Evaluation of Pharmacodynamic Responses to Cancer Therapeutic Agents Using DNA Damage Markers

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Deborah WilskerRobert J Kinders

Abstract

We sought to examine the pharmacodynamic activation of the DNA damage response (DDR) pathway in tumors following anticancer treatment for confirmation of target engagement. We evaluated the time course and spatial activation of 3 protein biomarkers of DNA damage recognition and repair (γH2AX, pS343-Nbs1, and Rad51) simultaneously in a quantitative multiplex immunofluorescence assay (IFA) to assess DDR pathway activation in tumor tissues following exposure to DNA-damaging agents. Because of inherent biological variability, baseline DDR biomarker levels were evaluated in a colorectal cancer microarray to establish clinically relevant thresholds for pharmacodynamic activation. Xenograft-bearing mice and clinical colorectal tumor biopsies obtained from subjects exposed to DNA-damaging therapeutic regimens demonstrated marked intratumor heterogeneity in the timing and extent of DDR biomarker activation due, in part, to the cell-cycle dependency of DNA damage biomarker expression. We have demonstrated the clinical utility of this DDR multiplex IFA in preclinical models and clinical specimens following exposure to multiple classes of cytotoxic agents, DNA repair protein inhibitors, and molecularly targeted agents, in both homologous r...Continue Reading

References

Apr 1, 1992·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·E K RowinskyS H Kaufmann
Nov 13, 1999·Nature Cell Biology·P Clute, J Pines
Mar 29, 2000·The Journal of Biological Chemistry·E P RogakouW M Bonner
Dec 2, 2000·Nature·B B Zhou, S J Elledge
Jul 11, 2002·The American Journal of Pathology·James A WohlschlegelAnindya Dutta
May 3, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Cherrie K DonawhoDavid J Frost
May 9, 2007·The Journal of Experimental Medicine·Simone DifilippantonioAndré Nussenzweig
Aug 24, 2007·The Journal of Biological Chemistry·Alan Yueh-Luen LeeXiaohua Wu
Jan 28, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Lihua H WangRobert J Kinders
Apr 8, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Asima MukhopadhyayNicola J Curtin
Aug 31, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Monika GraeserNicholas C Turner
Sep 9, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Christophe E RedonYves Pommier
Oct 7, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Robert J KindersUNKNOWN National Cancer Institute Phase 0 Clinical Trials Team
Nov 9, 2010·Methods in Molecular Biology·Christophe E RedonOlga A Sedelnikova
Dec 27, 2011·Cancer Letters·Alesia IvashkevichOlga A Martin
Apr 3, 2012·Nucleic Acids Research·Lumir KrejciXiaolan Zhao
Feb 13, 2013·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Moritz BirkelbachHenning Willers
Apr 19, 2013·British Journal of Clinical Pharmacology·Ruth Thompson, Alan Eastman
Jun 28, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Carl G EngelkeMeredith A Morgan
Oct 14, 2014·Mutation Research. Genetic Toxicology and Environmental Mutagenesis·Asako HaradaMasayuki Mishima
Jan 23, 2015·Journal of Cell Science·Indra A ShaltielRené H Medema
Mar 4, 2015·The Journal of Cell Biology·Ralph ZellwegerMassimo Lopes
Dec 10, 2015·Nature·Alexandre OrthweinDaniel Durocher
Feb 5, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Patricia M LoRussoGeoffrey I Shapiro
Mar 24, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Apurva K SrivastavaRalph E Parchment
Oct 19, 2017·Nature Communications·Sofija MijicMassimo Lopes
Dec 9, 2017·Molecular Cell·Annabel QuinetAlessandro Vindigni

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cell Cycle Pathways

Cell cycle is a complex process regulated by several signal transduction pathways and enzymes. Here is the latest research on regulation of cell cycle and cell cycle pathways.

Cancer Genomics (Keystone)

Cancer genomics approaches employ high-throughput technologies to identify the complete catalog of somatic alterations that characterize the genome, transcriptome and epigenome of cohorts of tumor samples. Discover the latest research using such technologies in this feed.