The overall objecfive of this project is to utilize genomic and genetic data obtained from human pancreatic cancer (PCa) samples and observations from mouse models of PCa to understand the genetic events that drive tumor progression and treatment resistance in this disease. These mouse models include recent observations about PCa genesis and novel Sleeping Beauty (SB) transposon-based, forward genefic screens for PCa. The human PCa samples have been obtained from a novel collection via a rapid autopsy program developed by co-leader Christine lacobuzio-Donahue and fine needle aspirations (FNA) obtained by members of this SPORE group. These samples are being profiled for genetic alterations and markers identified in the mouse models. This has provided insight into the genetic drivers of PCa development and candidates for causing speciflc PCa phenotypes such as metastatic spread. We will discover novel genefic correlates of tumor progression, metastasis, and outcome using gene copy number, mRNA levels, sequence alterations and immunohistochemistry. Functional validation of novel targets will take place using gene overexpression or shRNA gene "knockdown" in PCa cell lines, xenografts, and mouse transgenic models. Moreover, these mulfi-dimensional data will be the basis for investigafing pharmacological suppression of pathways that cooperate to drive PCa development and progression. Our inifial focus is on a novel regulator of the TGF-beta and other pathways called Usp9x, and PTEN-regulated pathways. These experiments will set the stage for new clinical trials for PCa to be carried out during the next project period.
Pancreatic cancer remains a massive clinical challenge because key steps in the progression of the disease are still not idenfified. Also, the specific cooperating mutations and pathways that combine to make this cancer deadly are not identifled. This proposal will idenfify these cooperafing pathways and test therapies based on this knowledge.
|Ramesh, Jayapal; Kim, Hwasoon; Reddy, Kartika et al. (2014) Impact of pancreatic stent caliber on post-endoscopic retrograde cholangiopancreatogram pancreatitis rates in patients with confirmed sphincter of Oddi dysfunction. J Gastroenterol Hepatol 29:1563-7|
|Kaliberov, S A; Kaliberova, L N; Buchsbaum, D J et al. (2014) Experimental virotherapy of chemoresistant pancreatic carcinoma using infectivity-enhanced fiber-mosaic oncolytic adenovirus. Cancer Gene Ther 21:264-74|
|Bohrer, Laura R; Chuntova, Pavlina; Bade, Lindsey K et al. (2014) Activation of the FGFR-STAT3 pathway in breast cancer cells induces a hyaluronan-rich microenvironment that licenses tumor formation. Cancer Res 74:374-86|
|Dmitriev, Igor P; Kashentseva, Elena A; Kim, Kenneth H et al. (2014) Monitoring of biodistribution and persistence of conditionally replicative adenovirus in a murine model of ovarian cancer using capsid-incorporated mCherry and expression of human somatostatin receptor subtype 2 gene. Mol Imaging 13:|
|Chio, Iok In Christine; Yordanov, Georgi; Tuveson, David (2014) MAX-ing out MYC: a novel small molecule inhibitor against MYC-dependent tumors. J Natl Cancer Inst 106:|
|Auer, H; Mobley, J A; Ayers, L W et al. (2014) The effects of frozen tissue storage conditions on the integrity of RNA and protein. Biotech Histochem 89:518-28|
|Hébert-Magee, Shantel; Varadarajulu, Shyam; Frost, Andra R et al. (2014) Primary pancreatic leiomyosarcoma: a rare diagnosis obtained by EUS-FNA cytology. Gastrointest Endosc 80:361-2|
|Kim, Hyunki; Rigell, Christopher J; Zhai, Guihua et al. (2014) Antagonistic effects of anti-EMMPRIN antibody when combined with chemotherapy against hypovascular pancreatic cancers. Mol Imaging Biol 16:85-94|
|Reddy, Kartika; Hooper, Kari; Frost, Andra et al. (2014) Intraductal papillary carcinoma of common bile duct diagnosed by endoscopic ultrasound-guided fine-needle aspiration. Endoscopy 46 Suppl 1 UCTN:E248-9|
|Desai, Leena P; Zhou, Yong; Estrada, Aida V et al. (2014) Negative regulation of NADPH oxidase 4 by hydrogen peroxide-inducible clone 5 (Hic-5) protein. J Biol Chem 289:18270-8|
Showing the most recent 10 out of 53 publications