Bioinformatics approach identifies Guanabenz as potential therapeutic for Pancreatic Ductal Adrenocarcinoma through attenuation of GPCRs and Ras Signaling

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Abstract/Contents

Abstract: Pancreatic ductal adrenocarcinoma (PDAC) is one of the most aggressive cancers with poor prognosis at time of diagnosis and high mortality due to few effective treatment options. This work seeks to show the power of bioinformatics to quickly and efficiently repurpose FDA-approved drugs for PDAC. We used a systematic drug repositioning bioinformatics approach that compared a concise and comprehensive array of gene expression profiles to identify potential FDA approved drugs. Initial screening of the top candidates by MTT survival assay narrowed the search to Guanabenz, an alpha-2 receptor (ADRA2) agonist and antihypertensive drug. MTT survival assays showed that Guanabenz significantly lowered survival of various human and mouse PDAC cell lines. Immunoblot analysis showed Guanabenz attenuating pCREB (involved in GPCR signaling) and ERK ½ kinase in the Ras signaling pathway. Mouse models treated with Guanabenz showed the drug’s tumor suppressive properties with the prevention of preneoplastic legion (PanIN) formation, a landmark precursor in tumorigenesis of pancreatitis induced PDAC. These experiments confirm the identity of Guanabenz as a novel treatment for PDAC as well as the potential in targeting the ADRA2 pathway in PDAC drug development. Further, this work confirms drug repositioning as an effective way of identifying novel treatments in PDAC.

Type of resource	text
Date created	June 15, 2014

Author	Castro Paz, Imilce
Advisor	Mazur, Pawel
Advisor	Jones, Patricia
Primary advisor	Sage, Julien
Degree granting institution	Stanford University, Department of Biology, 2014

Subject	Drug Repositioning
Subject	DNA microarray
Subject	KRAS signaling pathway
Subject	PanINs
Subject	Pancreatic ductal adrenocarcinoma
Subject	cerulein induced pancreatitis
Subject	Guanabenz
Subject	Biology
Genre	Thesis

Location	https://purl.stanford.edu/zt291fd2371

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Preferred Citation: Castro Paz, Imilce and Mazur, Pawel and Jones, Patricia and Sage, Julien. (2013). Bioinformatics approach identifies Guanabenz as potential therapeutic for Pancreatic Ductal Adrenocarcinoma through attenuation of GPCRs and Ras Signaling. Stanford Digital Repository. Available at: http://purl.stanford.edu/zt291fd2371

Undergraduate Theses, Department of Biology, 2013-2014

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