Yiping He

Positions:

Associate Professor in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2002

University of Pennsylvania

Post-doctoral Fellow, Pathology

Johns Hopkins University

Howard Hughes Researcher, Pathology

Johns Hopkins University

Research Associate, Pathology

Johns Hopkins University

Grants:

Exploiting MTAP deletion for GBM therapeutics

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Exploiting MTAP for more effective treatment of glioblastoma with temozolomide

Administered By
Pathology
Awarded By
Southeastern Brain Tumor Foundation
Role
Principal Investigator
Start Date
End Date

Developing novel mouse models for medulloblastoma

Administered By
Pathology
Awarded By
Circle of Service Foundation
Role
Principal Investigator
Start Date
End Date

Repurposing Remyelination Drugs for Oligodendroglioma Therapeutics

Administered By
Pathology
Awarded By
American Brain Tumor Association
Role
Principal Investigator
Start Date
End Date

Exploiting MTAP deletion for GBM therapeutics

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

TP53 wild-type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist.

Diffuse intrinsic pontine gliomas (DIPGs) are high-grade tumors of the brainstem that often occur in children, with a median overall survival of less than one year. Given the fact that DIPGs are resistant to chemotherapy and are not amenable to surgical resection, it is imperative to develop new therapeutic strategies for this deadly disease. The p53 pathway is dysregulated by TP53 (~ 60%) or PPM1D gain-of-function mutations (~ 30%) in DIPG cases. PPM1D gain-of-function mutations suppress p53 activity and result in DIPG tumorigenesis. While MDM2 is a major negative regulator of p53, the efficacy of MDM2 inhibitor has not been tested in DIPG preclinical models. In this study, we performed a comprehensive validation of MDM2 inhibitor RG7388 in patient-derived DIPG cell lines established from both TP53 wild-type/PPM1D-mutant and TP53 mutant/PPM1D wild-type tumors, as well in TP53 knockout isogenic DIPG cell line models. RG7388 selectively inhibited the proliferation of the TP53 wild-type/PPM1D mutant DIPG cell lines in a dose- and time-dependent manner. The anti-proliferative effects were p53-dependent. RNA-Seq data showed that differential gene expression induced by RG7388 treatment was enriched in the p53 pathways. RG7388 reactivated the p53 pathway and induced apoptosis as well as G1 arrest. In vivo, RG7388 was able to reach the brainstem and exerted therapeutic efficacy in an orthotopic DIPG xenograft model. Hence, this study demonstrates the pre-clinical efficacy potential of RG7388 in the TP53 wild-type/PPM1D mutant DIPG subgroup and may provide critical insight on the design of future clinical trials applying this drug in DIPG patients.
Authors
Xu, C; Liu, H; Pirozzi, CJ; Chen, LH; Greer, PK; Diplas, BH; Zhang, L; Waitkus, MS; He, Y; Yan, H
MLA Citation
Xu, Cheng, et al. “TP53 wild-type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist.Acta Neuropathol Commun, vol. 9, no. 1, Nov. 2021, p. 178. Pubmed, doi:10.1186/s40478-021-01270-y.
URI
https://scholars.duke.edu/individual/pub1500632
PMID
34732238
Source
pubmed
Published In
Acta Neuropathologica Communications
Volume
9
Published Date
Start Page
178
DOI
10.1186/s40478-021-01270-y

Epigenetic Regulation of Fanconi Anemia Genes Implicates PRMT5 Blockage as a Strategy for Tumor Chemosensitization.

Strengthened DNA repair pathways in tumor cells contribute to the development of resistance to DNA-damaging agents. Consequently, targeting proteins in these pathways is a promising strategy for tumor chemosensitization. Here, we show that the expression of a subset of Fanconi anemia (FA) genes is attenuated in glioblastoma tumor cells deficient in methylthioadenosine phosphorylase (MTAP), a common genetic alteration in a variety of cancers. Subsequent experiments in cell line models of different cancer types illustrate that this reduced transcription of FA genes can be recapitulated by blockage of Protein Arginine Methyltransferase 5 (PRMT5), a promising therapeutically targetable epigenetic regulator whose enzymatic activity is compromised in MTAP-deficient cells. Further analyses provide evidence to support that PRMT5 can function as an epigenetic regulator that contributes to the increased expression of FA genes in cancer cells. Most notably and consistent with the essential roles of FA proteins in resolving DNA damage elicited by interstrand crosslinking (ICL) agents, PRMT5 blockage, as well as MTAP loss, sensitizes tumor cells to ICL agents both in vitro and in xenografts. Collectively, these findings reveal a novel epigenetic mechanism underlying the upregulated expression of FA genes in cancer cells and suggest that therapeutically targeting PRMT5 can have an additional benefit of chemosensitizing tumor cells to ICL agents. IMPLICATIONS: PRMT5 positively regulates the expression of FA genes. Inhibition of PRMT5 attenuates FA-dependent DNA repair pathway and sensitizes tumor cells to ICL agents.
Authors
Du, C; Li, SW; Singh, SX; Roso, K; Sun, MA; Pirozzi, CJ; Yang, R; Li, J-L; He, Y
MLA Citation
Du, Changzheng, et al. “Epigenetic Regulation of Fanconi Anemia Genes Implicates PRMT5 Blockage as a Strategy for Tumor Chemosensitization.Mol Cancer Res, Sept. 2021. Pubmed, doi:10.1158/1541-7786.MCR-21-0093.
URI
https://scholars.duke.edu/individual/pub1497059
PMID
34521764
Source
pubmed
Published In
Mol Cancer Res
Published Date
DOI
10.1158/1541-7786.MCR-21-0093

Low levels of BRCA1 protein expression predict a worse prognosis in stage I-II colon cancer.

