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Dive into the research topics where Hee-Dong Han is active.

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Featured researches published by Hee-Dong Han.


Clinical Cancer Research | 2011

Targeting the Notch Ligand Jagged1 in Both Tumor Cells and Stroma in Ovarian Cancer

Adam D. Steg; Ashwini A. Katre; Blake W. Goodman; Hee-Dong Han; Alpa M. Nick; Rebecca L. Stone; Robert E. Coleman; Ronald D. Alvarez; Gabriel Lopez-Berestein; Anil K. Sood; Charles N. Landen

Purpose: Jagged1, a Notch ligand, is expressed on both tumor epithelial and endothelial cells and therefore may be amenable to dual targeting of the tumor stroma and malignant cell compartments of the tumor microenvironment. Experimental Design: We describe in vitro effects of targeting of Jagged1 on ovarian cancer cells and in vivo effects of independent targeting of stromal and malignant cell Jagged1 using species-specific human or murine siRNA constructs incorporated into chitosan nanoparticles and delivered intravenously in an orthotopic mouse model. Results: Jagged1 expression was prominent in SKOV3ip1 and IGROV-AF1, and significantly overexpressed in SKOV3TRip2, a taxane-resistant SKOV3 subclone. Jagged1 silencing with siRNA decreased cell viability and reversed taxane chemoresistance. In two different orthotopic ovarian cancer models, treatment with anti-human Jagged1 siRNA-CH reduced growth by 54.4% to 58.3% and with anti-murine Jagged1 siRNA-CH reduced growth by 41.7% to 48.8%. The combination of both species-specific constructs reduced tumor weight by 87.5% to 93.1% and sensitized SKOV3TRip2 tumors to docetaxel in vivo. Tumors showed reduced microvessel density with anti-murine Jagged1 constructs and decreased proliferation with anti-human Jagged1 siRNAs-CH. In addition, we show that Jagged1 downregulation does not sensitize cells to taxanes through a reduction in MDR1 expression, but at least in part by cross-talk with the GLI2 mediator of the Hedgehog pathway. Conclusions: Jagged1 plays dual roles in cancer progression through an angiogenic function in tumor endothelial cells and through proliferation and chemoresistance in tumor cells. Dual inhibition represents an attractive therapeutic strategy for ovarian and potentially other malignancies. Clin Cancer Res; 17(17); 5674–85. ©2011 AACR.


Cancer Research | 2014

Abstract 5403: Metronomic docetaxel in PRINT nanoparticles and EZH2 silencing have synergistic antitumor effect in ovarian cancer

Kshipra M. Gharpure; Kevin S. Chu; Charles J. Bowerman; Takahito Miyake; Sunila Pradeep; Lingegowda S. Mangala; Hee-Dong Han; Rajesha Rupaimoole; Sherry Y. Wu; Heather J. Dalton; Mary E. Napier; Gabriel Lopez-Berestein; Joseph M. DeSimone; Anil K. Sood

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CAnnPurpose: The purpose of this study was to investigate the combined antitumor effects of metronomic docetaxel-containing PLGA-PRINT nanoparticles and antiangiogenic mEZH2 siRNA incorporated into chitosan nanoparticles (CH-mEZH2 siRNA). Method: In vivo dose-finding studies and therapeutic experiments with PLGA-PRINT-docetaxel and CH-mEZH2 siRNA were conducted in well-established orthotopic mouse models of ovarian cancer (HeyA8 and SKOV3ip1). Antitumor effects were quantified through mean tumor weight and tumor nodule counts. Tumor tissues from these studies were stained to evaluate the proliferation index (Ki67), apoptosis index (cleaved caspase-3), and microvessel density (CD31). Result: Dose-finding studies for PLGA-PRINT-docetaxel revealed all doses (0.5, 1.5, 2 mg/kg for metronomic and 20mg/kg for MTD) significantly reduced tumor burden (p<0.05 for MTD; p<0.01 for metronomic doses). The lowest dose (0.5 mg/kg) reduced tumor weight by ∼80% and was selected for subsequent therapeutic studies. We then tested whether combining PLGA-PRINT-docetaxel particles with CH-mEZH2 siRNA would enhance antitumor effect. CH-mEZH2 siRNA alone reduced tumor weight by ∼70% in both models (p<0.01 for HeyA8; p<0.05 for SKOV3ip1). PLGA-PRINT-docetaxel treatment reduced tumor weight by ∼80% (p<0.01). Combination therapy showed the greatest therapeutic benefit with ∼95% reduction in tumor weight in both models (p<0.001 in HeyA8; p<0.01 in SKOV3ip1). In both the models, the combination therapy resulted in the greatest reduction of tumor nodules. Individual as well as combination therapies showed a significant reduction in proliferation (p<0.001). Metronomic PLGA-PRINT-docetaxel and CH-mEZH2 siRNA monotherapy increased the apoptotic index significantly (p<0.05), whereas the combination therapy had an additive effect (p<0.001). CH-mEZH2 siRNA as well as metronomic PLGA-PRINT-docetaxel therapy resulted in significant reduction in MVD (p<0.01). Conclusion: Metronomic delivery of PLGA-PRINT-docetaxel combined with CH-mEZH2 siRNA is an attractive therapeutic strategy.nnCitation Format: Kshipra M. Gharpure, Kevin S. Chu, Charles Bowerman, Takahito Miyake, Sunila Pradeep, Lingegowda S. Mangala, Hee-Dong Han, Rajesha Rupaimoole, Sherry Y. Wu, Heather J. Dalton, Mary E. Napier, Gabriel Lopez-Berestein, Joseph M. DeSimone, Anil K. Sood. Metronomic docetaxel in PRINT nanoparticles and EZH2 silencing have synergistic antitumor effect in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5403. doi:10.1158/1538-7445.AM2014-5403


