AU researcher believes she’s made new discovery in cancer research

AU cancer researcher Dr. Yan Cui photographed at the Georgia Cancer Center research building Wednesday morning May 17, 2017. MICHAEL HOLAHAN/STAFF

More than 20 years ago, the discovery of a protein that was mutated or absent in a majority of cancers caused great excitement about exploiting it to kill tumors, a potential that was never quite realized. But a researcher at Georgia Cancer Center at Augusta University said she has discovered a previously overlooked aspect to p53 that can be exploited to help trigger the immune system to destroy small tumors and even nearby cancers.

 

The trick is now to move it closer to becoming a therapy. The discovery of the role of tumor suppressor protein p53, which when mutated seems to drive cancer and cancer cell growth, caused a flurry of work in the scientific world and led Science magazine to name it the “Molecule of the Year” in 1993.

“The excitement generated by it and its fellow tumor suppressors is reaching a crescendo with exhilarating possibilities for prevention and cure of cancer,” the magazine said in an accompanying editorial.

Biotech companies created gene therapy strategies to try to add the molecule back to tumors as a way to attack them or strategies that tried to exploit its absence in many tumors. For the most part, those did not lead to an effective therapy in part because p53 is involved in a host of different cell functions and the therapies proved to be too toxic with too many side effects, said Dr. Yan Cui, a cancer immunologist at the Georgia Cancer Center.

“They not only kill the tumor but they kill a lot of other cells,” she said. Much of the work on p53 has focused on its role in inducing cell death in mutated cells and its control of cell growth, functions that goes awry in cancer.

“People called it a gatekeeper and a caretaker,” Cui said. “It’s important for well-being.”

But there was another function for p53 that was often overlooked.

“What we believe, from an immunological aspect, it is also involved in immune regulation,” she said. “Our early study also demonstrate that p53 inactivation causes the activation of many inflammatory genes.”

As with cancer, p53 mutation or inactivation causes chronic, low-grade information that also contributes to tumor cell growth, Cui said.

That kind of inflammation is really bad,” she said. “It supports the tumor growth, it suppresses the host immune function in the tumor microenvironment” and protects the tumor from the host’s immune system.

Cui took a known p53 activator drug called nutlin-3a that has been in clinical trials for a decade and has some of the same toxicity problems and decided to use it in a different way. The drug instead was injected directly into a few spots in the tumor itself.

“We don’t need the drug to reach the entire tumor,” she said. Instead, those injections create pockets of tumor cell deaths that release pieces of the tumor cell that cause a response by certain immune cells, that pick up those pieces of tumor and present them to the killer T cells of the immune system.

“T cells are the real soldiers that are needed to find the tumor and kill the tumor,” Cui said. “When the T cells are activated, either in the tumor or in the tumor draining lymph nodes they can mobilize all over the body to find tumor elsewhere.”

In a mouse with tumors on either side, for instance, treating only the tumor on one side created a response that then attacked the untreated tumor on the other side, she said. The injections also limit the side effects from the drug, Cui said.

Only a “very limited amount” of the drug is used and it results in “very limited toxicity,” she said.

There are some important limitations to the current approach. It has only been demonstrated in mice and it only appears to work with smaller tumors, Cui said.

Larger tumors have more support cells and more immune suppressor cells so “it really takes a lot more effort to overcome that,” she said. That is something her lab is studying now but it may be possible to combine the approach with other therapies, such as “checkpoint inhibitors” that target some immune-suppressing cells tumors employ in their defense, some of which are already being used to treat cancer patients.

Reach Tom Corwin at (706) 823-3213 or tom.corwin@augustachronicle.com

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