Gene therapy method targets tumor blood vessels

December 23, 2013
Gene therapy method targets tumor blood vessels
Embargoed until 5 p.m. ET Monday, Dec. 23, 2013. Working in mice, researchers at Washington University School of Medicine in St. Louis report developing a gene delivery method long sought in the field of gene therapy: a deactivated virus carrying a gene of interest that can be injected into the bloodstream and make its way to the right cells. The scientists designed a viral vector that homes in on the abnormal blood vessels of tumors, opening up new therapeutic possibilities for gene therapy against cancer and other conditions that involve abnormal vasculature. In one case, the primary kidney tumor spread to an ovary. The vectors gathering in the metastatic tumor vessels glow green, above. The red staining shows the normal blood vessels of the ovary. Credit: Curiel, Arbeit

Working in mice, researchers at Washington University School of Medicine in St. Louis report developing a gene delivery method long sought in the field of gene therapy: a deactivated virus carrying a gene of interest that can be injected into the bloodstream and make its way to the right cells.

In this early proof-of-concept study, the scientists have shown that they can target in mice without affecting healthy tissues.

"Most current gene therapies in humans involve taking cells out of the body, modifying them and putting them back in," said David T. Curiel, MD, PhD, distinguished professor of radiation oncology. "This limits to conditions affecting tissues like the blood or bone marrow that can be removed, treated and returned to the patient. Today, even after 30 years of research, we can't inject a to deliver a gene and have it go to the right place."

But now, investigators at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine say they have designed a "targetable injectable vector" – a deactivated virus that homes in on the inner lining of tumor blood vessels and does not get stuck in the liver, a problem that has plagued past attempts.

The findings are reported Dec. 23 in PLOS ONE.

Building on their own previous work and others', the researchers engineered this viral vector to turn on its gene payload only in the that help fuel and nurture tumor growth. But unlike most therapies aimed at tumor vasculature, the goal is not to destroy the cancer's blood supply.

"We don't want to kill ," said senior author Jeffrey M. Arbeit, MD, professor of urologic surgery and of cell biology and physiology. "We want to hijack them and turn them into factories for producing molecules that alter the tumor microenvironment so that it no longer nurtures the tumor. This could stop the itself or cooperate with standard chemotherapy and radiation to make them more effective. One advantage of this strategy is that it could be applied to nearly all of the most common cancers affecting patients."

In theory, Arbeit pointed out, this approach could be applied to diseases other than cancer in which the blood vessels are abnormal, including conditions like Alzheimer's disease, multiple sclerosis or heart failure.

The viral vector Curiel, Arbeit and their colleagues developed contains a section of DNA called ROBO4 known to be switched on in the cells lining blood vessels within tumors.

In mice, the researchers showed that they could inject the vector into the blood stream and that it accumulated in the tumor vasculature, largely avoiding the lung, kidney, heart and other healthy organs.

The researchers used the viral vectors to deliver a gene that simply caused cells lining the blood vessels to glow green so they could see whether the vectors gathered in the tumors and bypassed healthy areas.

These mice had tumors in the kidneys and cancerous kidney cells in the skin. In one case, the in the mouse kidney spontaneously spread to an ovary. The investigators showed that the blood vessels feeding the metastatic tumors glowed green but not vessels in the normal part of the ovary.

Adding the anti-clotting drug warfarin also blocked the vector from gathering in the liver by blocking viral interactions with the body's blood-clotting machinery, according to the study. While the researchers say treating cancer patients with warfarin would not be feasible because of the bleeding risk, previous work from their group has shown genetic ways to manipulate the viral vector to prevent it from accumulating in the liver.

"We used a combination of targeting strategies," said Curiel. "We combined a method we had developed to detarget the liver and a method to target the . This combination allowed us to inject the vector into the bloodstream of the mouse, where it avoided the liver and found the proliferative vessels of interest to us."

Explore further: Mouse model could help identify viral vectors that may cause tumors

More information: Lu ZH, Kaliberov S, Sohn RE, Kaliberova L, Curiel DT, Arbeit JM. Transcriptional targeting of primary and metastatic tumor neovasculature by an adenoviral type 5 roundabout4 vector in mice. PLOS ONE. Dec. 23, 2013.

Related Stories

Mouse model could help identify viral vectors that may cause tumors

October 26, 2012
Investigators at Nationwide Children's Hospital have identified a mouse model that could help evaluate the risk that viral vectors used in gene therapy might promote tumor formation as a side-effect. The study appears in ...

Study links cardiac hormone-related inflammatory pathway with tumor growth

June 28, 2013
(Medical Xpress)—A cardiac hormone signaling receptor abundantly expressed both in inflamed tissues and cancers appears to recruit stem cells that form the blood vessels needed to feed tumor growth, reports a new study ...

Blood-pressure drug may help improve cancer treatment

October 1, 2013
Use of existing, well-established hypertension drugs could improve the outcome of cancer chemotherapy by opening up collapsed blood vessels in solid tumors. In their report in the online journal Nature Communications, Massachusetts ...

Nano drug crosses blood-brain tumor barrier, targets brain tumor cells and blood vessels

July 17, 2013
(Phys.org) —An experimental drug in early development for aggressive brain tumors can cross the blood-brain tumor barrier and kill tumor cells and block the growth of tumor blood vessels, according to a recent study led ...

Gene therapy trial for 'Bubble boy' disease promising

December 9, 2013
(Medical Xpress)—Researchers reported promising outcomes data for the first group of boys with X-linked severe combined immunodeficiency syndrome (SCID-X1), a fatal genetic immunodeficiency also known as "bubble boy" disease, ...

Clarifying the effect of stem cell therapy on cancer

April 29, 2013
Injection of human stem cells into mice with tumors slowed down tumor growth, finds research published in BioMed Central's open access journal Stem Cell Research & Therapy. Human mesenchymal stem cells (MSC), isolated from ...

Recommended for you

Stem cell therapy attacks cancer by targeting unique tissue stiffness

July 26, 2017
A stem cell-based method created by University of California, Irvine scientists can selectively target and kill cancerous tissue while preventing some of the toxic side effects of chemotherapy by treating the disease in a ...

Understanding cell segregation mechanisms that help prevent cancer spread

July 26, 2017
Scientists have uncovered how cells are kept in the right place as the body develops, which may shed light on what causes invasive cancer cells to migrate.

Study uncovers potential 'silver bullet' for preventing and treating colon cancer

July 26, 2017
In preclinical experiments, researchers at VCU Massey Cancer Center have uncovered a new way in which colon cancer develops, as well as a potential "silver bullet" for preventing and treating it. The findings may extend to ...

Compound shows promise in treating melanoma

July 26, 2017
While past attempts to treat melanoma failed to meet expectations, an international team of researchers are hopeful that a compound they tested on both mice and on human cells in a petri dish takes a positive step toward ...

Study may explain failure of retinoic acid trials against breast cancer

July 25, 2017
Estrogen-positive breast cancers are often treated with anti-estrogen therapies. But about half of these cancers contain a subpopulation of cells marked by the protein cytokeratin 5 (CK5), which resists treatment—and breast ...

Breaking the genetic resistance of lung cancer and melanoma

July 25, 2017
Researchers from Monash University and the Memorial Sloan Kettering Cancer Center (MSKCC, New York) have discovered why some cancers – particularly lung cancer and melanoma – are able to quickly develop deadly resistance ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.