Over the last few weeks I've received quite a few questions relating to castration resistance and how it happens. After all, while we have several therapies now approved once androgen deprivation therapy (ADT) fails, if we could keep men hormone sensitive for longer, then overall outcomes would likely improve.
Writing about prostate cancer is always a tough topic for me after my Dad passed away 10 years ago from the disease. He was sadly diagnosed in stage IV so there wasn't much that could be done really. It took only 18 months or so for a series of hormone therapies to fail and he developed castration resistant prostate cancer (CRPC). He subsequently declined chemotherapy on the grounds that he wanted to go with dignity on his own terms, nor did he want to put my Mother through hell either. I rather respect that kind of mature and sensible approach in the face of a very difficult situation.
Ever since then though, I've always wondered what could we do inhibit androgen receptor (AR) signalling better and how could we improve on the therapies we have?After all, bicalutamide and similar therapies are not particularly effective agents because eventually, they all stop working and cycling through multiple therapies is very much the norm.
A new paper in Clinical Cancer Research attracted my attention recently (see journal link below). The authors took a look at various possible methods of castration resistance and defined the main ones from the literature as:
"(i) AR activation by androgens converted from adrenal androgens or synthesized intratumorally via the de novo route
(ii) hypersensitivity of ARs due to overexpression of AR proteins and/or changes in cofactor expression levels
(iii) promiscuous activation of AR signaling by various ligands following AR mutation
(iv) constitutive activation of AR signaling by truncated ARs lacking ligand-binding domains."
A prior article by Harris et al., in Nature Reviews Urology defined 6 potential pathways slightly differently, including:
"(1) Tissue and tumoral steroidogenesis contribute to synthesis of testosterone and DHT, and might lead to persistence of tissue-level androgen despite castration.
(2) Mutations in the AR allow activation by alternate ligands or increased affinity for androgens.
(3) Amplification increases AR abundance.
(4) Ligandindependent activation of AR through ligand-independent modifications or cross-talk with other pathways, including phosphorylation of AR leading to hypersensitization and increased nuclear translocation.
(5) Change in the balance of coactivators and corepressors augment AR activity.
(6) Bypass pathways functioning independently of AR activity through upregulation of antiapoptotic molecules, such as Bcl-2."
These were also described graphically in the following picture, with the source referenced below:
A lot of people have been asking how the 17,20 lyase inhibitors work. 17,20-lyase is essential for androgen and testosterone synthesis in both the adrenal glands and CRPC tissue, so the inhibitors have been developed to target this mechanism in both organs.
There are a number of 17,20 inhibitor in the oncology R&D pipeline including:
- abiraterone (J&J/Centocor) – phase III
- TAK-700 (Millennium-Takeda) – phase II
- TOK-001 (Tokai) – phase I/II
However, resistance to these therapies have already been observed in clinical trials, so while they may inhibit AR signalling for a period, they may not be the final answer.
The other drug in development that has garnered a lot of attention is MDV2100 (Medivation and Astellas). This agent works via a completely different mechanism. Rather than acting through the adrenal cortex or CRPC tissues, it may operate in the cell nucleus on the AR regulated genes, essentially acting through the “intracrine” production of androgens from adrenal androgen or intratumorally, blocking the the interaction between androgens and AR. The first generation agents such as bicalutamide, flutamide and nilutamide are not very effective because they have agonistic activity for CRPC so what is needed is a drug with more complete antagonist AR activity, especially against mutant ARs that develop over time.
What is particularly interesting in the new agents being developed to target advanced prostate cancer is what a poor marker of activity PSA is. New studies with circulating tumour cells (CTC's) may well ultimately help us learn more about the underlying biology of the disease.
I'm also looking forward to hearing more about TMPRRS2-ERG, a recently discovered fusion by Tomlins et al., (2005) of an androgen-controlled serine protease, TMPRSS2, and the erythroblast transformation-specific (ETS) family gene ERG by chromosomal rearrangement. Together with phosphoinositide-3 kinase (PI3K), this fusion gene is now thought to be involved in the pathogenesis and progression of prostate cancer.
The authors noted:
"By using fluorescence in situ hybridization, we demonstrated that 23 of 29 prostate cancer samples harbor rearrangements in ERG or ETV1."
Once you have a fusion gene identified, you have a potentially druggable target that may play a causal role in cancer. It will be interesting to see if what happens with this and how long it takes for a new agent to hit clinical trials targeting this aberration in prostate cancer.
Maybe there is already one out there and I missed it!?
Yamaoka M, Hara T, & Kusaka M (2010). Overcoming persistent dependency on androgen signaling after progression to castration-resistant prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research, 16 (17), 4319-24 PMID: 20647476
Harris, William P, Mostaghel, Elahe A, Nelson, Peter S, & Montgomery, Bruce (2009). Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion nature clinical practice UROLOGY, 6 (2), 76-85 DOI: 10.1038/ncpuro1296
Tomlins, SA, Rhodes, DR, & Perner, S (2005). Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science, 310, 644-648 DOI: 10.1126/science.1117679