Androgen receptor activity suggests androgen deprivation therapy response

November 1, 2008

Determining androgen receptor activity in castration-resistant prostate cancer may have potential for distinguishing patients who will respond to androgen deprivation from those who will not.

Durham, NC-Determining androgen receptor activity in castration-resistant prostate cancer may have potential for distinguishing patients who will respond to androgen deprivation from those who will not, investigators reported at the American Society of Clinical Oncology annual meeting in Chicago.

In studies from the laboratory of Phillip Febbo, MD, at the Institute for Genome Sciences & Policy, Duke University, Durham, NC, an androgen receptor activity signature predicted activity levels in prostate cancer cell lines, projected patients' hormonal status, and assigned an activity score that correlated with intraprostatic androgen levels in biopsy specimens.

Low-probability androgen receptor activity correlated with the predicted activity of a kinase associated with progression in localized and metastatic prostate cancer, first author Prateek Mendiratta, MD, reported. Low-probability activity also predicted response to dasatinib (Sprycel), a drug that inhibits the kinase.

By targeting different pathways, chemotherapy or a drug like dasatinib might improve low-androgen patients' chances for a clinical benefit, he added. Such a strategy would represent a step toward more individualized treatment of prostate cancer, as determined by a patient's tumor characteristics.

The transformation of normal prostatic epithelium to prostate cancer is associated with decreasing androgen receptor activity. Progression from localized cancer to metastatic and castration-resistant disease is associated with alterations in androgen receptor signaling and further reductions in receptor activity.

At each step in disease progression, some patients demonstrate greater responsiveness to hormone therapy than others, said Dr. Mendiratta. Even in castration-resistant prostate cancer, a subset of patients retains some responsiveness to hormone therapy.

To examine the feasibility of using androgen receptor activity as a marker of responsiveness, Duke investigators developed an androgen receptor signature based on gene expression. Microarray analysis identified 300 genes that were differentially expressed in LNCaP prostate cancer cells with and without androgen. The signature was validated in additional cells with and without androgen.

Androgen receptor activity signature also was evaluated in cancer-free prostate specimens treated with placebo, chemical castration, or chemical castration with supplemental testosterone. The probability of androgen-receptor activity had a strong positive correlation with tissue levels of dihydrotestosterone.

In addition, androgen receptor activity was examined in specimens from men with localized or metastatic castration-resistant prostate cancer. Patients with local disease were treated with immediate radical prostatectomy, 3 to 6 months of neoadjuvant androgen deprivation therapy, or 6 to 9 months of neoadjuvant hormonal therapy. Increasing duration of androgen deprivation therapy was associated with progressively decreasing androgen receptor activity, compared with immediate prostatectomy.

Mean androgen receptor activity also was lower in metastatic versus localized prostate cancer. However, the metastatic population exhibited considerable heterogeneity, as some cancers appeared dependent on androgen receptor activity and others did not.

Seeking possible explanations for the heterogeneity, the investigators examined various signaling pathways and found that the Src kinase seems to be driving the development of androgen independence.

Building on the evidence implicating Src, the Duke researchers used published data on cell-line sensitivity to dasatinib and data from the microarray analysis to develop a dasatinib sensitivity signature. When applied to prostate cancer specimens, the signature had a significant negative correlation with androgen receptor activity.

Dasatinib has demonstrated early activity in castration-resistant prostate cancer, said Dr. Mendiratta. However, this study suggests that the drug might be more effective if targeted to patients who are more likely to respond, such as those with low androgen receptor activity.