Progress Report: Gerhardt Attard, MD, Ph.D

Investigator: Gerhardt Attard, MD, PhD – Assistant Professor, Institute for Cancer Research, Royal Marsden Hospital, London

Predicting Resistance to Abiraterone: Molecular Analysis of CTCs

First-line treatment for recurrent prostate cancer involves blockade of male hormone (testosterone; androgen) production in a process known as androgen deprivation therapy (ADT). Androgens are synthesized in the testis and adrenal glands. Nearly all patients respond to ADT initially, however over time most become resistant; the cancer progresses even though plasma levels of androgens are greatly reduced. One mechanism of ADT resistance occurs when prostate tumors evolve to produce their own androgens.

CYP17 is a key enzyme responsible for the production of tumor androgens and is involved in the complex conversion of cholesterol to testosterone. Dr. Attard is studying Abiraterone, a first in class medication that targets androgen synthesis in tumors. Abiraterone blocks CYP17 and a Phase III clinical trial in patients with castrate resistant prostate cancer (CRPC; androgen independent prostate cancer) shows that the medication prolongs survival in many patients.

In 2009, Dr. Attard and colleagues published a report of an early clinical investigation of Abiraterone in CRPC patients and first showed significant clinical activity. Sixty-seven percent of patients demonstrated PSA declines greater than 50% and 19% experienced PSA decline greater than 90%. However, ~14% of patients did not respond to Abiraterone at all.

Dr. Attard is defining biomarkers of Abiraterone resistance to identify patients who won’t respond to Abiraterone. He is molecularly interrogating circulating tumor cells (CTCs; cancer cells that broke away from the tumor and entered circulation) to define a genetic signature that will predict Abiraterone responsiveness. Gene fusions occur when two distinct genes are rearranged and erroneously juxtaposed. The most common gene fusion in prostate cancer is TMPRSS2:ERG. In a study of 77 patients treated with Abiraterone, Dr. Attard and colleagues found that 12/15 patients who experienced a >90% decline in PSA values were positive for the TMPRSS2:ERG rearrangement. These findings suggest that patients with this gene fusion may be more sensitive to Abiraterone therapy and demonstrates that some CRPC tumors remain androgen dependent. However, there were other patients who had ERG rearrangements and had < 50% PSA decline, indicating that anlaysis of ERG rearrangement status alone is not sufficient to predict for Abiraterone sensitivity.

Dr. Attard is constructing the molecular blue-print for Abiraterone resistance in CTCs by analyzing many other molecular characteristics, including PTEN (a gene that suppresses cancer in normal cells) loss and androgen receptor (the nuclear hormone receptor that drives the growth and survival of prostate cancer) amplification. The data produced from his research will advance our understanding of the biology of CRPC and define the molecular profile of CTCs that predict Abiraterone resistance. The hope is that this work will define a predictive laboratory test for prostate cancer patients and will select for those most likely to respond to Abiraterone.

Terms to know from this article:

Hormone

A chemical made by glands in the body. Hormones circulate in the bloodstream and control the actions of certain cells or organs. Some hormones can also be made in a laboratory.

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.

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).

PSA

prostate-specific antigen (PSA): A substance produced by the prostate that may be found in an increased amount in the blood of men who have prostate cancer, benign prostatic hyperplasia, or infection or inflammation of the prostate.

Gene

The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein.