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Dual Gene Therapy Suppresses Lung Cancer

CancerWise - April 2007

In a preclinical laboratory test, researchers found that two tumor suppressor genes reduced non-small cell lung cancer (NSCLC) when used separately and had an even more powerful effect when used together.

Researchers from M. D. Anderson and The University of Texas Southwestern Medical Center in Dallas found the combination gene therapy drastically reduced the number and size of human non-small cell lung tumors in mice. The study was reported in the journal Cancer Research.

Significance of results

“In cancer treatment we use combination chemotherapy. We also combine different modes of therapy – surgery, radiation and chemotherapy,” says Jack Roth, M.D., a professor and chair of M. D. Anderson’s Department of Thoracic and Cardiovascular Surgery and a senior researcher on the project. “Now we have the possibility of combined targeted gene therapy.”

“We hope this approach will be more effective in lung cancer, but we also think it is likely to be much less toxic and have fewer side effects than other types of combined cancer therapy," he says. “These genes don't have much effect on normal tissue or normal cells. They seem to have an effect only on cancer cells.”

Background

The two genes tested in the study were:

p53 – This well-known tumor suppressor gene causes defective cells to commit suicide. It is often shut down or defective in cancer cells.

FUS1 – The study’s research group discovered this tumor suppressor gene, which is deficient in most human lung cancers.

Research methods

Researchers delivered the combination gene therapy to tumors in a lipid-based nanoparticle delivery system, which has been in use for years. The nanoparticles are wrapped in a form of cholesterol to protect them from the body's defense mechanisms.

The positively charged nanoparticles are:

  • Delivered to the negatively charged cancer cell membrane
  • Able to repeatedly produce p53 or FUS1 within the cell

Primary results

The study reports that FUS1 works with p53 to force lung cancer cells to self-destruct, a process known as apoptosis.

Lab experiments showed the gene combination:

  • Decreased live cancer cells 70% to 80% in 48 hours
  • Had no effect on a control group of normal cells
  • Killed two to three times more cells than individual genes

The research team then confirmed these findings in mouse studies.

Combination gene therapy reduced the:

  • Number of tumors by 75%
  • Weight of tumors by 80%

Secondary results

Further analysis showed combination therapy achieved greater cell death because FUS1 suppresses a gene that makes a protein known to rapidly degrade p53.

The FUS1/p53 combination also activates an apoptosis pathway based in the cells' mitochondria, their energy powerhouse.

What’s next?

Roth says he expects the research team to advance combination therapies (either of genes or of genes with other biologic or chemotherapy agents) to clinical trials in the coming years.

– From staff reports

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© 2014 The University of Texas MD Anderson Cancer Center