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Impaired gene helps nonsmall-cell lung cancer resist drug
October 02, 2006Findings suggest role as predictive biomarker, gene therapy target
HOUSTON-Lung cancer cells with a defective version of a potential tumor suppressor gene are highly resistant to attack by a platinum-based drug commonly used to treat the disease, researchers at The University of Texas M. D. Anderson Cancer Center and The University of Texas Southwestern Medical Center at Dallas report in the cover article of the Oct. 1 edition of Cancer Research.
The gene may provide a potential biomarker for selecting among chemotherapy choices for non-small-cell lung cancer as well as a therapeutic target for restoring the drug cisplatin's punch in treating resistant forms of the disease, says senior author Lin Ji, Ph.D., associate professor in M. D. Anderson's Department of Thoracic and Cardiovascular Surgery.
Researchers at the two institutions, working under a joint National Cancer Institute Specialized Program of Research Excellence (SPORE) in Lung Cancer grant, have identified three tumor-suppressor genes on chromosome 3. The latest paper refines the impact of one of those genes, NPRL2, on the most common form of lung cancer.
"NPRL2 has potential predictive value for care," Ji said. "If a patient's non-small-cell lung cancer lacks an active NPRL2 gene, then cisplatin likely would not be a suitable chemotherapy."
Researchers started by analyzing NPRL2 expression in 40 different lines of non-small-cell lung cancer. They found that 21 lines expressed the gene and of those 15 lines were sensitive to cisplatin. The other 19 lines had little or no expression of NPRL2 and 15 of those were cisplatin-resistant.
Follow-up laboratory experiments with resistant cell lines showed that NPRL2 expression with cisplatin drastically limited cancer cell proliferation and increased programmed cell death (apoptosis) of cancer cells by 2 to 3 fold.
"We also demonstrated in a mouse model of human cisplatin-resistant non-small-cell lung cancer that gene therapy to restore NPRL2's function makes the tumors once again sensitive to cisplatin," Ji says.
The team packaged a molecular NPRL2-producing machine called a plasmid expression vector in a nanoparticle ? a fatty sphere so small it's measured in billionths of a meter. The nanoparticles are injected into the mice, find their way to tumor cells, bind to them, and the NPRL2- producing plasmid cassette is taken up into the cell, where it expresses the gene.
Mice with a human form of cisplatin-resistant non-small-cell lung cancer who received both the NPRL2-nanoparticles and cisplatin had a 90 percent reduction in tumor volume compared with those treated only by cisplatin alone or by a combination of cisplatin and control delivery systems. The overall number of tumors was 67 to 77 percent lower in the mice who received the gene therapy/cisplatin combination compared to those in the other groups.
Ji said research continues on the possible mechanisms by which the gene kills cancer cells in combination with cisplatin and the gene's normal role in DNA damage repair and apoptosis. Interestingly, mice treated with the gene therapy nanoparticle alone showed a 40 percent reduction in tumor volume and a significant reduction in number of tumors.
Research also suggests that the NPRL2 tumor suppression pathway operates independently of the p53 pathway, a major cancer detection and destruction pathway that is often disabled in cancer.
Ji said additional preclinical and toxicity studies in animal models have been planned to develop a treatment protocol using the NPRL2-nanoparticle plus cisplatin for future clinical trials in lung cancer patients.
University of Texas M. D. Anderson Cancer Center
Researchers at the two institutions, working under a joint National Cancer Institute Specialized Program of Research Excellence (SPORE) in Lung Cancer grant, have identified three tumor-suppressor genes on chromosome 3. The latest paper refines the impact of one of those genes, NPRL2, on the most common form of lung cancer.
"NPRL2 has potential predictive value for care," Ji said. "If a patient's non-small-cell lung cancer lacks an active NPRL2 gene, then cisplatin likely would not be a suitable chemotherapy."
Researchers started by analyzing NPRL2 expression in 40 different lines of non-small-cell lung cancer. They found that 21 lines expressed the gene and of those 15 lines were sensitive to cisplatin. The other 19 lines had little or no expression of NPRL2 and 15 of those were cisplatin-resistant.
Follow-up laboratory experiments with resistant cell lines showed that NPRL2 expression with cisplatin drastically limited cancer cell proliferation and increased programmed cell death (apoptosis) of cancer cells by 2 to 3 fold.
"We also demonstrated in a mouse model of human cisplatin-resistant non-small-cell lung cancer that gene therapy to restore NPRL2's function makes the tumors once again sensitive to cisplatin," Ji says.
The team packaged a molecular NPRL2-producing machine called a plasmid expression vector in a nanoparticle ? a fatty sphere so small it's measured in billionths of a meter. The nanoparticles are injected into the mice, find their way to tumor cells, bind to them, and the NPRL2- producing plasmid cassette is taken up into the cell, where it expresses the gene.
Mice with a human form of cisplatin-resistant non-small-cell lung cancer who received both the NPRL2-nanoparticles and cisplatin had a 90 percent reduction in tumor volume compared with those treated only by cisplatin alone or by a combination of cisplatin and control delivery systems. The overall number of tumors was 67 to 77 percent lower in the mice who received the gene therapy/cisplatin combination compared to those in the other groups.
Ji said research continues on the possible mechanisms by which the gene kills cancer cells in combination with cisplatin and the gene's normal role in DNA damage repair and apoptosis. Interestingly, mice treated with the gene therapy nanoparticle alone showed a 40 percent reduction in tumor volume and a significant reduction in number of tumors.
Research also suggests that the NPRL2 tumor suppression pathway operates independently of the p53 pathway, a major cancer detection and destruction pathway that is often disabled in cancer.
Ji said additional preclinical and toxicity studies in animal models have been planned to develop a treatment protocol using the NPRL2-nanoparticle plus cisplatin for future clinical trials in lung cancer patients.
University of Texas M. D. Anderson Cancer Center
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Although morphine has been the gold-standard treatment for postoperative and chronic cancer pain for two centuries, a growing body of evidence is showing that opiate-based painkillers can stimulate the growth and spread of cancer cells.
Study raises concerns about outdoor second-hand smoke
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PET imaging response a prognostic factor after thoracic radiation therapy for lung cancer
A rapid decline in metabolic activity on a PET scan after radiation therapy for non-small cell lung cancer is correlated with good local tumor control, according to a study presented by researchers at Thomas Jefferson University Hospital at the 51st ASTRO Annual Meeting.
Study of concurrent radiotherapy, chemotherapy shows promise in small cell lung cancer
Treating limited stage small cell lung cancer(LSCL) with a combination of accelerated high-dose radiotherapy and chemotherapy has shown encouraging results.
Stereotactic radiotherapy offers noninvasive, effective treatment for frail patients with early-stage lung cancer
Stereotactic body radiation therapy (SBRT) should be considered a new standard of care for early-stage lung cancer treatment in patients with co-existing medical problems, according to results from a national clinical trial led by UT Southwestern Medical Center physicians.
Preventative brain radiation for lung cancer patients: Benefits and risks
A new study is taking a closer look at the benefits versus risks for lung cancer patients to undergo preventative brain radiation therapy as a means to stop cancer from spreading to the brain.
Study spotlights efficacy of questionnaire to identify patients at high risk for lung cancer
A study featured in the November issue of the Journal of Thoracic Oncology confirms the success of a simple questionnaire designed to identify patients at high risk of lung cancer.
Intervals between lung cancer diagnosis and treatment displays a health care disparity
Research published in the November 2009 issue of the Journal of Thoracic Oncology has found that intervals between lung cancer suspicion, diagnosis and treatment may be attributed to health care system discrepancies.
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