Scientists use genetically altered virus to get tumors to tattle on themselves

ScienceDaily (May 12, 2011) — Scientists have used a genetically re-engineered herpes virus that selectively hunts down and infects cancerous tumors and then delivers genetic material that prompts cancers to secrete a biomarker and reveal their presence.

According to a study appearing May 11 in PLoS ONE, published by the Public Library of Science, the novel technology has the potential to vastly improve cancer diagnosis by allowing the disease to be caught at much earlier stages and to monitor the effectiveness of therapy.

Researchers at Cincinnati Children's Hospital Medical Center who conducted the study say the new technique -- developed in preclinical mouse models -- could also be more cost effective and portable than current scanning technologies. This would make it useful for diagnosing cancers in less developed parts of the world.

"Our study represents a proof-of-principle in mice, and there is certainly room for further refinement. If ultimately validated in human trials, it could have implications for people with known cancer risk or who have a history of cancer and high risk of recurrence,'' said Timothy Cripe, M.D., Ph.D., senior investigator on the study and a physician and researcher in the Division of Oncology at Cincinnati Children's.

"Early cancer detection is vital to improve cure rates because cancer stage predicts prognosis, but biomarkers are known for only a few cancer types. We were able to use a reprogrammed herpes virus administered intravenously to deliver genetic information that induces a known blood biomarker for cancer to be secreted by cancer cells," explained Dr. Cripe, who collaborated on the study with first author, Andrew Browne, Ph.D., a fourth-year medical student at the University of Cincinnati (UC) College of Medicine and a recent graduate from UC's Department of Electrical and Computer Engineering.

The researchers engineered a herpes simplex virus mutant they called rQ-M38G, reprogramming its genetic makeup so it bypasses healthy tissues and instead targets rapidly dividing cancer cells for infection. They also genetically armed the virus so it prompts cancer cells to secrete Gaussia luciferase (GLuc).

GLuc is a luminescent, easily detectable protein the researchers used as a universal blood biomarker for cancer cells infected by rQ-M38G. Because rQ-M38G/GLuc might also help shrink cancer, it is part of a new class of agents dubbed "theragnostics" that can simultaneously be used for diagnosis and therapy, Dr. Cripe said.

Initially the researchers tested rQ-M38G on laboratory cell cultures of healthy dormant human skin cells and on rapidly dividing cancer cells. Virus replication and biomarker production were very low in the dormant normal cells. In contrast, virus replication and biomarker production were much higher in tumor cell lines of malignant peripheral nerve sheath tumors, osteosarcoma (bone cancer), rhabdomyosarcoma (muscle cancer) and Ewing sarcoma.

Researchers then tested the virus's detection capabilities in mouse models of these same cancers by injecting rQ-M38G into their tail veins, and for comparison into the tail veins of healthy control mice. Non-tumor bearing mice showed background signals for the virus without significant replications or biomarker production. More than 90 percent of the tumor bearing mice showed significant virus replication and biomarker production.

The technology even worked in some mice with only microscopic amounts of cancer in their kidneys, researchers report. If it were to work as well in humans, the scientists estimate that hidden tumors less than half-inch in diameter might be detectable. Because of the anticipated immune response against the virus and the GLuc protein in humans, further refinements of the technology will likely be needed to be able to use it more than once.

The study is one more example of the expanding research into using reprogrammed HSV as novel methods to treat or diagnose cancer, especially as medicine reaches the limits of modern chemotherapies. Dr. Cripe said this creates an urgent need for new strategies against stubborn metastatic disease. Less than 30 percent of patients with metastatic cancer survive beyond five years, despite the aggressive use of modern combination therapies that include chemotherapy.

Also collaborating on the current study were Jennifer Leddon, Mark Currier, Jon Williams, Jason Frischer, and Margaret Collins all of Cincinnati Children's.

Funding support for the study came from the CancerFree Kids Pediatric Cancer Research Alliance and the National Institutes of Health.

