Gene therapy shrinks tumors in mice, confirming gene's role in halting cancer

January 18, 2000

Halting cancer in mice isn't new, but using gene therapy to do so is. Or at least for the anticancer gene Rb2/p130

Researchers at Jefferson Medical College have for the first time used gene therapy to replace a damaged Rb2 gene with a healthy version and dramatically shrink lung cancer tumors in mice. The scientists, in showing the normal gene can actually reverse tumor growth, have demonstrated direct evidence that Rb2 is a "tumor suppressor." They hope the work may someday lead to human gene therapy trials for lung cancer.

"Rb2 is an important master switch in controlling the equilibrium of the cell," says Antonio Giordano, M.D., Ph.D., associate professor of pathology, anatomy and cell biology at Jefferson Medical College of Thomas Jefferson University in Philadelphia, who led the work.

"It's the first time that this tumor suppressor gene has been shown to be heavily mutated in primary tumors," he says. "This also proves also that this is a classical tumor suppressor gene, similar to another such gene, p53." Tumor suppressor genes such a p53, which may be involved in as many as half of all human cancers, are normal growth control genes. They contribute to cancer, it is thought, when they somehow malfunction.

Dr. Giordano and his co-workers report their findings Jan. 24 in the journal Cancer Research

Dr. Giordano and colleagues at Jefferson, the University of Naples, the University of Siena, Bristol-Myers Squibb, the University of Texas-Southwestern Medical Center, and the Sbarro Institute for Cancer Research and Molecular Medicine, which is affiliated with Jefferson Medical College, have developed a gene therapy model using a retrovirus as the delivery system. In their study, they inserted the Rb2/p130 gene inside the virus vehicle and introduced it into human lung cancer cell lines grown in the laboratory. The cancer cell lines were injected into mice, which subsequently grew tumors.

"We put the Rb2 into a retrovirus and transplanted the non-small cell lung tumor lines into the backs of the mice and suppressed tumor growth," he explains. And that gives the scientists hope that such therapy may someday be possible in humans. Non-small cell lung cancer is the most dangerous and prevalent type of the disease, making up about 75 percent of cases.

Rb2, or human retinoblastoma-related gene, Dr. Giordano notes, is a normal growth-control gene expressed in cells in all tissues. When it malfunctions, it may contribute to several types of cancer. One next step in the research is to try to understand how a dysfunctional Rb2 gene leads to cancer.

"We have found three different mechanisms for how the gene can cause cancer, which suggests Rb2 is a major guardian of the genome and controller of cellular processes," he says. In another recent paper in Cancer Research published Jan. 1, Dr. Giordano and his co-workers found important evidence about one of those mechanisms.

He and his co-workers already knew that some lung cancer cells lacked a working Rb2 gene by demonstrating a reduction in the protein it makes. But in some types of cancer in which Rb2 is heavily mutated, such as nasopharyngeal cancer, a head and neck cancer common in southern China, they found the mutation caused a cell signaling problem, which contributed to the cancer.

Similarly, in another article in the current issue of Cancer Research, Dr. Giordano's research group showed how an Rb2 mutation involved in Burkitt's lymphoma resulted from the Rb2 protein being misplaced within the cell.

There has been other evidence of Rb2's role in causing cancer as well. In earlier work, Dr. Giordano and his group showed that Rb-2/130 proteins ubiquitous throughout the body's tissues played vital roles in cell growth control. When missing, they may lead to cancer. And in 1998, Dr. Giordano and colleagues in Italy reported that five years after endometrial cancer surgery, lower levels of the Rb2 proteins correlated with a higher-than-normal risk of returning disease. The women were more likely to die of the cancer. "Understanding the mechanism of growth control of cancer begins with the identification of gene products responsible for that cancer," Dr. Giordano says.

"Knowing that Rb2 is part of a small group of tumor suppressors, we are trying to understand how the protein-cell interaction occurs," he says. "Rb2 behaves differently than other tumor suppressors. In some cancers, Rb2 may not be mutated. It is in lung cancer, which is consistent with the idea that multiple cellular events cause cancer.

"We would like to further analyze and better control this biological drug, the Rb2 retrovirus," he says. "We still need to make sure that we further develop the virus delivery system for genes as drugs. This is the major challenge. At the same time, we are learning more and more about how cancer works," he says. The researchers are learning about Rb2's role in growth control as well. He and colleague Pier Paolo Claudio, M.D., Ph.D., assistant professor of pathology, anatomy and cell biology, recently showed the gene's effectiveness in treating coronary artery disease in laboratory animals as an adjunct to angioplasty.

"We are identifying the words, building the dictionary and learning the rules of grammar to construct the proper syntax and determine the functional consequences of interactions between molecules," he says. "We would like to construct grammatically accurate sentences in order to be more precise therapeutically.

"In giving this information to oncologists, they can eventually change the therapeutic regimen by knowing how the genes behave."
The National Institutes of Health and the Sbarro Institute for Cancer Research and Molecular Medicine funded the work.

Thomas Jefferson University

Related Lung Cancer Articles from Brightsurf:

State-level lung cancer screening rates not aligned with lung cancer burden in the US
A new study reports that state-level lung cancer screening rates were not aligned with lung cancer burden.

The lung microbiome may affect lung cancer pathogenesis and prognosis
Enrichment of the lungs with oral commensal microbes was associated with advanced stage disease, worse prognosis, and tumor progression in patients with lung cancer, according to results from a study published in Cancer Discovery, a journal of the American Association for Cancer Research.

New analysis finds lung cancer screening reduces rates of lung cancer-specific death
Low-dose CT screening methods may prevent one death per 250 at-risk adults screened, according to a meta-analysis of eight randomized controlled clinical trials of lung cancer screening.

'Social smokers' face disproportionate risk of death from lung disease and lung cancer
'Social smokers' are more than twice as likely to die of lung disease and more than eight times as likely to die of lung cancer than non-smokers, according to research presented at the European Respiratory Society International Congress.

Lung cancer therapy may improve outcomes of metastatic brain cancer
A medication commonly used to treat non-small cell lung cancer that has spread, or metastasized, may have benefits for patients with metastatic brain cancers, suggests a new review and analysis led by researchers at St.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Lung transplant patients face elevated lung cancer risk
In an American Journal of Transplantation study, lung cancer risk was increased after lung transplantation, especially in the native (non-transplanted) lung of single lung transplant recipients.

Proposed cancer treatment may boost lung cancer stem cells, study warns
Epigenetic therapies -- targeting enzymes that alter what genes are turned on or off in a cell -- are of growing interest in the cancer field as a way of making a cancer less aggressive or less malignant.

Are you at risk for lung cancer?
This question isn't only for people who've smoked a lot.

Read More: Lung Cancer News and Lung Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to