Kimberly Leslie, MD, has always been interested in hormones and cancer. A New Mexico native and gynecologist specializing in high-risk pregnancies, Leslie has focused her research on uterine cancer since 1991.
Recently, the University of New Mexico Comprehensive Cancer Center researcher was awarded a four-year, $1.8 million grant from the Department of Defense (DOD) to further study high-risk uterine cancer.
“Only a few types of cancers have increased in incidence, morbidity and mortality,” Leslie says. “Cancer of the uterus is one of these. Clinical outcomes are worse today than in the 1980s.”
Leslie’s research has led her to study the differences between natural progesterone and synthetic progestins – hormones often used for birth control – and the influence of progesterone on a tumor suppressor protein called p53. The hormones, drugs and proteins, she’s learned, influence each other and the body’s cells in complex ways.
Progestins, like the hormone they mimic, bind to receptors on cells. Once bound, the receptors kick off a cascade of cellular reactions that control the cell’s behavior.
Women produce progesterone during their monthly cycles, and levels of the hormone skyrocket during pregnancy. But progesterone also affects tissues of the ovaries, uterus, breast and brain – all of which have progesterone receptors. Leslie wondered if progestins, too, affect these tissues and if so, how.
“It was not really known how these drugs truly impacted our bodies,” Leslie says, noting that they have been used for a very long time. “We now have more detailed molecular studies and protocols to understand at the level of gene transcription what these drugs are doing.”
Progestins are more shelf-stable than progesterone, are cheaper to produce, and can be taken orally as a pill. Women take progestins for many different reasons, Leslie says, including treatment for uterine cancer and endometrial cancer as well as for birth control. Leslie wants to be able to predict which progestins would work best for different women.
Leslie’s research on hormones and cancer led her to study the tumor suppressor gene called p53. Progesterone controls the TP53 gene, which produces the p53 protein.
“It’s called the guardian of the genome,” Leslie says. “Its job is to allow cells with damaged DNA to repair that DNA.”
But if the cell is unable to adequately repair the damage, the p53 protein programs the cell to self-destruct, preventing a cancer cell from developing.
“Cancer cells have to turn that tumor suppressor [p53 protein] off in order to become a cancer cell,” Leslie says.
A damaged or mutated TP53 gene creates a malfunctioning p53 protein, which permits cells with damaged DNA to continue reproducing. Eventually enough DNA damage accumulates in the surviving cells, and cancer develops. Most cancers result – at least partly – from a mutated TP53 gene.
Not every uterine cancer is a high-risk cancer, though. Leslie’s DOD grant will focus on discovering which tumors may benefit from a class of drugs called p53 reactivators.
These drugs were designed to reverse the effect of faulty TP53 genes and other genes that result in the mutant proteins that drive cancer. They have been approved for use in other types of cancers, but they have not yet been tested in women with uterine cancers.
Using the DOD grant, Leslie and her team have planned a series of studies that will test the effect of p53 reactivators on tumor cells donated by women with uterine cancer. She hopes the work will soon lead to new clinical trials that may help women receive personalized treatment for uterine cancer in the future.