Cancer Research | 2013

Abstract 3269: Enhancing chemotherapy response with sustained EphA2 silencing using multistage vector delivery .

Cristian Rodriguez-Aguayo; Haifa Shen; Vianey Gonzalez-Villasana; Guodong Zhang; Xiaoyong Deng; Xuewu Liu; Jason Sakamoto; Arturo Chavez-Reyes; Hee-Dong Han; Anil K. Sood; Mauro Ferrari; Gabriel Lopez-Berestein

RNA interference has the potential to specifically knock down the expression of target genes, and thereby transform cancer therapy. However, lack of effective delivery of small inhibitory RNA (siRNA) has dramatically limited its in vivo applications. We have developed a multistage vector (MSV) system, composed of discoidal porous silicon particles loaded with siRNA oligos packaged in dioleoyl phosphatidylcholine (DOPC) nanoliposomes, that directs effective delivery and sustained release of siRNA in tumor tissues. Tumor accumulation of siRNA was observed after i.v. administration of MSV/siRNA, and sustained release of siRNA from DMSV maintained high levels of siRNA in tumor for over one week after a single dose of DMSV/siRNA. Treatment of SKOV3ip2 tumor mice with DMSV carrying siRNA oligos specific for the human EphA2 gene (MSV/EphA2) biweekly for 6 weeks resulted in dose-dependent (5, 10 and 15 μg/mice) reduction of tumor weight (36%, 64%, and 83%) and number of tumor nodules compared with the control groups. In addition, tumor growth was completely inhibited when mice were treated with MSV/EphA2 in combination with paclitaxel. Furthermore, combination treatment with MSV/EphA2 and docetaxel inhibited growth of HeyA8-MDR tumors, which were otherwise resistant to docetaxel treatment. Taken together, MSV/EphA2 merits further development as a therapeutic approach for ovarian cancer. Citation Format: Cristian Rodriguez-Aguayo, Haifa Shen, Vianey Gonzalez-Villasana, Guodong Zhang, Xiaoyong Deng, Burcu Aslan, Xuewu Liu, Jason Sakamoto, Arturo Chavez-Reyes, Hee-Dong Han, Anil K. Sood, Mauro Ferrari1, Gabriel Lopez-Berestein. Enhancing chemotherapy response with sustained EphA2 silencing using multistage vector delivery . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3269. doi:10.1158/1538-7445.AM2013-3269


Cancer Research | 2012

Abstract 884: Basonuclin1 (BNC1): A novel therapeutic target in ovarian cancer identified through integrative TCGA-based functional genomic analysis

Sherry Y. Wu; Anna K. Unruh; Geoffrey Bartholomeusz; Cristina Ivan; Chad V. Pecot; Rajesha Rupaimoole; Hee-Dong Han; Justin Bottsford-Miller; Susan L. Tucker; Robert L. Coleman; Gabriel Lopez-Berestein; Keith A. Baggerly; Anil K. Sood

High-grade serous ovarian cancer (HGS-OvCa) is the most common and lethal type of ovarian carcinoma. While TCGA provides comprehensive genomic profiling of clinically annotated HGS-OvCa tumors, identification of novel therapeutic targets using this dataset is still needed. We coupled TCGA mRNA expression and clinical response data to systematically identify genes which could alter progression of HGS-OvCa and investigated associated alterations in DNA promoter methylation and microRNA expression. For selected targets, we also used siRNA functional studies to clarify gene-specific effects. We identified 102 genes as up-regulated in tumors from patients whose cancer had progressed within 7 months of diagnosis (chemo-resistant group: 53 cases) compared to tumors from patients who had no disease progression for more than 3 years (chemo-sensitive group: 57 cases). These genes had two-sample t-test p-values Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 884. doi:1538-7445.AM2012-884


