identifies LPAR1 in Melanoma Progression and Therapy Resistance.Cancer Res, vol. 81, no. 20, Oct. 2021, pp. 5230–41. Pubmed, doi:10.1158/0008-5472.CAN-20-1496.
URI
https://scholars.duke.edu/individual/pub1495150
PMID
34462276
Source
pubmed
Published In
Cancer Res
Volume
81
Published Date
Start Page
5230
End Page
5241
DOI
10.1158/0008-5472.CAN-20-1496

Pathway signatures derived from on-treatment tumor specimens predict response to anti-PD1 blockade in metastatic melanoma.

Both genomic and transcriptomic signatures have been developed to predict responses of metastatic melanoma to immune checkpoint blockade (ICB) therapies; however, most of these signatures are derived from pre-treatment biopsy samples. Here, we build pathway-based super signatures in pre-treatment (PASS-PRE) and on-treatment (PASS-ON) tumor specimens based on transcriptomic data and clinical information from a large dataset of metastatic melanoma treated with anti-PD1-based therapies as the training set. Both PASS-PRE and PASS-ON signatures are validated in three independent datasets of metastatic melanoma as the validation set, achieving area under the curve (AUC) values of 0.45-0.69 and 0.85-0.89, respectively. We also combine all test samples and obtain AUCs of 0.65 and 0.88 for PASS-PRE and PASS-ON signatures, respectively. When compared with existing signatures, the PASS-ON signature demonstrates more robust and superior predictive performance across all four datasets. Overall, we provide a framework for building pathway-based signatures that is highly and accurately predictive of response to anti-PD1 therapies based on on-treatment tumor specimens. This work would provide a rationale for applying pathway-based signatures derived from on-treatment tumor samples to predict patients' therapeutic response to ICB therapies.
Authors
Du, K; Wei, S; Wei, Z; Frederick, DT; Miao, B; Moll, T; Tian, T; Sugarman, E; Gabrilovich, DI; Sullivan, RJ; Liu, L; Flaherty, KT; Boland, GM; Herlyn, M; Zhang, G
MLA Citation
Du, Kuang, et al. “Pathway signatures derived from on-treatment tumor specimens predict response to anti-PD1 blockade in metastatic melanoma.Nat Commun, vol. 12, no. 1, Oct. 2021, p. 6023. Pubmed, doi:10.1038/s41467-021-26299-4.
URI
https://scholars.duke.edu/individual/pub1499010
PMID
34654806
Source
pubmed
Published In
Nature Communications
Volume
12
Published Date
Start Page
6023
DOI
10.1038/s41467-021-26299-4

A Modified Nucleoside 6-Thio-2'-Deoxyguanosine Exhibits Antitumor Activity in Gliomas.

PURPOSE: To investigate the therapeutic role of a novel telomere-directed inhibitor, 6-thio-2'-deoxyguanosine (THIO) in gliomas both in vitro and in vivo. EXPERIMENTAL DESIGN: A panel of human and mouse glioma cell lines was used to test therapeutic efficacy of THIO using cell viability assays, flow cytometric analyses, and immunofluorescence. Integrated analyses of RNA sequencing and reverse-phase protein array data revealed the potential antitumor mechanisms of THIO. Four patient-derived xenografts (PDX), two patient-derived organoids (PDO), and two xenografts of human glioma cell lines were used to further investigate the therapeutic efficacy of THIO. RESULTS: THIO was effective in the majority of human and mouse glioma cell lines with no obvious toxicity against normal astrocytes. THIO as a monotherapy demonstrated efficacy in three glioma cell lines that had acquired resistance to temozolomide. In addition, THIO showed efficacy in four human glioma cell lines grown as neurospheres by inducing apoptotic cell death. Mechanistically, THIO induced telomeric DNA damage not only in glioma cell lines but also in PDX tumor specimens. Integrated computational analyses of transcriptomic and proteomic data indicated that THIO significantly inhibited cell invasion, stem cell, and proliferation pathways while triggering DNA damage and apoptosis. Importantly, THIO significantly decreased tumor proliferation in two PDO models and reduced the tumor size of a glioblastoma xenograft and a PDX model. CONCLUSIONS: The current study established the therapeutic role of THIO in primary and recurrent gliomas and revealed the acute induction of telomeric DNA damage as a primary antitumor mechanism of THIO in gliomas.
Authors
Yu, S; Wei, S; Savani, M; Lin, X; Du, K; Mender, I; Siteni, S; Vasilopoulos, T; Reitman, ZJ; Ku, Y; Wu, D; Liu, H; Tian, M; Chen, Y; Labrie, M; Charbonneau, CM; Sugarman, E; Bowie, M; Hariharan, S; Waitkus, M; Jiang, W; McLendon, RE; Pan, E; Khasraw, M; Walsh, KM; Lu, Y; Herlyn, M; Mills, G; Herbig, U; Wei, Z; Keir, ST; Flaherty, K; Liu, L; Wu, K; Shay, JW; Abdullah, K; Zhang, G; Ashley, DM
MLA Citation
Yu, Shengnan, et al. “A Modified Nucleoside 6-Thio-2'-Deoxyguanosine Exhibits Antitumor Activity in Gliomas.Clin Cancer Res, Sept. 2021. Pubmed, doi:10.1158/1078-0432.CCR-21-0374.
URI
https://scholars.duke.edu/individual/pub1497999
PMID
34593527
Source
pubmed
Published In
Clinical Cancer Research
Published Date
DOI
10.1158/1078-0432.CCR-21-0374

Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma.

