Combining targeted therapies with already approved androgen receptor (AR) therapies may be worth investigating for some patients with renal cell carcinoma (RCC), according to researchers at the University of Rochester Medical Center. They report in the journal Nature Communications that androgen signaling can either stimulate or suppress tumor cell movement and invasion to different locations in the body in patients who have RCC.
Senior author Chawnshang Chang, PhD, a professor of pathology, urology, and radiation oncology at the University of Rochester Medical Center in Rochester, New York, said this discovery that AR signaling can either stimulate or suppress RCC cell invasion to different locations in the body was a surprise. “In our previous studies we only showed AR could stimulate bladder cancer cell invasion and suppress prostate cancer cell invasion. But here it is revealed that AR can have a differential or opposite effect on RCC cell invasion,” said Chang.
Chang's laboratory began its investigation with an epidemiology survey of nearly 4,000 cases of kidney cancer in China. Researchers found that males were almost three times more likely to get kidney cancer compared with females. They also found that among those patients whose cancer spread to the lungs within 12 months, the male-to-female ratio jumped to nearly 5-to-1. In contrast, the gender differences were much less significant among the patients whose cancer spread to lymph nodes.
The next phase of their research included studying human cells and tissue to understand the mechanisms by which signaling among AR proteins interacted with other known cancer-associated genes to enhance or reduce metastasis. In this current investigation, the researchers found there is a gender difference between pulmonary metastasis and lymph node metastasis, and that patients with AR-positive RCC may have a greater risk for metastasis to the lung rather than to lymph nodes. The team found that a higher AR expression increases RCC hematogenous metastasis yet decreases RCC lymphatic metastases. Chang said mechanism dissection indicates that AR enhances miR-185-5p expression via binding to the androgen response elements located on the promoter of miR-185-5p.
Chang said these findings may quickly translate into new treatment paradigms with combination therapies. He hypothesizes that it may be possible to develop newer treatment approaches that combine anti-androgens with other targeted drugs to achieve long-term disease suppression. “This finding suggests a molecule (AR) can have both opposite effects on the RCC cell invasion, and therefore any therapeutic approaches to targeting this AR should be carefully designed and may need to be combined with other strategies to get the best suppression effect,” Chang told OncoTherapy Network.