TY - JOUR
T1 - Aberrant epigenetic regulation
T2 - a central contributor to lung carcinogenesis and a new therapeutic target
AU - Juergens, Rosalyn A.
AU - Rudin, Charles M.
PY - 2013
Y1 - 2013
N2 - Carcinogenesis is driven by a combination of genetic and epigenetic abnormalities. Aberrancies in gene promoter methylation patterns and histone acetylation are associated with silencing of tumor suppressor genes in lung cancer and other solid tumors. Identification of key epigenetic modifications has been shown to be prognostic in early-stage non-small cell lung cancer. Previous clinical trials aimed at modifying the epigenome with single-agent demethylating agents or histone deacetylase inhibitors given at maximally tolerated doses have provided disappointing results. A recent clinical trial using a combination of a demethylating agent and a histone deacetylase inhibitor at "epigenetically targeted" doses concomitantly has shown promising results, including a patient with a complete objective response. Biomarkers associated with this clinical trial suggest that patients who undergo robust demethylation, as detected in the peripheral blood after a month on treatment, identifies those who gain the most benefit from this novel treatment strategy. Based on observations of unusually durable responses to subsequent therapy after administration of combined epigenetic therapy, epigenetic therapy may also play a role in "priming" patients to better respond to standard cytotoxic therapy or immunotherapy. This manuscript will review the data on the role of epigenetics in lung cancer and the history of epigenetic treatments in lung cancer spanning over the last 40 years.
AB - Carcinogenesis is driven by a combination of genetic and epigenetic abnormalities. Aberrancies in gene promoter methylation patterns and histone acetylation are associated with silencing of tumor suppressor genes in lung cancer and other solid tumors. Identification of key epigenetic modifications has been shown to be prognostic in early-stage non-small cell lung cancer. Previous clinical trials aimed at modifying the epigenome with single-agent demethylating agents or histone deacetylase inhibitors given at maximally tolerated doses have provided disappointing results. A recent clinical trial using a combination of a demethylating agent and a histone deacetylase inhibitor at "epigenetically targeted" doses concomitantly has shown promising results, including a patient with a complete objective response. Biomarkers associated with this clinical trial suggest that patients who undergo robust demethylation, as detected in the peripheral blood after a month on treatment, identifies those who gain the most benefit from this novel treatment strategy. Based on observations of unusually durable responses to subsequent therapy after administration of combined epigenetic therapy, epigenetic therapy may also play a role in "priming" patients to better respond to standard cytotoxic therapy or immunotherapy. This manuscript will review the data on the role of epigenetics in lung cancer and the history of epigenetic treatments in lung cancer spanning over the last 40 years.
UR - http://www.scopus.com/inward/record.url?scp=84946222432&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84946222432&partnerID=8YFLogxK
U2 - 10.1200/EdBook_AM.2013.33.e295
DO - 10.1200/EdBook_AM.2013.33.e295
M3 - Article
C2 - 23714528
AN - SCOPUS:84946222432
SN - 1548-8756
JO - American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting
JF - American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting
ER -