Share this story on Facebook, Twitter, and Google:

Other social bookmarking and sharing tools:

Story Source:

The above story is reprinted from materials provided by Cincinnati Children's Hospital Medical Center, via EurekAlert!, a service of AAAS.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Andrew W. Browne, Jennifer L. Leddon, Mark A. Currier, Jon P. Williams, Jason S. Frischer, Margaret H. Collins, Chong H. Ahn, Timothy P. Cripe. Cancer Screening by Systemic Administration of a Gene Delivery Vector Encoding Tumor-Selective Secretable Biomarker Expression. PLoS ONE, 2011; 6 (5): e19530 DOI: 10.1371/journal.pone.0019530

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

View the original article here

Genetically reprogrammed HSV given systemically shrinks distant sarcomas

ScienceDaily (July 8, 2010) — Scientists have used a genetically reprogrammed herpes virus and an anti-vascular drug to shrink spreading distant sarcomas designed to model metastatic disease in mice -- still an elusive goal when treating humans with cancer, according to a study in the July 8 Gene Therapy.

Less than 30 percent of patients with metastatic cancer survive beyond five years, despite the aggressive use of modern combination therapies, including chemotherapy. This creates a significant need for new sarcoma therapies to treat metastatic disease, said Timothy Cripe, M.D., Ph.D., a physician/researcher in the division of Hematology/Oncology at Cincinnati Children's Hospital Medical Center and the study's senior investigator.

The study results are even more significant because the oncolytic herpes virus, HSV-rRp450, was given to the mice systemically to attack tumors via the blood stream instead of being injected directly into tumors.

"Systemic bio-distribution has been a major stumbling block for using virus vectors in gene transfer and virotherapy to treat cancer, but we show that viruses can be used systemically by giving them intravenously to get an anti-tumor effect," Dr. Cripe said.

Also important to results of the current study was using the virus in conjunction with a drug (bevacizumab) that blocks the growth of tumor feeding-blood vessels. In the current study, researchers focused on spreading Ewing sarcoma and Rhabdomyosarcoma -- cancers that form in muscle, bone and connective tissue.

Anti-angiogenic agents like bevacizumab are usually given first in combination cancer therapies because they help enlarge intercellular openings to tumor cells and ease the delivery of drugs, such as chemotherapies. In this study, however, the researchers discovered that bevacizumab has to be given after the virus to maximize the anti-tumor effect of the combined therapy. In fact, giving bevacizumab first lowered the virus's uptake in cancer cells.

The rRp450 oncolytic virus used in the study was derived from herpes simplex type 1. The virus was genetically modified by scientists by removing a gene that makes the virus unable to replicate efficiently in dormant cells. This causes the virus to selectively target and replicate in rapidly growing cancer cells while leaving normally dormant healthy tissue cells alone.

After removing the one gene from the virus, researchers replaced it with a gene that encodes an enzyme that activates a class of anti-tumor chemotherapies called oxazaphosphorines. The overall therapeutic approach is for the virus to infect and degrade the cancer cells and then activate chemotherapy agents as anti-angiogenic agents cut off vascular growth and blood supply to the tumors.

In the current study, however, researchers treated the mice only with rRp450 and the anti-angiogenic drug bevacizumab. This allowed them to test whether the virus could be given systemically, how anti-angiogenic drugs affected virus tumor uptake and the impact this had on tumor growth.

In mice receiving bevacizumab prior to the rRp450, overall tumor shrinkage averaged 40 percent. In mice receiving rRp450 before bevacizumab, tumor size was reduced by an average of 75 percent. The researchers also reported that mice treated with rRp450 before bevacizumab had longer survival rates.

Results of the current study could be used immediately to help design subsequent research into treatment protocols for oncolytic viruses, particularly clinical trials involving combination therapeutic strategies, Dr. Cripe said. Clinical trials are underway in the United States and Europe using oncolytic herpes viruses similar to the one used in the current study.

Other researchers involved in the current study include the first author, Francis Eshun, M.D., and Mark Currier, Rebecca Gillespie, Jillian Fitzpatrick and William Baird, all of the Division of Hematology/Oncology at Cincinnati Children's and its Cancer and Blood Diseases Institute. Funding support for the study from the Cincinnati Children's Division of Hematology/Oncology, teeoffagainstcancer.org, the Katie Linz Foundation, the Limb Preservation Foundation, the American Cancer Society and the National Institutes of Health.

Share this story on Facebook, Twitter, and Google:

Other social bookmarking and sharing tools:

Story Source:

The above story is reprinted from materials provided by Cincinnati Children's Hospital Medical Center, via EurekAlert!, a service of AAAS.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

View the original article here

Scientists use genetically altered virus to get tumors to tattle on themselves

ScienceDaily (May 11, 2011) — Scientists have used a genetically re-engineered herpes virus that selectively hunts down and infects cancerous tumors and then delivers genetic material that prompts cancers to secrete a biomarker and reveal their presence.

