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Collateral Damage: Missing Tumor Suppressor Gene Creates Opening for Cancer Treatment

, by NCI Staff

Alpha-amanitin, a toxin derived from the death cap mushroom pictured here, may offer a way to attack tumor cells missing a copy of the TP53 tumor-suppressor gene. (Photo credit: Wikimedia Commons)

Tumor cells that are missing one copy of the tumor suppressor gene TP53 often harbor another genetic alteration that may make them susceptible to a targeted attack, according to a new study from researchers at the University of Texas M.D. Anderson Cancer Center.

In animal models of colorectal cancer, a treatment that took advantage of this additional genetic alteration—a deleted copy of the POLR2A gene—completely eliminated tumors, the research team reported April 22 in Nature.

Approximately half of human cancers have mutations or deletions of TP53. The protein product of this gene (p53) controls cell growth and a number of other important cellular processes. Although TP53 has been widely studied, researchers have yet to develop a treatment that can reactivate this gene and, thus, re-establish its ability to prevent tumors from forming.

Deletion of one of the two copies of TP53, known as a hemizygous deletion, is common in some cancers, including colorectal, breast, ovarian, and pancreatic, explained the study’s lead author Xiongbin Lu, Ph.D. The treatment approach tested in the study, Dr. Lu said, takes advantage of a phenomenon in cancer cells called collateral vulnerability—when the event that deletes a tumor suppressor gene also damages a neighboring gene that has critical cellular functions. The loss of this gene could create a fatal vulnerability in the cell, establishing a potential avenue to destroy cells with a deleted tumor suppressor gene.

By looking at data from The Cancer Genome Atlas, Dr. Lu and his colleagues found that POLR2A, a neighboring gene to TP53 on chromosome 17, is almost uniformly missing in colorectal cancer cells with a hemizygous deletion of TP53. POLR2A produces an enzyme that is integral to the synthesis of messenger RNA, and is essential for cell survival.

Cells with only one copy of POLR2A, the researchers suspected, might be sensitive to treatment with a drug that targets the POLR2A protein. One such drug is alpha-amanitin, a toxin derived from the poisonous “death cap” mushroom. However, although alpha-amanitin has previously demonstrated anticancer activity, it hasn’t been developed further because it’s toxic to liver cells and can cause substantial liver-related side effects.

To overcome this problem, Dr. Lu, in collaboration with scientists from Munich-based Heidelberg Pharma GmbH, chemically linked the toxin to an antibody that targets a protein specifically found on cancer cells, creating what is known as an antibody-drug conjugate (ADC).

Using the ADC to directly deliver alpha-amanitin to cancer cells dramatically reduced the dose required to kill them. In two separate colorectal cancer cell lines with one deleted copy of POLR2A, the alpha-amanitin dose needed to effectively kill cancer cells was reduced 10,000-fold compared to when it was not part of the conjugate.

And in two different mouse models of colorectal cancer with a deleted copy of TP53 and POLR2A, treatment with the alpha-amanitin ADC lead to complete tumor regressions, with no signs of toxicity. By contrast, the same treatment of mice with two copies of both genes had a much smaller effect on tumor growth.

The finding “opens a therapeutic window” for the treatment of “a common, genetically defined subtype of human cancer,” wrote James Bradner, M.D., of the Dana Farber Cancer Institute, in an accompanying editorial. But the approach has some limitations, he added, including the potential development of resistance to the treatment caused by amplification—the creation of multiple copies—of the intact copy of the POLR2A gene.

The M.D. Anderson team is continuing to study the alpha-amanitin ADC in animal models of other cancers with missing copies of TP53 and POLR2A, including breast and ovarian cancer, Dr. Lu said, as well as looking at “opportunities for further clinical development of alpha-amanitin-based ADCs.”

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