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Blocking TG2 in Mice Reduces Ovarian Cancer

CancerWise - October 2008

Ovarian tumors that make too much of a protein known as tissue type transglutaminase (TG2) grow more quickly and are more resistant to chemotherapy, lowering the patient’s survival chances, according to a laboratory study on mice.

When M. D. Anderson scientists blocked TG2, ovarian tumors stopped growing, posing the possibility of a treatment for late-stage ovarian cancer. Their findings were published in the July 15 issue of Cancer Research.

Significance of results

TG2 helps cancer grow in several ways, so it’s important to study it as a possible way to treat cancer, says Anil Sood, M.D., professor in M. D. Anderson’s departments of Gynecologic Oncology and Cancer Biology, who led the research team.

This group of scientists, consisting of Sood as well as Kapil Mehta, Ph.D., and Gabriel Lopez-Berestein, M.D., both professors in the Department of Experimental Therapeutics, is among the first to look at TG2 in ovarian cancer.

“Ovarian cancer often becomes resistant to chemotherapy and frequently spreads within the abdominal cavity,” Sood says. “Although TG2 seems to play a part in many steps involved in cancer growth, we had little information about its role in ovarian cancer until this study.”

Background

Mehta’s lab previously linked TG2 to treatment-resistant melanoma, breast and pancreatic cancers.

Research methods

The study examined 93 samples of human ovarian cancer in mice. Then researchers targeted TG2 and stopped its production using siRNA, a small strand of ribonucleic acid incorporated in small lipid particles injected in the vein.

Primary results

Levels of TG2 were higher in more advanced tumors.

Of the tumors that made too much TG2:

  • 69% were advanced stage
  • 30% were lower stage

Tumors with high levels of TG2 were more likely to invade healthy tissue and resist chemotherapy. But when production of TG2 was stopped, the ability of cancer cells to grow was reduced.

Additional results

When used with the chemotherapy drug Taxotere® (docetaxel), siRNA was even more effective in silencing TG2. Tumors shrunk by an average of 86%.

What’s next?

Taken together, these findings indicate that too much TG2 lessens chances for survival of patients with ovarian cancer and that blocking TG2 may be a possible treatment.

“We cannot predict if these results will be the same in humans, but in the future we hope that the blocking of TG2 with siRNA may be an effective treatment in advanced ovarian cancer,” Sood says.

Sood, Mehta and Lopez-Berestein are planning to create a Phase I clinical trial using siRNA to block TG2 in ovarian and pancreatic cancers.

“TG2 does so many different things,” Mehta says. “Normally you would have to develop a small-molecule drug to block each function. Using siRNA is exciting because it completely blocks everything TG2 does in one process.”

— Adapted by Dawn Dorsey from an M. D. Anderson news release

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