Lung cancer is responsible for approximately 1/3 of all cancer related deaths in the US each year. Investigation of new paradigms, including novel therapeutic approaches, has become an urgent priority for the oncology community. Aberrant CpG island methylation has been identified as a mechanism of inactivating critical regulatory genes, and may also be useful for directing therapy. Resistance of tumor cells to methylating and monocloroethylating agents in vitro and in vivo has been linked to expression of the DNA repair protein, O6-methylguanine-DNA methyltransferase (MGMT). We have developed a methylation- specific PCR assay (MS-PCR) which has given us high specificity and sensitivity, and have demonstrated that about 1/3 of non- small cell lung cancers (NSCLC) have aberrantly methylated MGMT genes. The objective of this proposal is to test the hypothesis that patients with advanced NSCLC and aberrant MGMT methylation will be sensitive to the nitrosourea CCNU. To test this hypothesis, we will conduct a Phase II trial of CCNU in patients with Stage IIIB and IV disease whose tumors have been found to have aberrant CpG island methylation of the MGMT gene.
The specific aims of the trial are to: (1) Determine the response rate of patients with advanced NSCLC with aberrant MGMT methylation to CCNU; secondary objectives will assess time to progression and overall survival. (2) Correlate MGMT levels on immunohistochemistry (IHC) with clinical outcome. (3) Correlate IHC staining of the MGMT protein and the MS-PCR. This grant could identify a novel treatment strategy that exploits the fact that the MGMT gene responsible for protecting cells from the cytotoxic effects of CCNU is inactivated in some tumors. If efficacy is demonstrated by enhanced response rates, these studies would lead to larger scale, multi-institutional clinical trials. Moreover, this approach could facilitate future studies in which patients receive more individualized combination treatment regimens to exploit pathways that are either inactivated or to reactivate genes needed to induce cell cycle arrest and apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA088937-02
Application #
6522798
Study Section
Special Emphasis Panel (ZRG1-CONC (01))
Program Officer
Wu, Roy S
Project Start
2001-09-01
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
2
Fiscal Year
2002
Total Cost
$236,163
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715