A microscopic look at a normal endometrium (top) and endometrial cancer, which arises from the epithelial glands.
An innovative plan of attack is offering new hope for treating the most common malignancy of the female reproductive system, endometrial cancer.
The research, published by Julie Kim, PhD, Susy Y. Hung Research Professor, in the online journal PLOS ONE, suggests that the synthetic hormone progestin in combination with a signaling inhibitor may provide an in-road to treatment when progestin therapy alone is not effective. Currently, the only other effective treatment option is hysterectomy.
Despite the fact that progestins have been used for decades in the treatment of pre-cancerous lesions of the uterine lining, it remains unknown why some women do not respond to them. Kim believes that this understanding is the key to unlocking better hormone-based options for the disease.
“In our lab, what we are doing is looking at progesterone receptor biology,” Kim said of the protein activated by the female hormone. “We know what it is supposed to do in terms of the genes regulated, how stable the protein is, and what it is supposed to do in the endometrium – the inner membrane of the uterus. With that knowledge we are trying to figure out what’s changed in cancer. One of the pathways we think could influence progesterone receptor response or action is the AKT pathway.”
A single mutated gene – PTEN – is responsible for 50-80 percent of endometrial cancer. The gene regulates the AKT pathway, however a direct relationship between AKT and progesterone receptor has yet to be shown.
“We are looking at the influence of this hyperactive network on progesterone function and we’ve found that when you inhibit the AKT pathway in a cancer cell where it is hyperactive, the progesterone receptor protein levels increase,” said Kim, associate professor in obstetrics and gynecology and an investigator at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “This is giving us a clue that maybe this hyperactive pathway is promoting that degradation of PR.”
Using in vivo models to demonstrate the significance of this finding, the team has found that AKT inhibitors in combination with progestins offer a more effective treatment option.
Such a combination of treatment regimens could be easily translatable to the clinic, as progestin therapy is available for treating endometrial cancer, and AKT inhibitors are in phase II clinical trials for recurrent endometrial cancer. Kim anticipates that the lab’s studies will provide the preclinical evidence needed to move forward.
“What we really want to know is why there is such suboptimal response to progestins for nearly half of all women,” Kim said. “I have always been interested in studying pathologies because I think the translational need is there; in this instance the combination treatment merits further investigation.”
Kim’s research is being funded by National Institutes of Health grant R01 CA155513.
