Another S. Gryaznov article.

[hiprock88]

Targeting homologous recombination and telomerase in Barrett's adenocarcinoma: impact on telomere maintenance, genomic instability and tumor growth.

Lu R1, Pal J2, Buon L2, Nanjappa P2, Shi J3, Fulciniti M3, Tai YT3, Guo L4, Yu M4, Gryaznov S5, Munshi NC3, Shammas MA2.
Author information: 11] Department of Adult Oncology, Harvard (Dana Farber) Cancer Institute and VA Health Care System, Boston, MA, USA [2] Department of Clinical Laboratory, Fudan University Shanghai Cancer Center and Shanghai Medical School, Shanghai, China.2Department of Adult Oncology, Harvard (Dana Farber) Cancer Institute and VA Health Care System, Boston, MA, USA.31] Department of Adult Oncology, Harvard (Dana Farber) Cancer Institute and VA Health Care System, Boston, MA, USA [2] Department of Medicine, Harvard Medical School, Boston, MA, USA.4Department of Clinical Laboratory, Fudan University Shanghai Cancer Center and Shanghai Medical School, Shanghai, China.5Department of Nucleic Acid Chemistry, Geron Corporation, Menlo Park, CA, USA.
Abstract

Homologous recombination (HR), a mechanism to accurately repair DNA in normal cells, is deregulated in cancer. Elevated/deregulated HR is implicated in genomic instability and telomere maintenance, which are critical lifelines of cancer cells. We have previously shown that HR activity is elevated and significantly contributes to genomic instability in Barrett's esophageal adenocarcinoma (BAC). The purpose of this study was to evaluate therapeutic potential of HR inhibition, alone and in combination with telomerase inhibition, in BAC. We demonstrate that telomerase inhibition in BAC cells increases HR activity, RAD51 expression, and association of RAD51 to telomeres. Suppression of HR leads to shorter telomeres as well as markedly reduced genomic instability in BAC cells over time. Combination of HR suppression (whether transgenic or chemical) with telomerase inhibition, causes a significant increase in telomere attrition and apoptotic death in all BAC cell lines tested, relative to either treatment alone. A subset of treated cells also stain positive for β-galactosidase, indicating senescence. The combined treatment is also associated with decline in S-phase and a strong G2/M arrest, indicating massive telomere attrition. In a subcutaneous tumor model, the combined treatment resulted in the smallest tumors, which were even smaller (P=0.001) than those that resulted from either treatment alone. Even the tumors removed from these mice had significantly reduced telomeres and evidence of apoptosis. We therefore conclude that although telomeres are elongated by telomerase, elevated RAD51/HR assist in their maintenance/stabilization in BAC cells. Telomerase inhibitor prevents telomere elongation but induces RAD51/HR, which contributes to telomere maintenance/stabilization and prevention of apoptosis, reducing the efficacy of treatment. Combining HR inhibition with telomerase renders telomeres more vulnerable to degradation and significantly increases/expedites their attrition, leading to apoptosis. We therefore demonstrate that a therapy targeting HR and telomerase has the potential to prevent both tumor growth and genomic evolution in BAC.
PMCID: PMC3940666 Free PMC Article

[Fishermangents]

Thanks, great article. Another case for combo therapy. Will be added to the repository of imetelstat.eu.

[cheng_ho]

Nice find.

[biopearl]

Hip, thanks for posting the article. This article is from 2014 and definitely worth adding to Fish's compendium. I do think devoting our collective time in trying to discern whether EU approval is close is worthwhile. Wish Annie hi links and some knowledge of EU protocols were available to us. bp

[Fishermangents]

Here is the link: http://www.ncbi.nlm.nih.gov/pubmed/23604115

[Fishermangents]

Joan_De: I made a mistake and disapproved your post. Could you send it again?