Medical Adrenalectomy to Abrogate Ligand Production in Castration-Resistant Prostate Cancer
Abstract
Rationale: New drugs for prostate cancer (PCa) such as abiraterone (ABI) or enzalutamide (ENZ) are effective in a subset of men, but not all men respond; the duration of response is variable; and most men eventually progress. ABI inhibits CYP17A, a key enzyme in the adrenal gland that mediates androgen synthesis. In men with castration-resistant prostate cancer (CRPC), we show that, while serum levels of adrenal androgens are suppressed in all patients on ABI, they are not suppressed as well in men with higher androgen levels before treatment. In particular, even among the men with high serum ABI levels on treatment, those who had higher serum androgen levels prior to starting ABI continued to have higher serum androgen levels while on therapy. This explains why clinical trials using dose-escalated ABI (e.g., doubling the daily dose) have not been effective and suggests that an alternative approach is needed to fully block adrenal androgen production. The reason fully blocking adrenal androgen production is important is because higher pre-treatment levels of the adrenal androgen DHEA have been associated with better clinical responses to ABI. Our data now show that it is in this precise group of ABI-sensitive patients with higher pre-treatment steroid levels that ABI is not actually being fully effective in suppressing their serum androgens. This suggests that these patients could have better and more durable responses if they were treated with a drug that did actually reduce their serum adrenal androgen levels to undetectable. (In contrast, in the men with lower serum androgen levels prior to ABI, their androgens are already being maximally suppressed by ABI, and a different drug would have no additional benefit.) Another critical point in the treatment of men with ABI is that current studies do not take into account serum levels of a different group of adrenally produced androgens (11-Keto steroids) that can also stimulate the AR and CRPC growth. Determining the presence of these steroids in men with CRPC is critical because these steroids are more resistant to being eliminated than the standard (or canonical) androgens currently measured, such that even low levels could persist in the serum and be available for uptake by the tumor cells. As well, these androgens are directly able to activate the AR, unlike standard androgens like DHEA, which first have to be converted to testosterone or DHT. Objectives: 1. Demonstrate the anti-tumor efficacy of a novel drug, ODM-208, that inhibits CYP11A. CYP11A is upstream of CYP17A in the pathway of adrenal androgen production, and we predict that it is a more effective target for blocking adrenal androgen production. 2. Show that the adrenal androgens currently being measured in men with CRPC are not actually the best predictors of response to ABI (or ultimately, ODM-208) and that serum levels of the 11-Keto steroids will be better predictors of response. Specific Aims: The Aims of this proposal are to (1) demonstrate the impact of CYP11A inhibition on CRPC tumor growth in vivo using the LuCaP patient derived xenografts; (2) identify mechanisms of resistance in tumors that do not respond or are poorly responsive to CYP11A inhibition; and (3) show that baseline levels of non-canonical androgens in CRPC serum are better predictors of response to adrenal androgen inhibition than DHEA. Contributions to PCa Research and Applicability: By targeting CYP11A, this proposal will explore the “next frontier” in inhibiting adrenal androgen synthesis. This work will show the clinical relevance of measuring 11-Keto steroids in response to existing adrenal androgen inhibitors. These studies will allow optimal stratification of men who are likely to respond to adrenal androgen inhibition (based on 11-Keto steroid levels) and provide a means to achieve optimal inhibition of adrenal androgen synthesis (via inhibition of CYP11A). This research is immediately applicab
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910809
Entities
People
- Elahe Mostaghel
Organizations
- Seattle Institute for Biomedical and Clinical Research
- United States Army