Methods of treating castration-resistant prostate cancer with glucocorticoid receptor antagonists, androgen deprivation therapy and anti-androgen receptor therapy

Inventors

Szmulewitz, Russell Z. • Conzen, Suzanne D.

Assignees

University of Chicago

Abstract

Embodiments of the invention are directed to the treatment of subjects with prostate cancer, in particular those with castration resistant prostate cancer, with glucocorticoid receptor antagonists. The prostate cancer may be one that has become resistant to androgen deprivation therapy, for example, by increase in glucocorticoid receptor expression and/or activity.

Core Innovation

The invention relates to treating castration-resistant prostate cancer by targeting the glucocorticoid receptor with a GR antagonist in the setting of androgen deprivation therapy. The disclosed rationale is that resistance to androgen deprivation therapy is associated with increased GR expression and/or GR activity, enabling glucocorticoid receptor signaling to support prostate cancer progression despite lowered androgen levels. The approach therefore combines GR blockade with testosterone-decreasing therapy and, in described embodiments, also includes an androgen receptor antagonist.

The disclosure describes clinical/translational associations involving AR, GR, and SGK1 expression, comparing treatment-naive prostate cancer tissue with androgen-deprived prostate cancer tissue, and reporting Kaplan-Meier/log-rank results for progression-free survival associations. Preclinical evidence is described in CRPC cell lines, including that GR activation using dexamethasone increases GR/SGK1 and that GR antagonism using mifepristone can synergistically impair survival. The disclosure also states that SGK1 inhibition can block GR-mediated protection, linking GR signaling to downstream SGK1 activity relevant to CRPC.

The invention further describes treatment embodiments that co-administer a GR antagonist with androgen deprivation therapy, where androgen deprivation therapy decreases circulating testosterone, and that the subject has been or is being treated with androgen deprivation therapy comprising specified options. The disclosure also describes that the subject has been or is being treated with an androgen receptor antagonist, and that GR-responsive genes and expression measurements, including GR expression and GR-responsive genes, may be used to characterize the subject or tumor context. Example GR antagonists and combination modalities are listed, including GR antagonist selection and co-administration with therapies that decrease testosterone.

Claims Coverage

The partial content provides one independent claim. The independent claim includes multiple inventive features: co-administration of a GR antagonist with androgen deprivation therapy that decreases circulating testosterone, treatment in an androgen-deprived prostate cancer setting where the subject has been or is being treated with androgen deprivation therapy and also has been or is being treated with an androgen receptor antagonist, with androgen deprivation therapy comprising specified testosterone-decreasing options. Dependent claims further narrow specific GR antagonist and AR antagonist candidate selections and constrain subject timing and cancer subtype, and may include subject biomarker status.

Across the provided claim material, the core coverage centers on treating androgen-deprived prostate cancer by co-administering a GR antagonist with androgen deprivation therapy that decreases circulating testosterone, in subjects who are or have been treated with both androgen deprivation therapy and an androgen receptor antagonist. The partial claim set further narrows GR antagonist and AR antagonist candidate choices, can impose an administration order in which testosterone-decreasing therapy precedes the GR antagonist, and specifies metastatic or recurrent disease and elevated GR expression as additional conditions.

Stated Advantages

Documented Applications