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Davis, California

Tuesday, September 21, 2021

Curing the incurable

In a recent multidisciplinary article published at the end of January in Nature Communications, lead author Peter Kaiser, professor of biochemistry at UC Irvine (UCI), along with co-leader Richard Lathrop and many others, announced the discovery of a potential new target for a cure for cancer.

Kaiser’s research focused on a specific protein, called p53, that has been heavily implicated in many different forms of cancer. P53’s primary role involves programmed cell death (apoptosis) and is thus crucial for preventing damaged cells from dividing. Mutations to the structure of p53 cause it to to be deactivated and thus lose its function, allowing for cancer cells to grow without regulation.

“There is a lot of machinery in a cell that needs to work together to create normal cell growth and division,” said Ryan Solis, a senior undergraduate researcher at UC Davis.

Unfortunately, there are a plethora of ways that this machinery can malfunction. Usually a cell has mechanisms to repair parts that break, but no system is perfect.

“If [DNA] is not repaired correctly after its strands break, it could lead to damaged or even missing genes,” Solis said.

Since DNA in a living organism is too difficult to work with, doctors need to be able to find other ways of potentially treating any genetically related disease.

“Current therapies generally target rapidly proliferating cells indiscriminate of whether they are tumor cells or rapidly dividing healthy cells,” Kaiser said in an email interview.

In order to provide a better course of treatment, Kaiser and his team set out to better understand the p53 protein in hopes of potentially discovering a way to reactivate it.

They succeeded. Utilizing complex computer models called “dynamic structural models” and some in-depth statistical analysis, the researchers were able to find a tiny spot in the protein’s structure that can be used to reactivate the mutated forms.

“These simulations basically predict how a protein moves and flexes over time, and often we see new pockets open in the [movement],” said Rommie Amaro, another one of the many co-leads on the article.

According to Kaiser this pocket exists in both the normal and mutant p53 variants, but is predicted to be in a more open shape in the mutants.

The more open shape makes it an easier target for potential drug therapies, and since p53 is already in an active form in normal cells, the drug would only really affect the cancerous cells.

After finding the pocket, Kaiser’s team went on the hunt for something that could fit in it. They looked at a database of 2,298 molecules and pulled out the 45 most promising ones. Of these 45 molecules, only a single one successfully reactivated p53: stictic acid.

So why isn’t cancer cured?

“Stictic acid is chemically not very accessible. Its synthesis is very difficult and chemical modifications are hard to make,” Kaiser said. “It will be easier for us to identify other compounds with similar activity but better chemical accessibility.”

This study represents a major breakthrough in the hunt for a cure, but a lot of work still has to be done before cancer is a disease of the past.

KYLE SCROGGINS can be reached at science@theaggie.org.


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