The past 5 years have brought the assemblage of an increasingly cohesive story that ties together elements of biochemistry, genetics, and steroid physiology to shed light on an important aspect of the nature of prostate cancer response and resistance to hormonal therapies that target gonadal and extragonadal androgens. Here, I briefly summarize how the discovery of distinct metabolic phenotypes of prostate cancer cells in the laboratory has been translated to elucidate the clinical behavior of the tumor in men with prostate cancer.
In normal male physiology, there are two major sources of endogenous androgens. First, the testes, the major source, secrete testosterone, which is converted in prostatic tissues by 5α-reductase to a more potent androgen, dihydrotestosterone (DHT), that stimulates the androgen receptor (AR). Second, the adrenal gland secretes dehydroepiandrosterone (DHEA) and DHEA-sulfate, which is converted in peripheral tissues to biologically active androgens and estrogens. For example, DHEA may be converted in two or three enzymatic steps to testosterone or DHT.
Following clinical responses to treatment with gonadal testosterone depletion (i.e., castration), tumors eventually develop into castration-resistant prostate cancer (CRPC). A weighty body of evidence generated by many research groups all shows that CRPC is accompanied by somatic genetic changes, including AR gene amplification and mutations, which lead to AR reactivation, in turn stimulating tumor progression. However, it has been recognized—for about 4 decades—that CRPC occurs alongside a much higher concentration of testosterone and/or DHT in the CRPC tumor cells and tissues than what is otherwise expected in men treated with castration.
This suggests that CRPC engages a metabolic mechanism that enables testosterone and/or DHT synthesis from extragonadal (e.g., adrenal) precursor steroids. The clinical activity and survival benefit associated with abiraterone, a CYP17A1 inhibitor that blocks extragonadal androgen synthesis, clearly show this mechanism to be a critical and clinically important metabolic driver of prostate cancer progression.
But which patients have tumors that more readily engage this metabolic mechanism that drives CRPC? Is there a way to identify them? Should they be treated differently? The clinical data on the survival benefit of upfront treatment with docetaxel plus castration and abiraterone acetate plus castration are both practice-changing (New Engl J Med 2015;373:737-746, Lancet 2016;387:1163-1177, New Engl J Med 2017;377:338-351, New Engl J Med 2017;377:352-360).
However, there is currently no way to distinguish between those who are more likely to benefit from docetaxel versus abiraterone in the castration-sensitive setting. The issue of matching biologic drivers of prostate cancer progression in individual patients with the appropriate treatment is thus of paramount clinical importance.
Our general approach has been to start with interrogating the cellular metabolic phenotype of the prostate cancer cell. We suspect that the identification of distinct metabolic phenotypes of how the tumor cell handles steroids will reveal underlying molecular mechanisms that in turn drive clinical behavior and clinical outcomes in patients with prostate cancer. Five years ago, we described completely divergent metabolic phenotypes in human prostate cancer cell line models (Cell 2013;154:1074-1084).
We observed that some cells rapidly convert adrenal DHEA to DHT, whereas others make DHT very slowly. These profoundly differing phenotypes are driven by a missense (or single amino acid change) in 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1), the first enzyme responsible for metabolizing DHEA. 3β-HSD1 is encoded by the gene HSD3B1. Normally, 3β-HSD1 is rapidly degraded by the proteasomal pathway and cellular levels are tightly regulated. A single nucleotide change in HSD3B1(1245C) encodes for a 3β-HSD1 enzyme that is resistant to degradation, raising cellular steady-state levels that effectively increase what is otherwise the rate-limiting step for DHT synthesis from extragonadal precursor steroids. Prostate cancer cells that have the wild-type HSD3B1 convert DHEA to DHT slowly, whereas those with the HSD3B1(1245C) variant robustly convert DHEA to DHT, a potent fuel source for AR stimulation (Cell 2013;154:1074-1084).
The HSD3B1(1245C) allele may occur as a somatic mutation in tumors; but perhaps more importantly, it coincides with an extraordinarily common (20-35% allele frequency) germline variant that is present in the general population, which interestingly varies widely by ethnicity. We reasoned that a germline-regulated increase in DHT synthesis from non-gonadal sources may drive tumor resistance to castration. Therefore, we investigated the association between HSD3B1(1245C) inheritance and clinical outcomes in three cohorts of men with advanced prostate cancer treated with castration (Lancet Oncol 2016;17:1435-1444). Subsequently, we described clinical outcomes from yet another institution (JAMA Oncol 2017; doi:10.1001/jamaoncol.2017.3164), and two independent validation cohorts have also been described (JAMA Oncol 2017;3(6):856-857, J Clin Oncol 2018;36(suppl 6S; abstr 179)).
