New therapy for lung cancer using radioiodide

Institution:	University of California, Los Angeles
Investigator(s):	Min Huang, M.D., M.S.
Award Cycle:	2000 (Cycle 9)	Grant #: 9KT-0215	Award: $225,000
Subject Area:	Cancer
Award Type:	New Investigator Awards

Abstracts

Initial Award Abstract

Tobacco-use is the leading preventable cause of death and disability in the United States. During the first decades of the 20th century, lung cancer was rare; however, as cigarette smoking became increasingly popular the incidence of lung cancer became epidemic. In 1930, the lung cancer death rate for men was 4.9 per 100,000; in 1990, the rate had increased to 75.6 per 100,000. Today, lung cancer is the leading cause of cancer death in both men and women in the United States. Currently, there is no reliably effective therapy for patients with inoperable lung cancer. The prognosis for inoperable lung cancer is dismal because current therapies cannot control widespread metastases, which will eventually cause excruciating pain, vital organ dysfunction, and death. Development of new therapies for lung cancer is clearly a clinical priority.

Our laboratory has engaged in developing new therapeutic strategies for lung cancer including gene therapy. The normal accumulation of iodide by the thyroid gland is accomplished by iodide uptake and retention. Using gene therapy, this iodide uptake and retention mechanism can be synthetically introduced into lung cancer cells. Recently, we have found that radioactive iodide (radioiodide) can be concentrated to therapeutic levels in lung cancer. Consequently, the elevated levels of radioiodide in lung cancer will lead to cancer cell death. To further explore the biological basis of this new therapy for lung cancer, we propose to define the parameters of radioiodide uptake and retention. This will include a series of studies to determine the optimal time and dose scheme for radioiodide administration, identification of intracellular proteins that bind radioiodide to facilitate slow turn-over, and cell death and repair mechanisms in response to radioiodide.

A marked increase in radioiodide uptake and retention in lung cancer is achieved by introducing genes that are normally found in the thyroid gland but not normally present in lung cancer cells. Referred to as gene therapy, we simultaneously transfer two genes known as the sodium iodide symporter (NIS) and thyroperoxidase (TPO) genes into lung cancer cells. NIS mediates iodide uptake and TPO causes iodide retention within the cells. Transfection of these two genes into lung cancer cells will lead to radioiodide accumulation and cell death. To improve the efficacy of this new therapy for lung cancer, we propose to construct new delivery systems for these genes by using viruses that can more efficiently enter tumor cells.

These studies will provide information that will assist in both understanding and improving the efficacy of this new therapy for lung cancer using radioiodide. This will lead to further perfection of the system that could be eventually applied for locally advanced lung cancer in clinical trials.

Publications

Thyroperoxidase gene transfer augments NIS-mediated radioiodide uptake and retention in non-small cell lung cancer
Periodical: American Journal of Respiratory and Critical Care Medicine			Index Medicus:
Authors: Huang M, Batra RK, Kogai T, et al				ABS
Yr: 2001	Vol: 163	Nbr: 5	Abs: A528	Pg:

Retinoic acid induces sodium/iodide symporter gene expression and radioiodide uptake in the MCF-7 breast cancer cell line
Periodical: Proceedings of the National Academy of Sciences of the United States of America			Index Medicus:
Authors: Takahiko K, Schultz JJ, Johnson LS, Huang M, Brent GA				ART
Yr: 2000	Vol: 97	Nbr: 15	Abs:	Pg: 8519-8524

Ectopic expression of the thyroperoxidase gene augments radioiodide uptake and retention mediated by the sodium iodide symporter in non-small cell lung cancer.
Periodical: Cancer Gene Therapy			Index Medicus:
Authors: Huang M, Batra RK, Kogai T, Lin Y, Hershman JM, Lichtenstein A, Sharma S, Zhu L, et al				ART
Yr: 2001	Vol: 8	Nbr: 8	Abs:	Pg: 612-618

Genetic modification of cyclooxygenase-2 regulates CD44 dependent invasion in non-small cell lung cancer.
Periodical: Journal of Biological Chemistry			Index Medicus:
Authors: Dohadwala M, Luo J, Lyn Y, Dougherty GL, Sharma S, Huang, M, Pold M, Batra RK et al				ART
Yr: 2001	Vol: 276	Nbr: 24	Abs:	Pg: 20809-12

