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Abstract: Poster Presentations |

PROOF-OF-PRINCIPLE CLINICAL TRIAL OF BEXAROTENE FOR THE TREATMENT OF NON-SMALL CELL LUNG CANCER FREE TO VIEW

W J. Petty, MD*; Konstantin H. Dragnev, MD; Vincent A. Memoli, MD; James R. Rigas, MD; David Johnstone, MD; Ethan Dmitrovsky, MD
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Dartmouth Medical School, Hanover, NH


Chest


Chest. 2005;128(4_MeetingAbstracts):312S. doi:10.1378/chest.128.4_MeetingAbstracts.312S
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Abstract

PURPOSE:  Certain non-classical retinoids including the rexinoid compound, bexarotene, bypass clinical resistance to classical retinoids. Bexarotene-treatment is associated with an improvement in survival in a subset of patients. We sought to determine mechanisms of reponse or resistance to bexarotene.

METHODS:  Bexarotene-treatment was studied using a derived, RA-resistant human bronchial epithelial cell line and several non-small cell lung cancer cell lines. We then performed a proof-of-principle clinical trial in patients with resectable NSCLC. Patients underwent a pre-treatment biopsy followed by eight days of oral bexarotene and surgical resection. Pharmacokinetics and biomarker changes were assessed.

RESULTS:  Bexarotene-treatment repressed expression of cyclin D1, cyclin D3, EGFR, and phospho-EGFR in vitro. In the proof-of-principle clinical trial, ten patients were evaluable for pharmacokinetic and lipid measurements and four patients were evaluable for changes in biomarkers. A strong correlation existed between hyperlipidemia and tumor tissue drug levels. The cases with the highest tissue concentrations of the drug demonstrated repression of cyclin D1, cyclin D3, or EGFR while cases with lower tissue concentrations did not.

CONCLUSION:  Bexarotene treatment represses cyclin D1 and cyclin D3 both in vitro and in clinical lung cancers. A tumor tissue pharmacokinetic and pharmacodynamic relationship exists for this drug.

CLINICAL IMPLICATIONS:  A correlation between tumor tissue bexarotene concentrations and bexarotene-induced hyperlipidemia may help to explain why this drug would prolong survival in patients who develop hyperlipidemia.

DISCLOSURE:  W. Petty, None.

Wednesday, November 2, 2005

12:30 PM - 2:00 PM


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