22P - Global epigenetic remodeling regulates chemoradiotherapy sensitivity of cancer

Date 17 December 2016
Event ESMO Asia 2016 Congress
Session Poster lunch
Topics Anti-Cancer Agents & Biologic Therapy
Basic Science
Presenter Jingjing li
Citation Annals of Oncology (2016) 27 (suppl_9): ix1-ix8. 10.1093/annonc/mdw573
Authors J. li, D. Hao, Y. Wang, L. Wang, Z. Zhao, P. Li, L. Di
  • Faculty Of Health Medicine, University of Macau, 111111 - Macau/MO

Abstract

Background

Targeting epigenetics has great potential in treating cancers with aberrant oncogene or tumor suppressor expression caused by deregulated epigenetic modifications. The FDA has approved seven epigenetic drugs (EDs) with indicated application on hematological malignancies. The potential use of EDs in solid tumors is also actively under investigation. Current ideas about EDs are largely based on the assumption that EDs are supposed to reverse repressed tumor suppressors.

Methods

We summarized ETDs clinical trials till now and performed meta-analysis. Gene expression enrichment analysis indicated the genome profile of oncogenes and tumor suppressors affected by ETDs. We explored MNase assay, MTT assay, Immunofluorescence to confirm the mechanism that ETDs increased DNA targeted drugs (DTDs) accessibilities to nuclei. Exnograftes NOD/SCID mice were created to assess the effect of DTDs combined with ETDs.

Results

ETDs show surprisingly limited effect (0% CR and 2% PR among 1153 cases) in clinical solid tumors therapies. However, the curative effects of ETDs delivered together with DTDs are quite encouraging according to meta-analysis. Gene expression profiling revealed significant amount of differentially expressed genes which are not solely limited to tumor suppressor genes, arguing that the mechanism of ETDs in treating hematopoietic cancers should be carefully reconsidered. We found both HDAC inhibitor (SAHA) and DNMT inhibitor (Decitabine) loosen chromatin through enhancing histone acetylation and reducing DNA methylation respectively. Increased chromatin integration of cisplatin or doxorubicin and enhanced cell death were observed. Xenografted tumors in NOD/SCID mice showed increased sensitivity to DTDs combined with ETDs.

Conclusions

Given the limited effect of EDs alone, these results strongly suggest that the combination of DNA targeting chemos or irradiation and the epigenetic targeting drugs is a very promising choice in clinical tumor therapy.

Clinical trial indentification

This basic reseach does not contain trial protocol number.

Legal entity responsible for the study

Faculty of Health Science, University of Macau

Funding

Research Grant

Disclosure

All authors have declared no conflicts of interest.