Targeting MAPK pathway using a combination of BRAF and MEK inhibitors is an efficient strategy to treat melanoma harboring BRAF-mutation. The development of acquired resistance is inevitable due to the signaling pathway rewiring. Combining western blotting, immunohistochemistry, and reverse phase protein array (RPPA), we aim to understanding the role of the mTORC1 signaling pathway, a center node of intracellular signaling network, in mediating drug resistance of BRAF-mutant melanoma to the combination of BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) therapy. The mTORC1 signaling pathway is initially suppressed by BRAFi and MEKi combination in melanoma but rebounds overtime after tumors acquire resistance to the combination therapy (CR) as assayed in cultured cells and PDX models. In vitro experiments showed that a subset of CR melanoma cells was sensitive to mTORC1 inhibition. The mTOR inhibitors, rapamycin and NVP-BEZ235, induced cell cycle arrest and apoptosis in CR cell lines. As a proof-of-principle, we demonstrated that rapamycin and NVP-BEZ235 treatment reduced tumor growth in CR xenograft models. Mechanistically, AKT or ERK contributes to the activation of mTORC1 in CR cells, depending on PTEN status of these cells. Our study reveals that mTOR activation is essential for drug resistance of melanoma to MAPK inhibitors, and provides insight into the rewiring of the signaling networks in CR melanoma.
Authors
Wang, B; Zhang, W; Zhang, G; Kwong, L; Lu, H; Tan, J; Sadek, N; Xiao, M; Zhang, J; Labrie, M; Randell, S; Beroard, A; Sugarman, E; Rebecca, VW; Wei, Z; Lu, Y; Mills, GB; Field, J; Villanueva, J; Xu, X; Herlyn, M; Guo, W
MLA Citation
Wang, Beike, et al. “Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma.Oncogene, vol. 40, no. 37, Sept. 2021, pp. 5590–99. Pubmed, doi:10.1038/s41388-021-01911-5.
URI
https://scholars.duke.edu/individual/pub1489676
PMID
34304249
Source
pubmed
Published In
Oncogene
Volume
40
Published Date
Start Page
5590
End Page
5599
DOI
10.1038/s41388-021-01911-5

Evolution of delayed resistance to immunotherapy in a melanoma responder.

Despite initial responses1-3, most melanoma patients develop resistance4 to immune checkpoint blockade (ICB). To understand the evolution of resistance, we studied 37 tumor samples over 9 years from a patient with metastatic melanoma with complete clinical response to ICB followed by delayed recurrence and death. Phylogenetic analysis revealed co-evolution of seven lineages with multiple convergent, but independent resistance-associated alterations. All recurrent tumors emerged from a lineage characterized by loss of chromosome 15q, with post-treatment clones acquiring additional genomic driver events. Deconvolution of bulk RNA sequencing and highly multiplexed immunofluorescence (t-CyCIF) revealed differences in immune composition among different lineages. Imaging revealed a vasculogenic mimicry phenotype in NGFRhi tumor cells with high PD-L1 expression in close proximity to immune cells. Rapid autopsy demonstrated two distinct NGFR spatial patterns with high polarity and proximity to immune cells in subcutaneous tumors versus a diffuse spatial pattern in lung tumors, suggesting different roles of this neural-crest-like program in different tumor microenvironments. Broadly, this study establishes a high-resolution map of the evolutionary dynamics of resistance to ICB, characterizes a de-differentiated neural-crest tumor population in melanoma immunotherapy resistance and describes site-specific differences in tumor-immune interactions via longitudinal analysis of a patient with melanoma with an unusual clinical course.
Authors
Liu, D; Lin, J-R; Robitschek, EJ; Kasumova, GG; Heyde, A; Shi, A; Kraya, A; Zhang, G; Moll, T; Frederick, DT; Chen, Y-A; Wang, S; Schapiro, D; Ho, L-L; Bi, K; Sahu, A; Mei, S; Miao, B; Sharova, T; Alvarez-Breckenridge, C; Stocking, JH; Kim, T; Fadden, R; Lawrence, D; Hoang, MP; Cahill, DP; Malehmir, M; Nowak, MA; Brastianos, PK; Lian, CG; Ruppin, E; Izar, B; Herlyn, M; Van Allen, EM; Nathanson, K; Flaherty, KT; Sullivan, RJ; Kellis, M; Sorger, PK; Boland, GM
MLA Citation
Liu, David, et al. “Evolution of delayed resistance to immunotherapy in a melanoma responder.Nat Med, vol. 27, no. 6, June 2021, pp. 985–92. Pubmed, doi:10.1038/s41591-021-01331-8.
URI
https://scholars.duke.edu/individual/pub1481495
PMID
33941922
Source
pubmed
Published In
Nat Med
Volume
27
Published Date
Start Page
985
End Page
992
DOI
10.1038/s41591-021-01331-8