Unmet Need in CRPC Patients with C-Terminal Loss

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The growth and survival of prostate cancer tumor cells depend primarily on the functioning of the androgen receptor signaling pathway. The pathway and tumor cell growth is ordinarily activated by the binding of androgens, such as testosterone and DHT, to the ligand binding domain of androgen receptors in prostate cancer cells. All proteins, including androgen receptors, are made up of a chain of amino acids that has an N-terminus at one end of the chain and a C-terminus at the other end of the chain as shown in the full-length androgen receptor depicted in the figure below.

In the case of androgen receptors, the C-terminus contains the ligand binding domain. The effectiveness of available therapies, which act solely through CYP17 inhibition or androgen receptor antagonism, requires a functional ligand binding domain. As depicted, in the case of prostate tumor cells that express truncated androgen receptors with C-terminal loss, there is no functional ligand binding domain. This lack of a functional ligand binding domain causes the truncated androgen receptor to be constitutively active, or continuously signaling, meaning that activation of the androgen receptor pathway and tumor growth occurs even in the absence of androgens and androgen binding. As a result, Tokai believes that patients with truncated androgen receptors with C-terminal loss may not be effectively treated by these therapies.

The limitations of CYP17 inhibitors and androgen receptor antagonists have been supported by recent clinical research, in which the presence of C-terminal loss generally, and AR-V7 specifically, in patients was associated with poor responsiveness of patients’ prostate tumors to standard of care therapies.[1,2] Based on findings in one study, Tokai believes that treatment with standard of care therapies may be associated with an increase in the prevalence of AR-V7, causing cross-resistance to sequential therapy and leaving patients who are treated with standard of care therapies with no currently available secondary hormonal treatment options. In contrast, galeterone has the potential to reduce the prevalence of AR-V7 through its mechanism of androgen receptor degradation.

1 Antonarakis E. Androgen receptor splice variant, AR-V7, and resistance to enzalutamide and abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC). Abstract #5001. ASCO 2014.

2 Efstathiou et. Al. Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer. European Urology, 2014.