Genomic Guided Therapy With Dasatinib or Nilutamide in Metastatic Castration-Resistant Prostate Cancer

Prostate cancer is the most commonly diagnosed non-cutaneous malignancy of men in the United
States and remains the second leading cause of cancer-related mortality among men. Novel
approaches are necessary to personalize and improve treatment. The androgen receptor (AR)
plays a critical role in the normal development and function of the prostate and promotes
growth in most prostate cancers. Most patients with advanced prostate cancer have cancer
that will initially respond to androgen-targeting therapy (focusing on decreasing the
circulating levels of testosterone which is the primary source of ligand for the AR
receptor). However, castrate resistance usually develops within 18 to 24 months and the
median survival of men with castration resistant prostate cancer (CRPC) ranges between 12 to
18 months. Current options are limited including: secondary hormonal manipulations,
radiopharmaceuticals, and chemotherapy and only docetaxel, a taxane that targets
microtubules, has been proven to prolong survival.

Importantly, it has become clear that for some patients with CRPC, the prostate tumors
remain dependent on AR activity. This has been supported by studies demonstrating different
genetic and metabolic mechanisms by which prostate cancer cells maintain AR activity despite
low levels of circulating androgen. An assay detecting AR activity that more comprehensively
reflects the variety of mechanisms by which AR activity is preserved has the potential to
accurately differentiate between men who have tumors still dependent on AR activity from
those that are truly independent of AR activity. The identification of patients with
continued AR activity has the potential to improve response to secondary hormonal
manipulations; men with tumors having low levels of AR activity are likely to require
alternative approaches.

We have developed a transcriptional "signature" for AR activity with the goal of identifying
the true status of AR in tumors of men with CRPC. After validating the AR signature on in
vitro and human prostate samples to ensure that it accurately and reproducibly detects AR
activity, we applied the AR signature to several independent datasets to determine the
distribution of CRPC tumors with preserved AR activity. Interestingly, there is consistent
heterogeneity with respect to predicted AR activity. While overall AR activity decreases in
CRPC, there is a subgroup of patients with persistently elevated AR activity. In tumors with
low AR activity, we observed that the probability of AR activity was negatively correlated
with predicted SRC activity in localized prostate cancer and CRPC.

Patients with persistently high AR activity will be treated with nilutamide, an approved
oral agent used in metastatic CRPC to target the AR. Patients with tumors having low AR
activity will be treated with dasatinib (an oral drug known to target the SRC family
kinases). As there is compelling pre-clinical evidence of interactions between the SRC
pathway and AR signaling, patients failing either single agent treatment will be treated
with the combination of nilutamide and dasatinib and followed again for progression.