""""""""Epigenetics"""""""" refers to changes in phenotype or gene expression caused by mechanisms other than changes in the underlying DNA sequence. Abnormal epigenetic control mechanisms are now regarded as significant contributing factors to the pathophysiology of different diseases, including cancer. The main epigenetic mechanisms that induce phenotypic changes in mammalian cells are DNA methylation, histone methylation and histone acetylation. Many recent targeted drug development efforts have been directed towards the modification of one or more of these epigenetic mechanisms. In that regard, several cell culture based assays are being used to analyze different epigenetic processes, and small molecule drugs modulate these epigenetic processes. However these tests are not capable of predicting the exact behavior of drug pharmacokinetics and pharmacodynamics in living subjects. The current intense efforts to develop such drugs, as well as an ever increasing interest in epigenetics research, creates a paramount need to develop new more meaningful molecular imaging strategies that can specifically interrogate different epigenetic mechanisms in vivo. The main goal of this proposal is to develop novel in vivo imaging strategies to monitor cellular epigenetic processes in living animals, evaluating these techniques when imaging the basic epigenetic shifts occurring in the development of different cancers, and to apply these imaging platforms to study therapeutic drugs that modulate these processes in cancer. Specifically, we wish to image and quantitate histone methylation in vivo, and to apply this novel analytical tool to evaluate drugs that modulate histone methylation, which may have important applications in molecular therapeutics of cancer. This will be achieved by developing: 1) Optical bioluminescence (Split-Luciferase-complementation), and 2) microPET (Split-Thymidine kinase complementation) imaging sensors. Combinatorial therapies using different epigenetic modulators (inhibitors of histone deacetylases in combination with histone methyltransferases) is curently considered as a new approach for treating cancers and several other intractable cellular diseases. The sensors we are planning to develop by this grant, are having the potential to image molecular events in both cells and in live animals. These sensors will improve the use of epigenetic modulators in translational clinical applications by enabling drug screening and their pre-clinical evaluations in living animals. The aberrant histone methylation has been considered as an important player in the development of cancer. In summary, this proposal will lead to the development of highly sensitive in vivo imaging methods that can be used to further epigenetic research, as well as accelerating the pre-clinical evaluation of drugs targeting different cancers and other cellular diseases.

Public Health Relevance

Currently, abnormal epigenetic mechanisms are regarded as significant contributing factors to the pathophysiology of different diseases, including cancer. Several cell-based assays are being used to identify and analyze drugs that target different epigenetic mechanisms. However most of these tests are not capable of predicting the exact behavior of drug pharmacokinetics and pharmacodynamics in living subjects. The ever- increasing interest in epigenetics research creates an immediate need to develop new more meaningful molecular imaging strategies that can specifically interrogate different epigenetic mechanisms in vivo. The main goal of this proposal is to develop novel in vivo imaging strategies to monitor cellular epigenetic processes in living animals. Specifically, we wish to image and quantitate histone methylation in vivo, and to apply this novel analytical tool to the evaluation of drugs that modulate epigenetic events, which may have important applications in molecular therapeutics of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA161091-01A1
Application #
8245609
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Menkens, Anne E
Project Start
2012-04-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$326,181
Indirect Cost
$118,681
Name
Stanford University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Gaur, Shuchi; Bhargava-Shah, Aarohi; Hori, Sharon et al. (2017) Engineering Intracellularly Retained Gaussia Luciferase Reporters for Improved Biosensing and Molecular Imaging Applications. ACS Chem Biol 12:2345-2353
Paulmurugan, Ramasamy; Bhethanabotla, Rohith; Mishra, Kaushik et al. (2016) Folate Receptor-Targeted Polymeric Micellar Nanocarriers for Delivery of Orlistat as a Repurposed Drug against Triple-Negative Breast Cancer. Mol Cancer Ther 15:221-31
Sekar, Thillai V; Paulmurugan, Ramasamy (2016) Imaging Histone Methylations in Living Animals. Methods Mol Biol 1461:203-15
Sekar, Thillai V; Foygel, Kira; Devulapally, Rammohan et al. (2016) Molecular Imaging Biosensor Monitors p53 Sumoylation in Cells and Living Mice. Anal Chem 88:11420-11428
Bhargava-Shah, Aarohi; Foygel, Kira; Devulapally, Rammohan et al. (2016) Orlistat and antisense-miRNA-loaded PLGA-PEG nanoparticles for enhanced triple negative breast cancer therapy. Nanomedicine (Lond) 11:235-47
Franchi, Federico; Peterson, Karen M; Paulmurugan, Ramasamy et al. (2016) Noninvasive Monitoring of the Mitochondrial Function in Mesenchymal Stromal Cells. Mol Imaging Biol 18:510-8
Sekar, Thillai V; Paulmurugan, Ramasamy (2016) Theranostic Imaging of Cancer Gene Therapy. Methods Mol Biol 1461:241-54
Devulapally, Rammohan; Foygel, Kira; Sekar, Thillai V et al. (2016) Gemcitabine and Antisense-microRNA Co-encapsulated PLGA-PEG Polymer Nanoparticles for Hepatocellular Carcinoma Therapy. ACS Appl Mater Interfaces 8:33412-33422
Sekar, Thillai V; Foygel, Kira; Massoud, Tarik F et al. (2016) A transgenic mouse model expressing an ER? folding biosensor reveals the effects of Bisphenol A on estrogen receptor signaling. Sci Rep 6:34788
Foygel, Kira; Sekar, Thillai V; Paulmurugan, Ramasamy (2015) Monitoring the Antioxidant Mediated Chemosensitization and ARE-Signaling in Triple Negative Breast Cancer Therapy. PLoS One 10:e0141913

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