Tumor-Suppressing Cell Surface Receptor May Provide New Options in Colorectal Cancer

The cannabinoid cell surface receptor 1 (CB1), already known for its role in relieving the side effects of radiotherapy and chemotherapy, plays a tumor-suppressing role in colorectal cancer, according to a recent study by researchers at M. D. Anderson and Vanderbilt-Ingram Cancer Center.

CB1 receives cannabinoids, a group of compounds that serve a variety of cell-signaling roles. (Among these is tetrahydrocannabinol, the active ingredient in marijuana.) Cannabinoids have been shown to induce apoptosis in cancer cells in vitro.

“We found that CB1 expression is lost in most human colorectal cancers, and when that happens, the cancer-promoting protein survivin is free to inhibit cell death,” said senior author Raymond DuBois, M.D., Ph.D., a professor in the Departments of Gastrointestinal Oncology and Cancer Biology and M. D. Anderson’s provost and executive vice president. By reactivating CB1, Dr. DuBois and his colleagues found that they could inhibit the expression of survivin, which is overexpressed in most tumors, and increase apoptosis in colorectal cancer cells.

In the study, CB1 was largely inactive in 18 of 19 human colorectal tumor specimens but was active in adjacent normal mucosa. CB1 was also inactive in 9 of 10 colorectal cancer cell lines. The researchers discovered that, in human colorectal cancers, the gene that encodes the CB1 protein, Cnr1, was not damaged but rather silenced by methylation. Treating the cell lines with decitabine, a demethylating agent that is used to treat some types of leukemia, restored normal gene expression in seven of eight cell lines and restored full CB1 expression in three lines.

Using a mouse model known to spontaneously develop precancerous polyps in the intestine, the group also found that mice in which the Cnr1 gene had been deleted developed 2.5–3.8 times more polyps in the small intestine and colon than control mice did. Deleting the gene also increased by 10 times the number of large growths in the intestine—the type most likely to become cancerous.

Dr. DuBois and his colleagues also found that mice with the Cnr1 gene that were treated with a cannabinoid agonist—a synthetic molecule that binds specifically to CB1 and enhances its function—developed fewer polyps in the small intestine and colon than control mice did. The researchers found as well that CB1 is required for the agonist to have a tumor-inhibiting effect.

Given this finding, “Just increasing the levels of cannabinoids to treat colorectal cancer won’t work if CB1 is not present,” Dr. DuBois said. Instead, giving patients a demethylating agent such as decitabine to reactivate CB1 in the tumor and then administering a cannabinoid might be an effective way to treat colorectal cancer. Less toxic demethylating agents that could also work are being developed.

The study was published in the journal Cancer Research.

Blocking Overexpressed Protein TG2 May Change Disease’s Course

Tissue type transglutaminase (TG2), already implicated by M. D. Anderson researchers in drug-resistant metastatic melanoma, pancreatic cancer, and breast cancer, is now also linked with increased chemoresistance and metastasis in ovarian cancer. Moreover, M. D. Anderson researchers have found that blocking the TG2 protein in ovarian cancer might lead to new treatment options.

“Drug resistance and metastasis are major impediments to the successful treatment of ovarian cancer, and until now we had little information about the role TG2 played in ovarian cancer,” said Anil K. Sood, M.D., a professor in the Departments of Gynecologic Oncology and Cancer Biology.

Dr. Sood and Kapil Mehta, Ph.D., a professor in the Department of Experimental Therapeutics, found that overexpression of TG2 is associated with decreased overall survival in metastatic ovarian cancer and that blocking the protein in mouse models decreased tumor volume, especially when the mice also received docetaxel. The findings were reported in the journal Cancer Research.

Dr. Sood and Dr. Mehta, who first studied the protein in tissue samples and cell lines, found that inhibiting TG2 with targeted siRNA delivered via liposomes reversed tumor progression, including cancer cell proliferation and blood vessel development. As another of the study’s authors, Gabriel Lopez-Berestein, M.D., a professor in Experimental Therapeutics, explained, “While it remains to be seen if these results will translate to humans, targeting TG2 could eventually be an attractive option against advanced ovarian cancer.”

Dr. Mehta also noted that TG2 seems to promote a variety of molecular pathways in cancer development, not only those related to tumor progression but also those involved in the tumor’s defenses against chemotherapy. That makes the promise of a drug that inhibits TG2 much more powerful, as it would fight cancer on several fronts.

“This aberrant protein [TG2] is doing so many different things, you would have to develop a small-molecule drug to block each function,” Dr. Mehta said. “Liposomal siRNA targeted to TG2 is exciting because it takes out TG2 completely, blocking everything that it does.”

For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

Other articles in OncoLog, December 2008 issue:

• Mantle Cell Lymphoma
• Sparing the Nipple During Mastectomy
• House Call: Taking Medicine? Be Aware of Food-Drug Interactions

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