"Non-small cell lung cancer, which accounts for about 80 percent of all lung cancers, has a high rate of recurrence even when treated early," said lead researcher William Bulman, M.D. "If we knew specifically in which patients the cancer was likely to come back, we could recommend more aggressive therapy to those patients." Dr. Bulman noted that genetic signatures for breast cancer are already commercially available and are used by physicians to guide treatment recommendations.
Dr. Bulman and his colleagues, Drs. Charles Powell and Alain Borczuk, tested five survival gene signatures in 21 patients, with squamous or adenocarinoma tumors who were followed for up to two years after their surgery. The accuracy of the tested signatures ranged from 40 to 80 percent and varied with the type of tumor. A 42-gene signature, for instance, was 82 percent accurate in predicting survival with lung adenocarcinoma, but only 70 percent accurate in predicting survival with squamous cell carcinoma.
"Lung cancer is a heterogeneous disease, and information captured in these tests helps to distinguish tumors in terms of clinical outcomes." explained Dr. Bulman. "Our findings not only indicate that genetic signatures have clinical utility in personalizing the treatment of lung cancer, but also that it may be necessary to use different gene-based risk predictors with different tumor subtypes."
Dr. Bulman noted that this research is part of a larger effort to understand the biological basis for why some early stage lung cancers progress and metastasize and why some do not. He added that he and his colleagues are planning to test these genetic signatures in new cohorts of patients for the purposes of targeting patients at high risk for recurrence.
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In tissue samples and in mice, all the new vectors worked better than a commonly used version of AAV. One of the versions in particular worked 11 times better in tissue samples after 48 hours. In mice, the results were staggering. Two weeks after the mice were injected with the corrective gene, one of the new AAV-gene combos was working 29 times better than the standard vector was at incorporating the new gene into cells, at a 10-fold lower dose.
"We were very surprised," Srivastava said. "It's amazing to think that changing one amino acid could produce these results.
"Now the virus actually completely avoids being phosphorylated, so it doesn't become degraded and it goes into the nucleus, and we get therapeutic levels of proteins. We can generate therapeutic levels of Factor IX."
The researchers are creating additional new vectors based on this concept, with the goal of creating what Srivastava calls "a perfect vector" that lacks all seven phosphate-attracting tyrosines. They are also teaming with University of North Carolina researchers to test the vectors in dogs with hemophilia. If these studies are successful, the vector could be used in human gene therapy trials.
In addition to being more efficient, the new version of AAV could also prove to be more economical, Srivastava said. Current gene therapy trials are expensive because scientists must administer so much of the vector containing the therapeutic gene to see results. Using the new vector, scientists could potentially scale back to using as little as 100 billion particles instead of 10 trillion, Srivastava said.
"I think this is a very promising step forward," said John Engelhardt, Ph.D., the director of the University of Iowa Center for Gene Therapy, who was not involved with the study but also plans to use the UF-developed vector in upcoming research. "From a basic biological standpoint, this clarifies our understanding of how the virus acts in the cell. The more we understand, the better we are going to be at engineering viruses for use in humans."
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