MISSION

were sequenced from NSCLC tissue and matched normal tissue. Somatic mutations of the estrogen
growth factor receptor (EGFR) gene were found in 15 out of 58 unselected tumors from Japan and 1 out
of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib caused NSCLC
regression more frequently in Japan, as well as in certain US cancer samples with EGFR gene mutations.
The results suggested that EGFR gene mutations might predict sensitivity to gefitinib. It may be necessary
to consider the power of clinical trials to identify differences within ethnic subgroups rather than assume
equality in responses to drug therapies.
ROLE OF ALDEHYDE DEHYDROGENASES IN THE PATHOGENESIS AND BIOLOGY OF LUNG CANCER
Jan Moreb, MD; University of Florida; CIA 2003
Dr. Moreb demonstrated that the enzymes aldehyde dehydrogenase (ALDH)1A1 and ALDH3A1 are
highly expressed in squamous cell lung cancer (SCCA), adenocarcinoma (AdenoCA), and NSCLC, while
very little expression can be detected in SCLC. Atypical pneumocytes demonstrated significantly higher
levels of expression of ALDH-1A1 and ALDH-3A1 than normal pneumocytes, the normal counterpart of
AdenoCA, which is suggestive of upregulation during malignant transformation to AdenoCA. On the
other hand, similar levels of expression were observed in bronchial epithelium, the normal counterpart of
SCCA. Cigarette smoking results in significantly increased expression of these enzymes in normal
pneumocytes. Small interfering RNAs were shown to specifically inhibit ALDH-1A1 or ALDH-3A1 and
result in increased 4-hydroperoxycyclophosphamide toxicity in the A549 lung cancer cell line. An Aldefluor
assay was adapted successfully to measure ALDH activity in lung cancer cells and provided real-time
changes in ALDH activity in viable cells treated with siRNA or chemotherapy. Lentiviral vectors had great
efficacy and specificity in the inhibition of either enzyme. Differences in gene transcription were
determined between wild-type A549 cells and lenti 1+3 cells and a number of genes were categorized that
are either repressed or induced two-fold when compared with the wild-type cells.
FAMRI Supported Publications
Moreb JS, Gabr A, Vartikar GR, Gowda S, Zucali JR, Mohuczy D. Retinoic acid down regulates aldehyde
dehydrogenase and increases cytotoxicity of 4-hydroperoxycyclophosphamide and acetaldehyde. J
Pharmacol Exp Ther 2005;312:339-345.
IDENTIFICATION OF NEW MOLECULAR TARGETS IN LUNG CANCER
Pierre P. Massion, MD; Vanderbilt University; CIA 2003
Dr. Massion and collaborators identified molecular abnormalities in invasive and preinvasive lung
cancers. Their aims were 1) to identify amplified and deleted genomic regions in invasive squamous,
adeno, large, and small cell lung cancers using array-comparative genomic hybridization; 2) to identify
potential targets in preinvasive lung cancer using matrix-assisted laser desorption/ionization mass
spectrometry; and 3) to clinically validate candidate genes and proteins associated with lung cancer. They
characterized eight tissue microarrays from a total of 360 lung cancers for validation of biomarkers in a
high-throughput fashion.
FAMRI Supported Publications
Gonzalez AL, Roberts RL, Massion PP, Olson SJ, Shyr Y, Shappell SB. 15-lipoxygenase-2 expression in
benign and neoplastic lung: an immunohistochemical study and correlation with tumor grade and
proliferation. Hum Pathol 2004;35:840-849.
Massion PP, Taflan PM, Rahman SM, Yildiz P, Shyr Y, Edgerton MR, Westfall MD, Roberts JR, Pietenpol
JA, Carbone DP, Gonzalez AL. Analysis of p63 in lung tumorigenesis. Cancer Res 2003;7113-7121.
Massion PP, Taflan PM, Rahman SM, Yildiz P, Shyr Y, Carbone DP, Gonzalez AL. Role of p63
amplification and overexpression in lung cancer development. Chest 2004;125 (5 Suppl):102S.
Massion PP, Taflan PM, Shyr Y, Rahman SM, Yildiz P, Shakthour B, Edgerton ME, Ninan M, Andersen
JJ, Gonzalez AL. Early involvement of the phosphatidylinositol 3-kinase/Akt pathway in lung cancer
progression. Am J Respir Crit Care Med 2004;170:1088-1094.
Rahman SM, Shyr Y, Yildiz PB, Gonzalez AL, Li H, Zhang X, Chaurand P, Yanagisawa K, Slovis BS,
Miller RF, Ninan M, Miller YE, Franklin WA, Caprioli RM, Carbone DP, Massion PP. Proteomic
patterns of preinvasive bronchial lesions. Am J Respir Crit Care Med 2005;172:1556-1562.
Wardwell NR, Massion PP. Novel strategies for the early detection and prevention of lung cancer. Semin
Oncol 2005;32:259-268.
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