Androgen receptor signaling influences the response of melanoma patients to targeted therapy

Androgen receptor (AR) signaling affects response to BRAF / MEK inhibitor therapy in both men and women melanomaResearchers at the University of Texas MD Anderson Cancer Center said in a study published today Nature.. The findings provide new goals for combating treatment resistance and one possible answer to why men face a worse prognosis than women when diagnosed with melanoma.

AR is a type of nuclear receptor activated by the male hormone testosterone. Women have low levels of androgens, including testosterone. This study confirms the effect of biological gender on response to BRAF / MEK targeted therapy and shows for the first time that these inhibitors increase AR signaling, leading to treatment resistance and poor response to treatment. I am. In a preclinical model of melanoma, blocking AR improved the response to BRAF / MEK targeted therapy in both men and women.

This study, coupled with other recent publications investigating the effects of AR signaling on responses to other types of cancer treatments such as immune checkpoint inhibition, has had significant impact in this area. We know that men and women get cancer at different rates and have different mortality rates. Our study increases the likelihood that AR and testosterone are working and provides new goals for improving the response to treatment in men and women. “

Jennifer Wargo, Maryland, Senior Corresponding Author, Professor of Genomic Medicine and Surgical Oncology

Biological gender is important for targeted therapeutic response to melanoma

This study began with observations from a neoadjuvant clinical trial of BRAF / MEK inhibitors in stage III melanoma (NCT02231775). In this study, the rate of recurrence-free survival (RFS) was higher in female patients than in male patients, who had a higher rate of major pathological reactions (MPR, defined as less than 10% of surviving tumors at surgery).

To validate these findings, the group added locally advanced metastatic melanoma, including 51 patients (30 women and 21 men) treated with neoadjuvant BRAF / MEK inhibitors. I studied patients with. The MPR rate was 66% for women and 14% for men, and the RFS rate for two years was 64% for women and 32% for men.

After excluding other possible factors that contribute to MPR-; including age, performance status, body mass index (BMI), stage and mutation status-; the research team found sexual dimorphism in several other cohorts. I verified the shape. The analysis included a total of 664 patients who received BRAF and / or MEK-targeted treatment for stage III or stage IV melanoma. In multiple studies, researchers found that women and men tended to improve progression-free survival (PFS) and overall survival (OS).

Longitudinal evaluation of available tissue samples reveals significantly higher levels of AR in male patients being treated compared to baseline, and in male and female patients whose cancer did not respond to the targeted therapy combination. Significantly higher levels of AR were revealed during treatment.

Role of AR signaling validated in preclinical studies

Working with MD Anderson’s Translational Research (TRACTION) platform to drive treatment and innovation in oncology, researchers validated observations in several preclinical models.

“This study demonstrates our commitment to transforming patient care through the reverse translation strategy exemplified by MD Anderson,” said MD Anderson, Vice President and Head of Oncology Research, Therapeutic Discovery Division. One co-author, Dr. Timothy Hefernan, said. Of TRACTION.

First, female mice transplanted with melanoma tumors were shown to respond better to BRAF / MEK inhibitor therapy than male mice. Administration of testosterone to all mice resulted in tumor progression and treatment resistance in both sexes. Finally, administration of AR inhibitors and targeted therapies to mice improved the response to melanoma treatment in both men and women.

“By using a translational study of patient samples with a preclinical model, we have shown that treatment with BRAF / MEK inhibitors is associated with upregulation of AR in tumor cells and promotes resistance to treatment. “It was,” said co-author Dr. Joseph Marszalek. .. , Co-leader of TRACTION. “We found that blocking AR actually improved the treatment response in men and women, and activating AR signaling with testosterone ineffective the treatment response.”

Recent studies have shown that AR-mediated resistance can affect other cancers and types of treatment. Current findings underscore the need to better understand the effects of receiving hormone therapy while receiving BRAF and / or MEK inhibitor therapy for melanoma and other cancers.

“There are many factors that can influence the difference between biological gender and cancer outcomes, but hormones will be one of the next major areas of research focus,” Wargo said. I am. “Fortunately, there are already ways to regulate hormones, so this area is well-positioned for research into clinics and the development of new therapies. MD Anderson and the use of AR around the world. There are excellent researchers who are studying. Blocking in combination with other cancer treatments that span several cancer types. “

The study was supported by Melanoma Moonshot^®Part of MD Anderson’s Moonshot Program^®A joint effort designed to accelerate the development of scientific discoveries to clinical advances that save lives for patients, and the Texas Cancer Prevention Institute (RP170002).

Wargo is a consultant / advisory board member of GlaxoSmithKline and Novartis with research support.