Although some differences exist among these cohorts, the data from these six cohorts consistently show that patients who inherit the HSD3B1(1245C) variant have profoundly worse clinical outcomes after castration compared with patients who are homozygous wild-type (Nat Rev Urol 2018;15(3):191-196). Together, these data indicate that HSD3B1(1245C) inheritance permits tumors with germline-encoded steroidogenic enzyme machinery to exploit and utilize extragonadal precursor steroids to make potent intratumoral androgens that drive AR stimulation and CRPC. HSD3B1(1245C) is therefore a biomarker of adverse clinical outcomes after castration. But is it a predictive biomarker of adverse outcomes after castration or a prognostic biomarker of poor outcomes that functions independent of treatment?
Similar to the setting of oncogene dependencies or other metabolic dependencies, one might anticipate that inheritance of the more active enzyme variant that enables tumors to utilize extragonadal precursor steroids would be accompanied by a tumor dependency on these extragonadal steroids. If that is true, then clinical responses to CYP17A1 inhibitors may be more sustained for patients with the HSD3B1(1245C) variant.
In at least one cohort of patients with CRPC treated with ketoconazole, a non-steroidal CYP17A1 inhibitor, this is the case and men who inherit the HSD3B1(1245C) variant have a longer duration of response to extragonadal androgen ablation therapy (JAMA Oncol 2017; doi:10.1001/jamaoncol.2017.3159). Therefore, the HSD3B1(1245C) variant is not only a predictive biomarker of adverse outcomes after castration, but it also appears to be a predictive biomarker of better outcomes after CYP17A1 inhibition.
However, ketoconazole is no longer commonly used. Abiraterone is today's CYP17A1 inhibitor of choice, with level 1 evidence to support its use as a life-prolonging therapy both in men with metastatic castration-sensitive prostate cancer and metastatic CRPC. What is the relevance of the HSD3B1(1245C) variant to duration of response to abiraterone?
Here, it is important to note that abiraterone shares a chemical structure with DHEA, which allows the enzyme encoded by HSD3B1 to commonly metabolize both steroids. One of the abiraterone metabolites downstream of 3β-HSD1 is an AR agonist and promotes tumor progression in preclinical mouse models (Nature 2015;523:347-351, Nature 2016;533:547-551). In fact, inheritance of the HSD3B1(1245C) variant is associated with elevated serum concentrations of this metabolite in patients treated with abiraterone, effectively increasing exposure to this androgenic substance for patients otherwise treated with gonadal and extragonadal androgen ablation (J Clin Oncol 2018; doi:10.1200/JCO.2018.36.6_suppl.325). This pharmacogenetic effect might partially negate any increased clinical benefit of abiraterone in this subset of patients with HSD3B1(1245C) variant-defined tumors that depend on extragonadal androgens.
In fact, in a study of first-line abiraterone acetate for treatment of CRPC, there was no association between HSD3B1(1245C) variant inheritance and clinical response (J Clin Oncol 2018;3(suppl 6S; abstr 173)). The absence of any association in this study is quite possibly explained by dual and opposing effects of HSD3B1(1245C) variant inheritance on extragonadal steroid precursor metabolism and on abiraterone metabolism.
More Research Needed
In summary, the HSD3B1(1245C) variant confers more rapid castration resistance, is associated with more durable response to CYP17A1 inhibition, and is associated with higher levels of an androgenic abiraterone metabolite that stimulates AR. It is quite possible that patients with HSD3B1(1245C) variant inheritance might instead have greater benefit from a nonsteroidal agent that blocks CYP17A1 or directly inhibits AR.
Furthermore, it is likely that HSD3B1(1245C) variant inheritance and tumor engagement with extragonadal androgens define a group of patients who may benefit from intensification of hormonal therapy in other clinical scenarios where castration alone is utilized, such as in the context of adjuvant treatment for local radiation therapy. The biochemical and clinical data summarized here suggest that these and other concepts related to germline-determined extragonadal androgen dependence should be tested in prospective clinical trials.
NIMA SHARIFI, MD, is the Kendrick Family Chair for Prostate Cancer Research at the Cleveland Clinic.