BACKGROUND: BRCA1 and BRCA2 have been well studied for their roles in tumorigeneis, plus cancer diagnosis and treatment, but their prognostic value in colon cancer, especially for early-stage cancer, has not been fully illuminated. This study examined the expression levels of BRCA1 and BRCA2 proteins in sporadic colon cancer cases and investigated their value in prognosis. METHODS: The expression levels of BRCA1 and BRCA2 in 275 colon cancer patients who underwent radical surgeries were assayed by immunohistochemical staining in dissected tumor samples. Also, its correlation with clinicopathological characteristics, disease-free survival, and overall survival was investigated. RESULTS: Tumors with low expression levels of BRCA1, BRCA2, and both were 19.6%, 17.8%, and 6.5%, respectively. The levels of BRCA1/2 expression were not associated with clinicopathological parameters (gender, age, histological differentiation, and tumor node metastasis stage). Patients with low-levels of BRCA1 protein in their tumors demonstrated a lower chance of 5-year disease-free survival (55.6% vs. 69.7%, P=0.046), which was more obvious in the patients with stage I-II tumors without chemotherapy (52.6% vs. 82.6%, P=0.006). Neither BRCA1 nor BRCA2 affected overall survival in this cohort. Multivariate analysis revealed that pathologic stage and the level of BRCA1 protein were independent factors of long-term disease-free survival. CONCLUSION: This study highlights BRCA1 as an independent prognosticator of early-stage colon cancer.
Authors
Du, C; Peng, Y; He, Y; Chen, G; Chen, H
MLA Citation
Du, Changzheng, et al. “Low levels of BRCA1 protein expression predict a worse prognosis in stage I-II colon cancer.Int J Biol Markers, vol. 36, no. 1, Mar. 2021, pp. 47–53. Pubmed, doi:10.1177/1724600820986572.
URI
https://scholars.duke.edu/individual/pub1474775
PMID
33583275
Source
pubmed
Published In
Int J Biol Markers
Volume
36
Published Date
Start Page
47
End Page
53
DOI
10.1177/1724600820986572

Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy.

Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10-20% of patients. Here we perform genomic analysis of tumor tissue from recurrent WHO grade IV glioblastoma patients acquired prior to immunotherapy intervention. We report that very low tumor mutation burden is associated with longer survival after recombinant polio virotherapy or after immune checkpoint blockade in recurrent glioblastoma patients. A relationship between tumor mutation burden and survival is not observed in cohorts of immunotherapy naïve newly diagnosed or recurrent glioblastoma patients. Transcriptomic analyses reveal an inverse relationship between tumor mutation burden and enrichment of inflammatory gene signatures in cohorts of recurrent, but not newly diagnosed glioblastoma tumors, implying that a relationship between tumor mutation burden and tumor-intrinsic inflammation evolves upon recurrence.
Authors
Gromeier, M; Brown, MC; Zhang, G; Lin, X; Chen, Y; Wei, Z; Beaubier, N; Yan, H; He, Y; Desjardins, A; Herndon, JE; Varn, FS; Verhaak, RG; Zhao, J; Bolognesi, DP; Friedman, AH; Friedman, HS; McSherry, F; Muscat, AM; Lipp, ES; Nair, SK; Khasraw, M; Peters, KB; Randazzo, D; Sampson, JH; McLendon, RE; Bigner, DD; Ashley, DM
MLA Citation
Gromeier, Matthias, et al. “Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy.Nat Commun, vol. 12, no. 1, Jan. 2021, p. 352. Pubmed, doi:10.1038/s41467-020-20469-6.
URI
https://scholars.duke.edu/individual/pub1471754
PMID
33441554
Source
pubmed
Published In
Nature Communications
Volume
12
Published Date
Start Page
352
DOI
10.1038/s41467-020-20469-6

The integrated genomic and epigenomic landscape of brainstem glioma.

Brainstem gliomas are a heterogeneous group of tumors that encompass both benign tumors cured with surgical resection and highly lethal cancers with no efficacious therapies. We perform a comprehensive study incorporating epigenetic and genomic analyses on a large cohort of brainstem gliomas, including Diffuse Intrinsic Pontine Gliomas. Here we report, from DNA methylation data, distinct clusters termed H3-Pons, H3-Medulla, IDH, and PA-like, each associated with unique genomic and clinical profiles. The majority of tumors within H3-Pons and-H3-Medulla harbors H3F3A mutations but shows distinct methylation patterns that correlate with anatomical localization within the pons or medulla, respectively. Clinical data show significantly different overall survival between these clusters, and pathway analysis demonstrates different oncogenic mechanisms in these samples. Our findings indicate that the integration of genetic and epigenetic data can facilitate better understanding of brainstem gliomagenesis and classification, and guide future studies for the development of novel treatments for this disease.
Authors
Chen, LH; Pan, C; Diplas, BH; Xu, C; Hansen, LJ; Wu, Y; Chen, X; Geng, Y; Sun, T; Sun, Y; Zhang, P; Wu, Z; Zhang, J; Li, D; Zhang, Y; Wu, W; Wang, Y; Li, G; Yang, J; Wang, X; Xu, C; Wang, S; Waitkus, MS; He, Y; McLendon, RE; Ashley, DM; Yan, H; Zhang, L
MLA Citation
Chen, Lee H., et al. “The integrated genomic and epigenomic landscape of brainstem glioma.Nat Commun, vol. 11, no. 1, June 2020, p. 3077. Pubmed, doi:10.1038/s41467-020-16682-y.
URI
https://scholars.duke.edu/individual/pub1447966
PMID
32555164
Source
pubmed
Published In
Nature Communications
Volume
11
Published Date
Start Page
3077
DOI
10.1038/s41467-020-16682-y