PDX-1 Acts as a Potential Molecular Target for Treatment of Human Pancreatic Cancer

Liu, Shihe; Ballian, Nikiforos; Belaguli, Narasimhaswamy S.; Patel, Sanjeet G.; Li, Min; Templeton, Nancy Smyth; Gingras, Marie Claude; Gibbs, Richard A.; Fisher, William E.; Brunicardi, F. Charles

doi:10.1097/mpa.0b013e31816a4a33

Cited by 53 publications

(81 citation statements)

References 74 publications

(52 reference statements)

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“…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. It is able to induce both RNase-H like cleavage and non-cleavage mediated degradation of the target mRNA and inhibit translation concurrently, leading to more rapid onset of gene silencing, higher efficacy and greater durability (17,(20)(21)(22) (5,7). Intravenous infusions of bi-shRNA PDX1 nanoplexes in a large bio-relevant Yucatan mini-pig model were associated minimal toxicity (23).…”

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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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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“…These findings suggest that Pdx1 could be a potential molecular target for the diagnosis, treatment and prognostic evaluation of cancer. Virtually all studies which have evaluated this hypothesis are published from the same group [36][37][38].…”

Section: Strategies For Therapeutic Targeting Of Pdx1mentioning

confidence: 99%

The role of pancreatic and duodenal homeobox 1 as a therapeutic target in pancreatic cancer

Fendrich

Lauth

2014

Expert Opinion on Therapeutic Targets

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“…PDX1 up-regulation in these models suggests its possible role in metaplasia and neoplasia. Indeed, PDX1 has been proposed as an oncogene, as its overexpression in PDA cell lines increases proliferation, invasiveness, and growth in soft agar (Liu et al 2008). However, a more recent large-scale study suggests that PDX1 loss is associated with a more aggressive subtype of PDA (Bailey et al 2016).…”

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confidence: 99%

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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PDX-1 Acts as a Potential Molecular Target for Treatment of Human Pancreatic Cancer

Abstract: PDX-1 regulates cell proliferation and invasion in human pancreatic cancer cells. Down-regulation of PDX-1 expression inhibits pancreatic cancer cell growth in vitro and in vivo, implying its use as a potential therapeutic target for the treatment of pancreatic cancer.

Cited by 53 publications

References 74 publications

PDX1 associated therapy in translational medicine

PDX1 associated therapy in translational medicine

The role of pancreatic and duodenal homeobox 1 as a therapeutic target in pancreatic cancer

PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance

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