ncbi.nlm.nih.gov/pmc/articl...
Hi Fellow Warriors, above is a new and very detailed article on, all things Androgens with respect to prostate cancer. LOTS of fantastic tables and graphics. It helps to open a seperate window for the pathways to follow along with the article.
My big interest here is the AKR1C3 backdoor pathway to castrate resistance as I and 50% of advanced PCa warriors have the TMPRSS2/ERG fusion.
Since I am on ADT+ Darolutamide AKR1C3 is ONE the several most important pathways I need to address to prevent or slow down drug resistance.
Data from Gene Expression Omnibus for 25 mCRPC tumors revealed a significant correlation (p <0.0001 r = 0.69) between AKR1C3 and ERG co-expression. The TMPRSS2-ERG fusion protein overrides the repressive activity of AR on the AKR1C3 promoter to establish a positive feed-back loop whereby AKR1C3 synthesizes potent androgens to induce its own transcription factor in late stage disease (69)
Below is a large snip of the end of the article (don't miss the middle parts of the article)
5. Enzyme Inhibitors
Labrie maintained that by identifying the discrete enzyme isoforms responsible for the intracrine formation of steroid hormones, targets for drug development would be revealed. In prostate cancer, a case could be made to inhibit STS, HSD3B1, HSD17B6 and AKR1C3.
5. 1. Steroid Sulfatase Inhibitors.
The steroid sulfatase inhibitor irosustat (STX-64) inhibited DHEA-SO4 mediated growth of prostate cancer cells in vitro (45). The drug was advanced to a phase I clinical trial in CRPC patients where it was found to be well tolerated and inhibited the conversion of DHEA-SO4 to DHEA (83).
5. 2. HSD3B1 Inhibitors.
The similarity in amino-acid sequences for HSD3B1 and HSD3B2 suggests that it would be challenging to develop inhibitors that would not block steroidogenesis in gonad, adrenal and peripheral tissues simultaneously. Trilostane and epostane are two compounds that show some discrimination between isoforms, but the difference in IC50 values is unimpressive (84–86).
5. 3. HSD17B6 Inhibitors.
Compounds that specifically inhibit HSD17B6 would block the backdoor pathway to 5α-DHT. However since there are multiple pathways to 5α-DHT, it is likely that inhibition of this single pathway could lead to adaptive upregulation of one or of the others to synthesize compensatory amounts of 5α-DHT. With this caveat, combined inhibition of 5α-reductase and HSD17B6 has been described as a therapeutic strategy (87).
5.4. AKR1C3 Inhibitors.
AKR1C3 acts downstream from CYP17A1 and plays a pivotal role in all pathways to 5α-DHT. Moreover, it is involved in metabolism of 11-oxo-Δ4-AD to 11-oxo-T and conversion of 11-oxo-5α-Adione to 11-oxo-DHT (88). Thus, adaptive responses in the canonical, alternative and backdoor pathways due to ADT would be effectively surmounted by inhibition of AKR1C3. The challenge is to develop AKR1C3 isoform selective inhibitors that do not inhibit the highly related AKR1C1 and AKR1C2 enzymes. Following the observation that AKR1C enzymes demonstrate variable sensitivity to inhibition by NSAIDs (89,90), NSAID analogs have been repurposed to generate compounds that inhibit only AKR1C3 and not AKR1C1, AKR1C2 or AKR1C4 and lack inhibition of PGH2 synthases (COX-1 and COX-2). This has led to a series of drugs including indomethacin analogs (91), N-phenylaminobenzoates (92,93), and R-naproxen analogs (94) that have the desired properties. Moreover, indomethacin was found to surmount abiraterone and enzalutamide drug resistance in xenograft models over expressing AKR1C3 (71,72). These observations lead to the development of ASP9521 by Astellas. ASP9521 has attractive preclinical data and was subsequently taken into a phase1/1b clinical trial in CRPC (95,96). The primary end-point was progression free survival and a secondary end point was a reduction in PSA. The drug was found to be well tolerated but without efficacy. However, tumor biopsies were not pre-screened for the expression of AKR1C3 and patients were excluded if they had been on prior ADT, the very treatment that would upregulate AKR1C3 expression in the first place. Thus the trial may have failed due to inadequate patient selection.
Two other drug candidates which act as inhibitors of AKR1C3 are of interest, these are GTx-560 and BMT4–158. GTx-560, a competitive inhibitor of AKR1C3, also blocked a hitherto unknown property of the enzyme which was its AR coactivator function (97). BMT4–158, also a competitive inhibitor of AKR1C3 was found to also act as a AR antagonist by competing for the binding of R1881 (98). Since combination therapy may override adaptive responses that may compensate for AR antagonism or inhibition of prostate androgen biosynthesis, bifunctional compounds provide important leads for CRPC treatment.
5.5. Steroid 5α-Reductase Inhibitors (SRD5A).
There are two SRD5A isoforms in human prostate and the isoform most implicated in the conversion of T to 5α-DHT is SRD5A2. However, in the 5α-Adione pathway, evidence suggests that SRD5A1 is the important driver of tumor growth. Thus, a cautious approach would be the use of a dual SRD5A1 and SRD5A2 inhibitor, e.g. dutasteride. However even with inhibition of this enzyme, T would continue to build up and may be sufficient to cause tumor growth (99). In fact data from the Montgomery group showed that in advanced mCRPC, the tumor may be more dependent on T than DHT based on measurement of their ratios in biopsy material (100). Currently, there is a FDA black-box warning on the use of SRD5A inhibitors for the treatment of prostate cancer, since chemopreventive clinical trials indicated that both finasteride (in the Prostate Cancer Prevention Trial) and dutasteride (REDUCE Trial) could give rise to more advanced tumors (101).
6. Conclusions.
Fredinand Labrie was the father of the field of “intracinology”. His legacy solidified the concept that hormone dependent malignancies synthesize their own steroid hormones and that the major precursor for this synthesis in post-menopausal women and castrate or aging men was DHEA. While there is much debate as to whether DHEA is itself a hormone, Labrie was correct. Many steroid endocrinologists have embraced his concept, and his group and others have devoted their efforts to identify the discrete enzymes involved in this process with the intent of developing inhibitors for the treatment of hormone dependent malignancies. In the case of prostate cancer, competing pathways exist to form the potent ligands T and 5α-DHT. It is likely that no single pathway will dominate and their involvement in drug resistance may be dependent on the tumor itself, supporting precision approaches to the treatment of disease. This task is made even more daunting because as one pathway is inhibited another may compensate. In addition, prostate cancer that is independent of AR ligand may emerge due to the formation of AR-splice variants and substitution of other nuclear receptors for the AR, e.g. the GR (102).
Prostate Cancer Highlights from ESMO23
