Single cell resolution in vivo imaging of DNA damage following PARP inhibition

Targeting DNA repair pathways is a powerful strategy to treat cancers. To gauge efficacy in vivo , typical response markers include late stage effects such as tumor shrinkage, progression free survival, or invasive repeat biopsies. These approaches are often difficult to answer critical questions su...

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Bibliographic Details
Published in:	Scientific reports Vol. 5; no. 1; p. 10129
Main Authors:	Yang, Katherine S., Kohler, Rainer H., Landon, Matthieu, Giedt, Randy, Weissleder, Ralph
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 18-05-2015 Nature Publishing Group
Subjects:	14 631/1647 631/1647/328 Adenosine diphosphate Animals Antineoplastic Agents - pharmacology BRCA1 Protein - genetics BRCA1 Protein - metabolism Cancer Cell Line, Tumor Deoxyribonucleic acid Disease Models, Animal DNA DNA damage DNA Damage - drug effects DNA repair Drug Resistance, Neoplasm Gene Expression Genes, Reporter Humanities and Social Sciences Humans Intracellular Signaling Peptides and Proteins - metabolism Invasiveness Mice Molecular Imaging multidisciplinary Mutation Pharmacodynamics Pharmacokinetics Phthalazines - pharmacology Piperazines - pharmacology Poly(ADP-ribose) Poly(ADP-ribose) polymerase Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Poly(ADP-ribose) Polymerases - genetics Poly(ADP-ribose) Polymerases - metabolism Ribose Sarcoma, Ewing - genetics Sarcoma, Ewing - metabolism Science Single-Cell Analysis Tumor Suppressor p53-Binding Protein 1 Tumors
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Summary:	Targeting DNA repair pathways is a powerful strategy to treat cancers. To gauge efficacy in vivo , typical response markers include late stage effects such as tumor shrinkage, progression free survival, or invasive repeat biopsies. These approaches are often difficult to answer critical questions such as how a given drug affects single cell populations as a function of dose and time, distance from microvessels or how drug concentration (pharmacokinetics) correlates with DNA damage (pharmacodynamics). Here, we established a single-cell in vivo pharmacodynamic imaging read-out based on a truncated 53BP1 double-strand break reporter to determine whether or not poly(ADP-ribose) polymerase (PARP) inhibitor treatment leads to accumulation of DNA damage. Using this reporter, we show that not all PARP inhibitor treated tumors incur an increase in DNA damage. The method provides a framework for single cell analysis of cancer therapeutics in vivo .
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/srep10129