Jung Wook Park

Positions:

Rollie Assistant Professorship of Correlative Pathology

Pathology
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. 2013

University of Wisconsin - Madison

Grants:

Unveiling the roles of neuroendocrine cells in prostate cancer development

Administered By
Pathology
Awarded By
Mike Slive Foundation
Role
Co-Principal Investigator
Start Date
End Date

Defining the Essential Determinants of Prostate Cancer Differentiation States

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

Defining the Essential Determinants of Prostate Cancer Differentiation States

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

Interrupting the aberrant cancer development sequence in epithelial cancer progression

Administered By
Pathology
Awarded By
Prostate Cancer Foundation
Role
Principal Investigator
Start Date
End Date

Transcriptional reprogramming of lethal small cell prostate cancer

Administered By
Pathology
Awarded By
Department of Defense
Role
Principal Investigator
Start Date
End Date

Publications:

Targeting RET Kinase in Neuroendocrine Prostate Cancer.

The increased treatment of metastatic castration-resistant prostate cancer (mCRPC) with second-generation antiandrogen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost dependence on androgen receptor (AR) signaling. These AR-independent tumors may also transdifferentiate to express neuroendocrine lineage markers and are termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing several AR-independent to AR-dependent prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-independent cell lines. Clinical NEPC patient samples and NEPC patient-derived xenografts displayed upregulated RET transcript and RET pathway activity. Genetic knockdown or pharmacologic inhibition of RET kinase in multiple mouse and human models of NEPC dramatically reduced tumor growth and decreased cell viability. Our results suggest that targeting RET in NEPC tumors with high RET expression could be an effective treatment option. Currently, there are limited treatment options for patients with aggressive neuroendocrine prostate cancer and none are curative. IMPLICATIONS: Identification of aberrantly expressed RET kinase as a driver of tumor growth in multiple models of NEPC provides a significant rationale for testing the clinical application of RET inhibitors in patients with AVPC.
Authors
VanDeusen, HR; Ramroop, JR; Morel, KL; Bae, SY; Sheahan, AV; Sychev, Z; Lau, NA; Cheng, LC; Tan, VM; Li, Z; Petersen, A; Lee, JK; Park, JW; Yang, R; Hwang, JH; Coleman, I; Witte, ON; Morrissey, C; Corey, E; Nelson, PS; Ellis, L; Drake, JM
MLA Citation
VanDeusen, Halena R., et al. “Targeting RET Kinase in Neuroendocrine Prostate Cancer.Mol Cancer Res, vol. 18, no. 8, Aug. 2020, pp. 1176–88. Pubmed, doi:10.1158/1541-7786.MCR-19-1245.
URI
https://scholars.duke.edu/individual/pub1446944
PMID
32461304
Source
pubmed
Published In
Mol Cancer Res
Volume
18
Published Date
Start Page
1176
End Page
1188
DOI
10.1158/1541-7786.MCR-19-1245

High incidence of female reproductive tract cancers in FA-deficient HPV16-transgenic mice correlates with E7's induction of DNA damage response, an activity mediated by E7's inactivation of pocket proteins.

Fanconi anemia (FA) is a rare genetic disorder caused by defects in a DNA damage repair system, the FA pathway. FA patients frequently develop squamous cell carcinoma (SCC) at sites that are associated with human papillomavirus (HPV)-driven cancer including the female reproductive tract. To assess experimentally whether FA deficiency increases susceptibility to HPV-associated cervical/vaginal cancer, we monitored cancer incidence in the female lower reproductive tract of FA-deficient mice expressing HPV16 oncogenes, E6 and/or E7. FA deficiency specifically increased the incidence of cancers in mice expressing E7; but this effect was not observed in mice just expressing E6. We also observed that E7, but not E6, induced DNA damage as scored by induction of γ-H2AX and 53BP1 (p53 binding protein 1) nuclear foci, and this induction was heightened in FA-deficient tissue. Finally, we discovered that this induction of DNA damage responses was recapitulated in mice deficient in expression of 'pocket' proteins, pRb, p107 and p130, which are established targets of E7. Our findings support the hypothesis that E7 induces cancer by causing DNA damage at least in part through the inactivation of pocket proteins. This hypothesis explains why a deficiency in DNA damage repair would increase susceptibility to E7-driven cancer.
Authors
Park, JW; Shin, M-K; Lambert, PF
URI
https://scholars.duke.edu/individual/pub1437957
PMID
24013229
Source
pubmed
Published In
Oncogene
Volume
33
Published Date
Start Page
3383
End Page
3391
DOI
10.1038/onc.2013.327

A genetically defined disease model reveals that urothelial cells can initiate divergent bladder cancer phenotypes.

