Abstract
BackgroundFactors influencing differential responses of prostate tumors to androgen receptor (AR) axis-directed therapeutics are poorly understood, and predictors of treatment efficacy are needed. We hypothesized that the efficacy of inhibiting DHT ligand synthesis would associate with intra-tumoral androgen ratios indicative of relative dependence on DHT-mediated growth.MethodsWe characterized two androgen-sensitive prostate cancer xenograft models after androgen suppression by castration in combination with the SRD5A inhibitor, dutasteride, as well as a panel of castration resistant metastases obtained via rapid autopsy.ResultsIn LuCaP35 tumors (intra-tumoral T:DHT ratio 2∶1) dutasteride suppressed DHT to 0.02 ng/gm and prolonged survival vs. castration alone (337 vs.152 days, HR 2.8, p = 0.0015). In LuCaP96 tumors (T:DHT 10∶1), survival was not improved despite similar DHT reduction (0.02 ng/gm). LuCaP35 demonstrated higher expression of steroid biosynthetic enzymes maintaining DHT levels (5-fold higher SRD5A1, 41 fold higher, 99-fold higher RL-HSD, p<0.0001 for both), reconstitution of intra-tumoral DHT (to ∼30% of untreated tumors), and ∼2 fold increased expression of full length AR. In contrast, LuCaP96 demonstrated higher levels of steroid catabolizing enzymes (6.9-fold higher AKR1C2, 3000-fold higher UGT2B15, p = 0.002 and p<0.0001 respectively), persistent suppression of intra-tumoral DHT, and 6–8 fold induction of full length AR and the ligand independent V7 AR splice variant. Human metastases demonstrated bio-active androgen levels and AR full length and AR splice-variant expression consistent with the range observed in xenografts.ConclusionsIntrinsic differences in basal steroidogenesis, as well as variable expression of full length and splice-variant AR, associate with response and resistance to pre-receptor AR ligand suppression. Expression of steroidogenic enzymes and AR isoforms may serve as potential biomarkers of sensitivity to potent AR-axis inhibition and should be validated in additional models.
Highlights
[18] The most straightforward explanation for the lack of greater efficacy is the inability of these androgen receptor (AR) antagonists to outcompete residual testosterone (T) and dihydrotestosterone (DHT), [19] or a failure to effectively target AR splice variants (ARsv) lacking the ligand binding domain (LBD)
To evaluate tumor characteristics associated with response and resistance to AR pathway-directed therapy, we first determined intratumoral androgens and steroidogenic gene expression in two prostate cancer patient derived xenografts, LuCaP35 and LuCaP96
LuCaP35 and LuCaP96 tumors resected from mice with intact gonadal function exhibited marked differences in basal levels of intratumoral androgens (Figure 1D): LuCaP96 tumors have higher levels of T and similar levels of DHT, and a higher ratio of intratumoral T:DHT compared to LuCaP35 tumors, at 10:1 and 2:1, respectively (LuCaP96 T = 10.266.5 ng/ gm; DHT = 0.960.4 ng/gm; LuCaP35 T = 2.662.0 ng/gm; DHT = 1.460.8 ng/gm, Table S1)
Summary
The effectiveness of inhibiting AR activation in prostate cancers, either through enhanced pre-receptor approaches or those directly targeting AR, varies substantially between patients, and the factors contributing to these differential outcomes are unknown. We sought to determine tumor-specific characteristics that influence response of prostate cancers to inhibition of pre-receptor AR signaling, using androgen deprivation combined with the dual SRD5A inhibitor dutasteride. We hypothesized that the impact of SRD5A inhibition on tumor growth would associate with intra-tumoral androgen levels and/or the expression of steroid biosynthetic enzymes suggestive of a relative dependence on DHT-mediated growth. Factors determining the relative response of prostate tumors to pre-receptor androgen suppression with agents such as SRD5A inhibitors are unknown, but could serve as predictors of efficacy for these agents in prostate cancer prevention, or as a component of ADT in advanced disease. We hypothesized that the efficacy of inhibiting DHT ligand synthesis would associate with intra-tumoral androgen ratios indicative of relative dependence on DHT-mediated growth
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