Vertically integrated translational studies of PDX1 as a therapeutic target for pancreatic cancer via a novel bifunctional RNAi platform

Wu, James X.; Liu, S; Yu, Juehua; Zhou, Guisheng; Rao, Donald D.; Jay, Chris M.; Kumar, Padmasini; Sanchez, Robbi; Templeton, Nancy Smyth; Senzer, Neil; Maples, Phillip B.; Nemunaitis, John; Brunicardi, F. Charles

doi:10.1038/cgt.2013.84

Cited by 18 publications

(14 citation statements)

References 54 publications

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“…Pdx1 deficiency blocked cell growth, suggesting protumorigenic functions of PDX1 (Supplemental Fig. S4A, bottom), consistent with previous reports (Wu et al 2014). As PDA can originate from neoplastic lesions other than PanIN, we asked next whether Pdx1 has analogous oncogenic activities in PDA emerging from PanIN or intraductal papillary mucinous neoplasia (IPMN).…”

Section: Lsl-g12d/+mentioning

confidence: 56%

PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance

et al. 2016

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Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression.

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Section: Lsl-g12d/+mentioning

confidence: 56%

PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance

et al. 2016

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“…So far, PDX1 has been proved to promote Kras G12D oncogenic proteininduced development of PanIN, metaplasia and PDAC. Overexpression of PDX1 in benign human cells (HEK293 and Human pancreatic ductal cells), as well as PDAC cell lines (PANC1 and MiaPaca2) and insulinoma cell lines (Min6 and βTC6 cells) lead to significant increases in cell proliferation, invasion and colony formation in vitro, as well as promotion of tumor growth in xenograft severe combined immunodeficiency (SCID) mouse models (8)(9)(10)(11)(12). These studies suggest that PDX1 is involved in tumorigenesis of both PDAC and insulinoma.…”

Section: Pdx1 and Pdx1 Involved Diseasesmentioning

confidence: 86%

“…Conventional siRNA generated from double-stranded RNA molecules can bind target RNA sequences and interfere with their translation or target them for destruction (17). Having demonstrated PDX1 is a potential gene target for PDAC, we developed our first therapeutic platform targeting PDX1 using a novel RNAi technology bi-functional shRNA (11,18,19). The bifunctional shRNA consists of two stem-loop shRNA (shorthairpin RNA) structures: one cleavage-dependent unit with a perfectly matched passenger-strand and guide-strand, and one cleavage-independent unit composed of a mismatched double strand.…”

Section: Pdx1-rnai Effectively Silences Pdx1 Expression and Ablates Hmentioning

confidence: 99%

PDX1 associated therapy in translational medicine

Yu¹,

Liu²,

Sanchez³

et al. 2016

Ann. Transl. Med.

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely poor prognosis and a low median survival due to lack of the early and reliable detection and effective therapeutic options, despite improvements observed for many other cancers in last decade. Pancreatic and duodenal homeobox 1 (PDX1), which is a homeodomain-containing transcription factor and a key regulator for insulin gene expression, β cell maturation and proper β cell function maintenance in the pancreas. Our previous studies revealed that PDX1 promotes tumorigenesis and it is a promising therapeutic target for PDAC. For translational purposes, we developed three therapeutic platforms utilizing RNA interference (RNAi), gene therapy and small inhibitory drug targeting PDX1, and further validated them in PDAC preclinical models both in vitro and in vivo. These PDX1 targeted therapies significantly inhibited PDX1 expression in PDAC cells, ablated PDX1-expressing human PDAC xenograft tumor growth, and prolonged survival in the PDAC mouse models. The data from these preclinical studies proved the translational potentials of PDX1 targeted therapies in PDAC and suggest that the strategy of developing PDX1 targeted therapies would permit a rapid bench-to-bedside translation of other relevant gene therapies, which would eventually benefit the patients suffering from this deadly disease.

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“…В зависимости от потребностей в функциях, выполняемых генами-регуляторами, в разных подвидах опухолей может происходить их активация или репрессия. Например, фактор PDX1 активен в классическом типе ПА-ПЖ и отвечает за пролиферацию клеток и рост опухоли, однако в квазимезенхимальном типе экспрессия его гена подавляется, что является необходимым условием запуска ЭМП, необходимого для метастазирования [72,88,89].…”

Section: основных подвида папж роль эмпunclassified

SOX9 as one of the central units of regulation axis of pancreas embryogenesis and cancer progression

Буланенкова¹,

Snezhkov²,

Akopov³

2019

Mol. genet. mikrobiol. virusol.

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Vertically integrated translational studies of PDX1 as a therapeutic target for pancreatic cancer via a novel bifunctional RNAi platform

Cited by 18 publications

References 54 publications

PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance

PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance

PDX1 associated therapy in translational medicine

SOX9 as one of the central units of regulation axis of pancreas embryogenesis and cancer progression

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