Cancer Research | 2011

Abstract 1735: Silencing survivin splice variant 2B leads to antitumor activity in taxane-resistant ovarian cancer

Cristian Rodriguez-Aguayo; Pablo Vivas-Mejia; Hee-Dong Han; Mian M.K. Shahzad; Fatma Valiyeva; Mineko Shibayama; Arturo Chavez-Reyes; Anil K. Sood; Gabriel Lopez-Berestein

Survivin, a protein highly expressed in human cancers is involved in both control of cell cycle progression and inhibition of apoptosis. Transcription of the survivin gene locus (BIRC-5) yields at least 5 alternative splice variants including survivin wild-type (WT), survivin ΔEx3, survivin 2B, survivin 3B, and survivin 2α. Here, we studied the role of survivin and its splice variants in taxane-resistant ovarian cancer. Taxane-resistant ovarian cancer cells express higher survivin mRNA levels than their taxane-sensitive counterparts. Survivin 2B expression was significantly higher in taxane-resistant compared to sensitive cells. Small-interference RNAs (siRNAs) targeting survivin were designed to silence all survivin splice variants (T-siRNA) or survivin 2B (2B-siRNA). Silencing survivin 2B induced growth inhibitory effects similar to silencing total survivin in vitro. In addition, survivin 2B siRNA incorporated into DOPC nanoliposomes resulted in significant reduction in tumor growth (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1735. doi:10.1158/1538-7445.AM2011-1735


Cancer Research | 2011

Abstract 141: miR520d-3p regulates EphA2 and inhibits ovarian cancer growth

Masato Nishimura; Eun-Jung Jung; Riccardo Spizzo; Mian M.K. Shahzad; Koji Matsuo; Justin Bottsford-Miller; Rebecca L. Stone; Alpa M. Nick; Chunnhua Lu; Hee-Dong Han; Nicholas B. Jennings; George A. Calin; Anil K. Sood

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FLnnEphA2 is a receptor tyrosine kinase that is over-expressed in various malignancies including ovarian cancer. EphA2 is known to promote tumor growth, however its regulation is not well understood. On the basis of data available from The Cancer Genome Atlas, we predicted that miR520d-3p would be a potent inhibition of EphA2. To investigate interaction between miR520d-3p and EphA2, we first examined the mRNA level of these genes in 123 tumors of ovarian cancer patients. There was an inverse correlation between miR520d-3p level and EphA2 mRNA levels (p<0.001); and the prognosis of patients with high miR520d-3p expression was significantly better than those with low miR520d-3p (p<0.001). Next, we established stable clones over-expressing miR520d-3p in HeyA8 and SKOV3ip1 ovarian cancer cells, in which baseline EphA2 levels are high. Compared with parental cell and clones transfected empty vector, EphA2 protein levels were decreased by ∼60%. MiR520d-3p transfection also resulted in significantly decreased migration and invasion in vitro and tumor growth in vivo in orthotopic mouse models. Tumor with high miR520d-3p had decreased EphA2 levels and decreased microvessel density (p<0.01). In conclusion, miR520d-3p is a key regulator of EphA2 levels and may represent a novel therapeutic approach.nnCitation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 141. doi:10.1158/1538-7445.AM2011-141


Cancer Research | 2010

Abstract 677: Targeting the survivin splice variant 2β in taxane-resistant ovarian cancer

Pablo Vivas; Cristian Rodriguez-Aguayo; Hee-Dong Han; Mian M.K. Shahzad; Anil K. Sood; Gabriel Lopez-Berestein

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DCnnSurvivin, a protein highly expressed in human cancers is involved in both control of cell cycle progression and inhibition of apoptosis. Transcription of the survivin gene locus (BIRC-5) yields at least 5 alternative splice variants that have been designed survivn-WT, survivin-ΔEx3, survivin-2β, surivivn-3β, and survivin 2α. It has been shown that the survivin splice variants have different expression levels and subcellular localization patterns that could be associated with unique functional properties. Whereas the effects of survivin on apoptosis and mitosis have been extensively studied and explored therapeutically, the role of specific survivin splice variants in ovarian cancer has not been investigated. Our compelling studies indicate that, compared with their taxane-sensitive counterparts, taxane-resistant ovarian cancer cells express higher survivin mRNA (particularly the WT, ΔEx3 and 2β isoforms) levels. Studies have shown that survivin-2β has proapoptotic properties: whereas, forced expression of survivin-2β sensitized cells to taxane-induced apoptosis, small-interference RNA (siRNA)-based silencing of survivin-2β protected cells from cells from apoptotic cell death. We have observed opposite results: siRNA-based silencing of survivin-2β induced cell growth arrest and apoptosis of taxane-resistant ovarian cancer cells. Furthermore, liposomes-encapsulated siRNA targeting survivin-2β inhibited tumor growth in orthotopic murine models of ovarian cancer. The anti-tumor effect was further increased by combination with docetaxel. Finally, we found a significant association of survivin-2β expression with progression free survival in the 117 epithelial ovarian cancers obtained at primary debulking therapy. Further studies are necessary to clarify the role of survivin-2β in ovarian cancer. The key finding from our study is that survive-2β is present in a substantial proportion of ovarian cancers, and is predictive of decreased progression-free survival (PFS) of ovarian cancer patients. These studies also show the feasibility of survivin-2β-targeting siRNA liposomal as a clinically applicable therapeutic modality for taxane-resistant ovarian cancer.nnCitation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 677.


