Also are there androgen receptor mutations, which confer agonistic activity to enzalutamide or abiraterone, like we’ve previously seen with flutamide?
I’m interested whether the androgen receptor pathway still plays a role at this advanced stage of disease (after enzalutamide / abiraterone treatment) or whether these tumors may have become indeed androgen-insensitive. In this case I would expect that this tumors look very undifferentiated in histology, with cytoplasmic AR staining (if any). I can’t find much literature on histology and androgen receptor staining of enzalutamide/abiraterone-resistant patient material. I’m just not sure whether growth of these tumors is mainly stimulated by constitutively active androgen receptor variants, like some claim. It could also be that these tumors have bypassed the androgen receptor by activation of alternative growth pathways.
What are your thoughts about this issue? If possible, support with literature references.
Biopsies of patients progressing on abiraterone or enzalutamide show nuclear staining for AR indicating continued AR activation. Also, enzalutamide has activity after abiraterone and the reverse is also true, although the response rates are lower indicating some degree of cross-resistance but also contiued sensitivty to AR targeting agents in other patients (see also publications Loriot Annals of Oncology 2013, Bianchini EJC 2013, Noonan Annals of Oncology 2013, Schrader Eur Urol 2013).
I recommend you papers by Wu et al. Trends in Endocrinology and Metabolism 2011, 22, 474-80; by Lee et al Cancer Res 2002, 62, 6039-44; , and by Dillard et al. Mol Cell Endo 2008, 295, 115-20
I personally believe AR is still there and functional....but do not use AR location as an indicator, since surrounding cells may provide additional support for tumor cells, which may also trigger AR function...
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