Good Abi, Bad Abi - Charles Ryan

Hormonal signaling is an intriguing process with a lot of redundancy, promiscuity and feedback. Androgen metabolism is particularly complicated and likely reflects the absolute necessity of intact hormonal signaling for mammalian evolution. I have spent over 15 years studying many aspects of prostate cancer but probably the two most prominent facets of my research life relate to the development of treatments like abiraterone for mCRPC but also the study of the measure of hormones, their signaling patterns and its relationship to outcome in CRPC.

The two interests, not surprisingly, collide quite a bit. One of the most intriguing and potentially clinically interesting areas of overlap has to do with the metabolism of abiraterone and how that relates to its ability to block or enhance hormonal signaling.

Recall that abiraterone is not a complicated molecule, it is simply a slightly altered version of progesterone, a naturally occurring hormone. What makes it special is that it is able to competitively block the processing of androgen precursors by the CYP17 enzyme complex in tumors or the adrenal gland, thus reducing the production of androgens. By the same token, however, abiraterone is subject to the redundant and promiscuous metabolizing capabilities of the enzymes that nature has provided for the formation and clearance of a variety of steroid molecules. And now we are beginning to see how this might affect the efficacy of abiraterone as a therapy.

In a paper published in June of 2018, a team led by Nima Sharifi from the Cleveland Clinic identified that certain metabolites of abiraterone are AR agonists.1 As such, abiraterone metabolism creates its own competitor, in a manner of speaking.

A critical enzyme for hormonal metabolism, especially as pertains to intratumoral androgen synthesis, is 3β-hydroxysteroid dehydrogenase isoenzyme 1 (3βHSD1). The gene that is responsible for encoding the enzyme is HSD3B1. About 50% of us carry one or both of the variant allele for HSD3B1 and thus will process androgens a little differently. The enzyme produced by the variant allele gene is more resistant to degradation, and thus is more of an active enzyme, essentially a gain of function. For those who carry two copies of this gene, the homozygous variant individuals, there are two results. First, they make more androgen. This may not be a bad thing throughout life but it is if you get prostate cancer. If you have prostate cancer and carry this variant enzyme with a gain of function,  it is more likely that CRPC will develop. This has been shown in published studies from Sharifi's group in Cleveland.

Paradoxically, however, it is possible that the disease in those with the HSD3B1 variant allele is thus more ‘androgen sensitive’ which -  said in reverse -  means that your disease is more sensitive to further androgen reduction. The type of androgen reduction that comes via treatments like ketoconazole, and potentially abiraterone. The ketoconazole connection has been observed and published, by the same group.

So, some patients have this revved-up androgen production enzyme in the form of a variant 3BHSD and thus are more sensitive to reduction in this androgen.

That’s mixed news. The disease is worse but the treatments may be more effective. 

But that’s not the whole story. There are actually four abiraterone-like molecules that need to be considered in the story of individuals who carry this polymorphism:

  1. Abiraterone itself. This blocks CYP17A and decreases androgen production
  2. D4 Abiraterone- The first product of 3βHSD1 metabolism of abiraterone. D4 abiraterone is a very potent AR antagonist, on the level of Enzalutamide.
  3. 3-keto-5-alpha abiraterone. This is the breakdown product of D4 abi. It is a potent AR agonist
  4. 3-keto-5-beta abiraterone. This is the other breakdown product of D4 abi. It is neither a strong agonist or antagonist of the androgen receptor. 
The default pathway for D4 breakdown is through 5 alpha reductase, to produce the 3-keto-5 alpha androgen receptor agonist, not through 5 beta-reductase, which produces the relatively inert 3-keto-5 beta form. Thus, abiraterone ends up as an androgen agonist, thus potentially mitigating its antitumor potency.

The enzyme that catalyzes the conversion of D4 abiraterone to 3-keto-5-alpha abiraterone is 5 alpha reductase, the very enzyme that could be catabolized by the addition of a 5 alpha-reductase inhibitor such as finasteride or Dutasteride. Although such treatments have not resulted in substantial antitumor activity, they have not been studied in this context. 

Where we go from here is not fully known. One possibility is that patients with the variant allele who make more AR agonists could benefit from the addition of further AR antagonists, such as Enzalutamide, Apalutamide or Darolutamide. Analysis of patients treated with the combination of any of these drugs with Abiraterone will be available soon as the phase III studies that combined Enzalutamide +Abi or Apalutamide + Abi mature.

The second possibility is that we could combine abiraterone with 5 alpha reductase inhibitors. This has been done on a small scale but not based on the genetics of these polymorphisms. The third possibility is that we could simply look at the variant allele in the context of other factors such as serum androgen levels and proteins associated with androgen transport ( more on this in a future entry).  Finally, if we see these patterns in CRPC, we can maybe do even better by looking at them in the setting of CSPC.

Thus taken together, it is becoming more clear that thinking about the ‘androgen supply chain’ in its totality may allow us to look at the relative contributions of these variances in order to optimize outcomes for patients with CRPC.

Written by: Charles J. Ryan, MD

References: 
  1. Almassi N, Reichard C, Li J, et al. HSD3B1 and Response to a Nonsteroidal CYP17A1 Inhibitor in Castration-Resistant Prostate Cancer. JAMA Oncol. 2018; 4(4):554–557. doi:10.1001/jamaoncol.2017.3159
  2. Alyamani et al J Clin Invest. 2018. https://doi.org/10.1172/JCI98319. 
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