MISSION

prostaglandin E2 in non-small-cell lung cancer cells by up-regulating 15-hydroxyprostaglandin
dehydrogenase. Mol Pharmacol 2007;71:1715-20.
Hazra S, Dubinett SM. Ciglitazone mediates COX-2 dependent suppression of PGE2 in human non-small
cell lung cancer cells. Prostaglandins Leukot Essent Fatty Acids 2007;77:51-8.
Hazra S, Kostyantyn K, Walser T, Gardner B, Lee G, Shay J, Minna J, Horvath S, Dubinett S. A systems
approach to the preclinical evaluation of targeted chemoprevention for lung cancer. Cancer Prevention
Research 1 (7 Supplement), A136, November 1, 2008).
CANCER, LUNG
COMPLETED RESEARCH
METHYLATION ANALYSIS OF LUNG CANCERS FROM SMOKING AND NON-SMOKING WOMEN
William P. Bennett, MD, MS; City of Hope; CIA 2004
Tobacco carcinogens cause distinctive mutations in lung cancers. For example, the p53 “mutation
signature” can discriminate groups of tumors from smokers and non-smokers, but it cannot classify
individual tumors effectively, because informative mutations are sparse. Epigenetic changes occur more
frequently than mutations, so Dr. Bennett and colleagues developed a “methylation signature” of
incinerated tobacco.
The group accomplished this goal by isolating genomic DNA from formalin-fixed, paraffin-embedded
tissues, which was subsequently subjected to bisulfite modification, which converts unmethylated cytosines
to uracils. Segments of CpG islands were amplified by PCR, and methylation was quantified by mass
spectrometry (www.sequenom.com). The two principal advantages over other technologies were: 1)
increased efficiency because many CpG sites are interrogated within a single PCR product; and 2)
quantitative assessments because the methylated and unmethylated forms of a single CpG site are separated
by mass differences that can be measured by mass spectrometry.
The group analyzed the methylation status of 27 CpG units in promoter regions of the following genes:
CDH13, p16/CDKN2A, and RassF1A from 30 smokers and 8 non-smokers. They found that: 1) 12 of
30 (40%) tumors from smokers have more methylation in p16/CDKN2A and RassF1A than any of the
eight non-smokers; 2) smokers have more moderate to high-level (30-100%) methylation than nonsmokers
in p16/CDKN2A and RassF1A; 3) non-smokers have more low-level (1-10%) methylation than
smokers; and 4) smokers and non-smokers have comparable amounts of methylation in CDH13.
By developing a robust “tobacco signature” based on methylation rates at hotspot CpG sites lung
cancers in non-smokers caused by exposure to SHS will be more readily identified.
FAMRI Supported Publications
Bennett, WP, Larson G, Xiong W, Rivas G, Kernstine KH, Pfeifer GP. Methylation analysis of lung cancers
from smoking and non-smoking women. Proc Am Assoc for Cancer Res 2008;49:7.
TGF BETA SIGNALING IN LUNG CANCER: A THERAPEUTIC TARGET
Pran Datta, PhD; Vanderbilt University; CIA 2005
Dr. Datta’s hypothesis stated that loss of transforming growth factor-beta receptor type II (TGF
betaRII) in NSCLC and SCLC is primarily due to the epigenetic change, histone deacetylation. This
promotes unresponsiveness to transforming growth factor-beta (TGF- beta)-induced tumor suppressive
effects, and restoration of this signaling may be a potential alternative or addition to radiation as a lung
cancer treatment. The aims of the study were: 1) to determine the molecular mechanism of TGF beta RII
downregulation in primary lung cancer; 2) to determine if restoration of TGF beta signaling re-establishes
tumor suppressor function or tumor-promoting effects of TGF beta; and 3) to investigate the radiationsensitizing
effects of the histone deacetylase inhibitor MS-275 in vitro and in vivo in human lung cancer
preclinical models. Thus far, they have observed that TGF-beta-induced tumor suppressor function is
restored in TGF beta-resistant lung cancer cells either by exogenous expression of TGF betaRII or by the
treatment with histone deacetylase inhibitors (HDI). Dr. Datta’s group has identified a region of the TGF
betaRII promoter required for its activation by HDI and proteins that are involved in the regulation of
TGF betaRII expression using proteomics and biochemical methods.
FAMRI Supported Publications
Anumanthan G, Halder SK, Friedman D, Datta PK. Oncogenic STRAP modulates the function of Ewing
1 1 8 P A G E