A collaborative study by researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine and colleagues has identified a novel therapeutic target for incurable prostate cancer. The research found a critical role for thioredoxin-1, a protein that protects cells from oxidative stress, in the progression of prostate cancer to the incurable castration-resistant stage.
Their findings were described in an article, “Thioredoxin-1 protects against androgen receptor-induced redox vulnerability in castration-resistant prostate cancer,” that was published online on October 31 by the journal Nature Communications.
“We used a novel prostate cancer cell model system developed in my lab to assess the first steps in the progression to castration resistance. It showed that elevated levels of thioredoxin-1 underlie aggressive disease,” said Priyamvada Rai, Ph.D., associate professor of medicine in the Division of Medical Oncology and a member of Sylvester’s Tumor Biology Program. Rai led the study and was corresponding author of the journal article.
Fortunately, there is a chemical inhibitor of thioredoxin-1, PX-12, which had already passed Phase I trials in several cancers, but had never been tested in prostate cancer. The study showed that PX-12 treatment in conjunction with androgen deprivation therapy significantly reduces tumor formation by aggressive castration-resistant cells. In fact, the tumor of one mouse never recurred even when the drug was withdrawn for several weeks
Rai’s team, in collaboration with androgen receptor biology expert Kerry Burnstein, Ph.D., professor of molecular and cellular pharmacology and Sylvester’s associate director for education and training, found that inhibiting thioredoxin-1 sensitized therapeutic-resistant cells to androgen deprivation by an unexpected mechanism, elevation of androgen receptor levels.
“This result was surprising because maintenance of androgen receptor levels under androgen deprivation therapy is viewed as a driver of castration-resistant prostate cancer,” said Burnstein.
The investigators showed that, in fact, androgen receptor expression under androgen deprivation therapy produces oxidative stress that typically is masked by thioredoxin and possibly other similar redox-protective proteins. Hence, inhibiting thioredoxin-1 in conjunction with androgen deprivation therapy led to a rapid increase in cellular oxidant levels in the castration-resistant tumor cells (but not normal prostate cells), leading to cell death.
Rai and Burnstein, along with their research teams, are now investigating how thioredoxin-1 inhibition alters androgen receptor activity and function, and carrying out advanced preclinical studies with the PX-12 inhibitor, through a recently funded Partnered DOD Idea Development grant.
Rai added, “I’m especially proud that this study was largely driven by my graduate and undergraduate trainees.”
The two co-first authors of this study, Govindi (Jaya) Samaranayake and Clara Troccoli, are Ph.D. candidates in the Sheila and David Fuente Cancer Biology (CAB) graduate program. Other current trainee authors include Mai (Catherine) Huynh, a University of Miami senior who has been working in the Rai lab for the past two years, and Rolando Lyles, a first-year CAB student in the Rai lab. Other University of Miami investigators on this study include Steven Chen, Ph.D., associate professor of public health sciences, who heads Sylvester’s Biostatistics and Bioinformatics Core Facility, and Merce Jorda, M.D., Ph.D., M.B.A., professor of pathology.
Miller School of Medicine