Progress Report: Eleni Efstathiou, MD, Ph.D

Investigator: Eleni Efstathiou, MD, PhD – Assistant Professor, University of Texas, M.D. Anderson Cancer Center

Biomarker Driven Application of Therapy

Androgens (male hormones such as testosterone) fuel prostate cancer growth and survival. Androgens are synthesized in the testis and adrenal glands. Therapeutic agents that block the production of androgens (androgen deprivation therapy; ADT) are first-line treatments for advanced prostate cancer. Nearly all patients will respond to ADT but will eventually become resistant and cancer will progress even with greatly reduced levels of androgen.

Prior PCF-funded research demonstrated that prostate tumors evolve to produce their own androgens. Dr. Efstathiou is studying a new class of medications that target androgen synthesis in tumors. The first in class is Abiraterone. This agent blocks an enzyme known as CYP17 that converts cholesterol to testosterone. Her research is different from many others in the field as she is studying the effect of Abiraterone in bone, the site of lethal progression of prostate cancer.

Dr. Efstathiou reported that the patients who benefited from this therapy had high levels of the androgen receptor (the protein that binds testosterone and turns on cancer cell proliferation and survival pathways) and CYP17 protein in prostate cancer cells found in bone. She also found that Abiraterone resistance was associated with complete elimination of testosterone in the bone and in some cases a loss in CYP17 in prostate cancer cells. These findings define a molecular signature of Abiraterone therapy response in patients with both AR and CYP17 protein expression. Larger confirmatory clinical investigations planned to rigorously test this Abiraterone response signature that will help physicians identify which patients will benefit from Abiraterone treatment.

In another project, Dr. Efstathiou has found that a signaling pathway called Hedgehog (a network of proteins important for proper embryogenesis) is elevated as a result of ADT in advanced prostate cancer. She found that the increase in Hedgehog protein expression may directly increase CYP17 expression and therefore drive the production of prostate cancer fuel within the tumor to develop castrate resistance. Using a prostate cancer mouse model she has shown that treating mice with both Abiraterone (CYP17 inhibitor) and GDC-0449 (Hedgehog inhibitor) produces a dramatic reduction in testosterone levels in the bone. Dr. Efstathiou is currently conducting a clinical trial testing the use of GDC-0449 plus ADT prior to radical prostatectomy in locally advanced prostate cancer patients. This trial will determine whether the development of castrate resistance can be blocked by impeding the Hedgehog pathway from turning on CYP17 activity in prostate cancer tumors.

Terms to know from this article:

Testosterone

A hormone that promotes the development and maintenance of male sex characteristics.

androgen

A type of hormone that promotes the development and maintenance of male sex characteristics.

Abiraterone

Zitaga Abiraterone is an oral medication that blocks the synthesis of androgens (male hormones), such as testosterone, inside the tumor. Abiraterone is FDA approved for the treatment of patients with metastatic castrate resistant prostate cancer.

Progression

Increase in the size of a tumor or spread of cancer in the body.

Radical prostatectomy

Surgery to remove the entire prostate. The two types of radical prostatectomy are retropubic prostatectomy and perineal prostatectomy.

Tumor

A mass of excess tissue that results from abnormal cell division. Tumors perform no useful body function. They may be benign (not cancerous) or malignant (cancerous).