Small cell carcinoma of the bladder (SCCB) is a rare and lethal phenotype of bladder cancer. The pathogenesis and molecular features are unknown. Here, we established a genetically engineered SCCB model and a cohort of patient SCCB and urothelial carcinoma samples to characterize molecular similarities and differences between bladder cancer phenotypes. We demonstrate that SCCB shares a urothelial origin with other bladder cancer phenotypes by showing that urothelial cells driven by a set of defined oncogenic factors give rise to a mixture of tumor phenotypes, including small cell carcinoma, urothelial carcinoma, and squamous cell carcinoma. Tumor-derived single-cell clones also give rise to both SCCB and urothelial carcinoma in xenografts. Despite this shared urothelial origin, clinical SCCB samples have a distinct transcriptional profile and a unique transcriptional regulatory network. Using the transcriptional profile from our cohort, we identified cell surface proteins (CSPs) associated with the SCCB phenotype. We found that the majority of SCCB samples have PD-L1 expression in both tumor cells and tumor-infiltrating lymphocytes, suggesting that immune checkpoint inhibitors could be a treatment option for SCCB. We further demonstrate that our genetically engineered tumor model is a representative tool for investigating CSPs in SCCB by showing that it shares a similar a CSP profile with clinical samples and expresses SCCB-up-regulated CSPs at both the mRNA and protein levels. Our findings reveal distinct molecular features of SCCB and provide a transcriptional dataset and a preclinical model for further investigating SCCB biology.
Authors
Wang, L; Smith, BA; Balanis, NG; Tsai, BL; Nguyen, K; Cheng, MW; Obusan, MB; Esedebe, FN; Patel, SJ; Zhang, H; Clark, PM; Sisk, AE; Said, JW; Huang, J; Graeber, TG; Witte, ON; Chin, AI; Park, JW
MLA Citation
Wang, Liang, et al. “A genetically defined disease model reveals that urothelial cells can initiate divergent bladder cancer phenotypes.Proc Natl Acad Sci U S A, vol. 117, no. 1, Jan. 2020, pp. 563–72. Pubmed, doi:10.1073/pnas.1915770117.
URI
https://scholars.duke.edu/individual/pub1424500
PMID
31871155
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
117
Published Date
Start Page
563
End Page
572
DOI
10.1073/pnas.1915770117

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

Loss of Dependence on Continued Expression of the Human Papillomavirus 16 E7 Oncogene in Cervical Cancers and Precancerous Lesions Arising in Fanconi Anemia Pathway-Deficient Mice.

Fanconi anemia (FA) is a rare genetic disorder caused by defects in DNA damage repair. FA patients often develop squamous cell carcinoma (SCC) at sites where high-risk human papillomaviruses (HPVs) are known to cause cancer, including the cervix. However, SCCs found in human FA patients are often HPV negative, even though the majority of female FA patients with anogenital cancers had preexisting HPV-positive dysplasia. We hypothesize that HPVs contribute to the development of SCCs in FA patients but that the continued expression of HPV oncogenes is not required for the maintenance of the cancer state because FA deficiency leads to an accumulation of mutations in cellular genes that render the cancer no longer dependent upon viral oncogenes. We tested this hypothesis, making use of Bi-L E7 transgenic mice in which we temporally controlled expression of HPV16 E7, the dominant viral oncogene in HPV-associated cancers. As seen before, the persistence of cervical neoplastic disease was highly dependent upon the continued expression of HPV16 E7 in FA-sufficient mice. However, in mice with FA deficiency, cervical cancers persisted in a large fraction of the mice after HPV16 E7 expression was turned off, indicating that these cancers had escaped from their dependency on E7. Furthermore, the severity of precancerous lesions also failed to be reduced significantly in the mice with FA deficiency upon turning off expression of E7. These findings confirm our hypothesis and may explain the fact that, while FA patients have a high frequency of infections by HPVs and HPV-induced precancerous lesions, the cancers are frequently HPV negative. IMPORTANCE  : Fanconi anemia (FA) patients are at high risk for developing squamous cell carcinoma (SCC) at sites where high-risk human papillomaviruses (HPVs) frequently cause cancer. Yet these SCCs are often HPV negative. FA patients have a genetic defect in their capacity to repair damaged DNA. HPV oncogenes cause an accumulation of DNA damage. We hypothesize, therefore, that DNA damage induced by HPV leads to an accumulation of mutations in patients with FA deficiency and that such mutations allow HPV-driven cancers to become independent of the viral oncogenes. Consistent with this hypothesis, we found that cervical cancers arising in HPV16 transgenic mice with FA deficiency frequently escape from dependency on the HPV16 oncogene that drove its development. Our report provides further support for vaccination of FA patients against HPVs and argues for the need to define mutational profiles of SCCs arising in FA patients in order to inform precision medicine-based approaches to treating these patients.
Authors
Park, S; Park, JW; Pitot, HC; Lambert, PF
URI
https://scholars.duke.edu/individual/pub1411007
PMID
27190216
Source
pubmed
Published In
Mbio
Volume
7
Published Date
DOI
10.1128/mBio.00628-16