SLC reduces pulmonary tumor burden in spontaneous murine bronchoalveolar carcinoma.
Periodical: Cancer Research			Index Medicus:
Authors: Sharma S, Stolina M, Zhu L, Lin Y, Batra RK, Huang M, Streiter R, and Dubinett SM				ART
Yr: 2001	Vol: 61	Nbr: 17	Abs:	Pg: 6406-12

Interleukin-7 inhibits fibroblast TGF-beta production and signalin in pulmonary fibrosis.
Periodical: Journal of Clinical Investigation			Index Medicus:
Authors: Huang M, Sharma S, Dohadwala M, Pold M, Dubinett SM				ART
Yr: 2002	Vol: 109	Nbr:	Abs:	Pg: 1-7

Cyclooxygenase 2-dependent regulation of antitumor immunity in lung cancer.
Periodical: Methods in Molecular Medicine			Index Medicus:
Authors: Sharma S, Huang M, Dohadwala M, Pold M, Dubinett SM				ART
Yr: 2003	Vol: 75	Nbr:	Abs:	Pg: 723-736

Tumor cyclooxygenase 2-dependent suppression of dendritic cell function.
Periodical: Cancer Research			Index Medicus:
Authors: Sharma S, Stolina M, Yang SC, Baratelli F, Lin JF, Atianzar K, Luo J, Zhu L, Lin Y				ART
Yr: 2003	Vol: 9	Nbr: 3	Abs:	Pg: 961-968

Thyroperoxidase gene transfer augments NIS-mediated radioiodide uptake and retention in non-small cell lung cancer
Periodical: American Journal of Respiratory and Critical Care Medicine			Index Medicus:
Authors: Huang M, Batra RK, Kogai T, et al				ABS
Yr: 2001	Vol: 163	Nbr: 5	Abs: A528	Pg:

Retinoic acid induces sodium/iodide symporter gene expression and radioiodide uptake in the MCF-7 breast cancer cell line
Periodical: Proceedings of the National Academy of Sciences of the United States of America			Index Medicus:
Authors: Takahiko K, Schultz JJ, Johnson LS, Huang M, Brent GA				ART
Yr: 2000	Vol: 97	Nbr: 15	Abs:	Pg: 8519-8524

Ectopic expression of the thyroperoxidase gene augments radioiodide uptake and retention mediated by the sodium iodide symporter in non-small cell lung cancer.
Periodical: Cancer Gene Therapy			Index Medicus:
Authors: Huang M, Batra RK, Kogai T, Lin Y, Hershman JM, Lichtenstein A, Sharma S, Zhu L, et al				ART
Yr: 2001	Vol: 8	Nbr: 8	Abs:	Pg: 612-618

Genetic modification of cyclooxygenase-2 regulates CD44 dependent invasion in non-small cell lung cancer.
Periodical: Journal of Biological Chemistry			Index Medicus:
Authors: Dohadwala M, Luo J, Lyn Y, Dougherty GL, Sharma S, Huang, M, Pold M, Batra RK et al				ART
Yr: 2001	Vol: 276	Nbr: 24	Abs:	Pg: 20809-12

SLC reduces pulmonary tumor burden in spontaneous murine bronchoalveolar carcinoma.
Periodical: Cancer Research			Index Medicus:
Authors: Sharma S, Stolina M, Zhu L, Lin Y, Batra RK, Huang M, Streiter R, and Dubinett SM				ART
Yr: 2001	Vol: 61	Nbr: 17	Abs:	Pg: 6406-12

Interleukin-7 inhibits fibroblast TGF-beta production and signalin in pulmonary fibrosis.
Periodical: Journal of Clinical Investigation			Index Medicus:
Authors: Huang M, Sharma S, Dohadwala M, Pold M, Dubinett SM				ART
Yr: 2002	Vol: 109	Nbr:	Abs:	Pg: 1-7

Cyclooxygenase 2-dependent regulation of antitumor immunity in lung cancer.
Periodical: Methods in Molecular Medicine			Index Medicus:
Authors: Sharma S, Huang M, Dohadwala M, Pold M, Dubinett SM				ART
Yr: 2003	Vol: 75	Nbr:	Abs:	Pg: 723-736

Tumor cyclooxygenase 2-dependent suppression of dendritic cell function.
Periodical: Cancer Research			Index Medicus:
Authors: Sharma S, Stolina M, Yang SC, Baratelli F, Lin JF, Atianzar K, Luo J, Zhu L, Lin Y				ART
Yr: 2003	Vol: 9	Nbr: 3	Abs:	Pg: 961-968