According to a study appearing May 11 in PLoS ONE, published by the Public Library of Science, the novel technology has the potential to vastly improve cancer diagnosis by allowing the disease to be caught at much earlier stages and to monitor the effectiveness of therapy.

Researchers at Cincinnati Children's Hospital Medical Center who conducted the study say the new technique -- developed in preclinical mouse models -- could also be more cost effective and portable than current scanning technologies. This would make it useful for diagnosing cancers in less developed parts of the world.

"Our study represents a proof-of-principle in mice, and there is certainly room for further refinement. If ultimately validated in human trials, it could have implications for people with known cancer risk or who have a history of cancer and high risk of recurrence,'' said Timothy Cripe, M.D., Ph.D., senior investigator on the study and a physician and researcher in the Division of Oncology at Cincinnati Children's.

"Early cancer detection is vital to improve cure rates because cancer stage predicts prognosis, but biomarkers are known for only a few cancer types. We were able to use a reprogrammed herpes virus administered intravenously to deliver genetic information that induces a known blood biomarker for cancer to be secreted by cancer cells," explained Dr. Cripe, who collaborated on the study with first author, Andrew Browne, Ph.D., a fourth-year medical student at the University of Cincinnati (UC) College of Medicine and a recent graduate from UC's Department of Electrical and Computer Engineering.

The researchers engineered a herpes simplex virus mutant they called rQ-M38G, reprogramming its genetic makeup so it bypasses healthy tissues and instead targets rapidly dividing cancer cells for infection. They also genetically armed the virus so it prompts cancer cells to secrete Gaussia luciferase (GLuc).

GLuc is a luminescent, easily detectable protein the researchers used as a universal blood biomarker for cancer cells infected by rQ-M38G. Because rQ-M38G/GLuc might also help shrink cancer, it is part of a new class of agents dubbed "theragnostics" that can simultaneously be used for diagnosis and therapy, Dr. Cripe said.

Initially the researchers tested rQ-M38G on laboratory cell cultures of healthy dormant human skin cells and on rapidly dividing cancer cells. Virus replication and biomarker production were very low in the dormant normal cells. In contrast, virus replication and biomarker production were much higher in tumor cell lines of malignant peripheral nerve sheath tumors, osteosarcoma (bone cancer), rhabdomyosarcoma (muscle cancer) and Ewing sarcoma.

Researchers then tested the virus's detection capabilities in mouse models of these same cancers by injecting rQ-M38G into their tail veins, and for comparison into the tail veins of healthy control mice. Non-tumor bearing mice showed background signals for the virus without significant replications or biomarker production. More than 90 percent of the tumor bearing mice showed significant virus replication and biomarker production.

The technology even worked in some mice with only microscopic amounts of cancer in their kidneys, researchers report. If it were to work as well in humans, the scientists estimate that hidden tumors less than half-inch in diameter might be detectable. Because of the anticipated immune response against the virus and the GLuc protein in humans, further refinements of the technology will likely be needed to be able to use it more than once.

The study is one more example of the expanding research into using reprogrammed HSV as novel methods to treat or diagnose cancer, especially as medicine reaches the limits of modern chemotherapies. Dr. Cripe said this creates an urgent need for new strategies against stubborn metastatic disease. Less than 30 percent of patients with metastatic cancer survive beyond five years, despite the aggressive use of modern combination therapies that include chemotherapy.

Also collaborating on the current study were Jennifer Leddon, Mark Currier, Jon Williams, Jason Frischer, and Margaret Collins all of Cincinnati Children's.

Funding support for the study came from the CancerFree Kids Pediatric Cancer Research Alliance and the National Institutes of Health.

Share this story on Facebook, Twitter, and Google:

Other social bookmarking and sharing tools:

Story Source:

The above story is reprinted from materials provided by Cincinnati Children's Hospital Medical Center, via EurekAlert!, a service of AAAS.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Andrew W. Browne, Jennifer L. Leddon, Mark A. Currier, Jon P. Williams, Jason S. Frischer, Margaret H. Collins, Chong H. Ahn, Timothy P. Cripe. Cancer Screening by Systemic Administration of a Gene Delivery Vector Encoding Tumor-Selective Secretable Biomarker Expression. PLoS ONE, 2011; 6 (5): e19530 DOI: 10.1371/journal.pone.0019530

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

View the original article here