Cancer Research | 2010

Abstract 1793: Platelet-derived growth factor receptor alpha blockade significantly enhances sensitization to docetaxel in ovarian carcinoma

Koji Matsuo; Rebecca L. Stone; Mian M.K. Shahzad; Amy R. Carroll; Hee-Dong Han; Sun-Joo Lee; Masato Nishimura; Edna Mora; Chunhua Lu; Nick Loizos; Anil K. Sood

Objective: Platelet-derived growth factor receptor alpha (PDGFRα) is a member of class III receptor tyrosine kinase and is associated with cell survival. Here, we examined whether PDGFRα blockade enhances the anti-tumor activity of taxanes in ovarian carcinoma. Methods: PDGFRα expression was evaluated with RT-PCR and Western blot in multiple ovarian cancer cell lines. Human-specific monoclonal antibody to PDGFRα (IMC-3G3, ImClone Systems, NJ, USA) was used for in-vitro (cell viability assay, apoptosis assay) and in-vivo experiments with or without docetaxel. Results: All eleven tested ovarian cancer cell lines had variable expression of PDGFRα. OVCA433 cell line had the highest level of expression of PDGFRα. IMC-3G3 blocked PDGFRα phosphorylation in response to PDGF-AA stimulation. IMC-3G3 alone had no affect on cell viability in all tested cell lines. However, IMC-3G3 significantly enhanced sensitization to docetaxel: IC50 reduction rate, SKOV3-ip1, 25.5%; HeyA8-parental, 31.7%; OVCA433, 35.3%; and HeyA8-MDR, 44.2% (all, p 0.05). Concurrent use of IMC-3G3 with docetaxel significantly reduced tumor weight compared to docetaxel alone (mean tumor weight, 0.22 ± 0.07 vs 0.63 ± 0.14 grams, tumor reduction rate 65.1%, p Conclusion: IMC-3G3 significantly enhances the anti-tumor effects of docetaxel. Therefore, targeting PDGFRα may be an attractive approach for increasing the cytotoxic effects of chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1793.


Archive | 2014

show increased loading into the RISC complex and enhanced anti-tumour activity

Sherry Y. Wu; Xianbin Yang; Kshipra M. Gharpure; Hiroto Hatakeyama; Martin Egli; Michael McGuire; Archana S. Nagaraja; Takahito Miyake; Rajesha Rupaimoole; Chad V. Pecot; Morgan Taylor; Sunila Pradeep; Malgorzata Sierant; Cristian Rodriguez-Aguayo; Hyun J. Choi; Rebecca A. Previs; Guillermo N. Armaiz-Pena; Li Huang; Carlos Martinez; Tom Hassell; Cristina Ivan; Vasudha Sehgal; Richa Singhania; Hee-Dong Han; Chang Su; Ji Hoon Kim; Heather J. Dalton; Chandra Kovvali; Khandan Keyomarsi; Willem W. Overwijk


Archive | 2012

Delivering siRNA Using Nanoparticles to the Central Nervous System

Sultan Neslihan Alpay; Bulent Ozpolat; Hee-Dong Han; Gabriel Lopez-Berestein; Anil K. Sood; Hui-Lin Pan

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Anil K. Sood

University of Texas MD Anderson Cancer Center

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Gabriel Lopez-Berestein

University of Texas MD Anderson Cancer Center

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Mian M.K. Shahzad

University of South Florida

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Cristian Rodriguez-Aguayo

University of Texas MD Anderson Cancer Center

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Koji Matsuo

University of Southern California

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Alpa M. Nick

University of Texas MD Anderson Cancer Center

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Chad V. Pecot

University of North Carolina at Chapel Hill

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Justin Bottsford-Miller

University of Texas MD Anderson Cancer Center

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Rajesha Rupaimoole

University of Texas MD Anderson Cancer Center

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