CDK4/6 Therapeutic Intervention and Viable Alternative to Taxanes in CRPC.

Resistance to second-generation androgen receptor (AR) antagonists and CYP17 inhibitors in patients with castration-resistant prostate cancer (CRPC) develops rapidly through reactivation of the androgen signaling axis and has been attributed to AR overexpression, production of constitutively active AR splice variants, or the selection for AR mutants with altered ligand-binding specificity. It has been established that androgens induce cell-cycle progression, in part, through upregulation of cyclin D1 (CCND1) expression and subsequent activation of cyclin-dependent kinases 4 and 6 (CDK4/6). Thus, the efficacy of the newly described CDK4/6 inhibitors (G1T28 and G1T38), docetaxel and enzalutamide, was evaluated as single agents in clinically relevant in vitro and in vivo models of hormone-sensitive and treatment-resistant prostate cancer. CDK4/6 inhibition (CDK4/6i) was as effective as docetaxel in animal models of treatment-resistant CRPC but exhibited significantly less toxicity. The in vivo effects were durable and importantly were observed in prostate cancer cells expressing wild-type AR, AR mutants, and those that have lost AR expression. CDK4/6i was also effective in prostate tumor models expressing the AR-V7 variant or the AR F876L mutation, both of which are associated with treatment resistance. Furthermore, CDK4/6i was effective in prostate cancer models where AR expression was lost. It is concluded that CDK4/6 inhibitors are a viable alternative to taxanes as therapeutic interventions in endocrine therapy-refractory CRPC.Implications: The preclinical efficacy of CDK4/6 monotherapy observed here suggests the need for near-term clinical studies of these agents in advanced prostate cancer. Mol Cancer Res; 15(6); 660-9. ©2017 AACR.

Unexpected novel relational links uncovered by extensive developmental profiling of nuclear receptor expression.

Nuclear receptors (NRs) are transcription factors that are implicated in several biological processes such as embryonic development, homeostasis, and metabolic diseases. To study the role of NRs in development, it is critically important to know when and where individual genes are expressed. Although systematic expression studies using reverse transcriptase PCR and/or DNA microarrays have been performed in classical model systems such as Drosophila and mouse, no systematic atlas describing NR involvement during embryonic development on a global scale has been assembled. Adopting a systems biology approach, we conducted a systematic analysis of the dynamic spatiotemporal expression of all NR genes as well as their main transcriptional coregulators during zebrafish development (101 genes) using whole-mount in situ hybridization. This extensive dataset establishes overlapping expression patterns among NRs and coregulators, indicating hierarchical transcriptional networks. This complete developmental profiling provides an unprecedented examination of expression of NRs during embryogenesis, uncovering their potential function during central nervous system and retina formation. Moreover, our study reveals that tissue specificity of hormone action is conferred more by the receptors than by their coregulators. Finally, further evolutionary analyses of this global resource led us to propose that neofunctionalization of duplicated genes occurs at the levels of both protein sequence and RNA expression patterns. Altogether, this expression database of NRs provides novel routes for leading investigation into the biological function of each individual NR as well as for the study of their combinatorial regulatory circuitry within the superfamily.

Molecular cloning and developmental expression patterns of thyroid hormone receptors and T3 target genes in the turbot (Scophtalmus maximus) during post-embryonic development.

Thyroid hormones (TH) are pleiotropic factors important for many developmental and physiological functions in vertebrates and particularly in amphibian metamorphosis. Their effects are mediated by two specific receptors (TRalpha and TRbeta), which are ligand-dependent transcription factors, members of the nuclear hormone receptor superfamily. Besides their pivotal role in amphibian metamorphosis, TH are also critical for fish metamorphosis. As this later role of TH is less studied, we analyzed their action in the turbot (Scophtalmus maximus), a metamorphosing flat fish. We describe the isolation of sequences for the turbot orthologs of a number of Xenopus genes, which are induced during amphibian metamorphosis. Developmental expression of these genes during turbot metamorphosis was studied by several methods and the expression patterns of these genes compared with those in Xenopus and flounder. We find that the period between the onset and the end of eye migration (day 22 to day 30 post-hatching) most likely corresponds to the metamorphic climax with either high TRalpha or high TH levels. Our results show that in contrast to amphibians, it is TRalpha and not TRbeta mRNA that is up-regulated during metamorphosis. Our results highlight the notion that TH regulates, through a rise of TR expression, a genetic cascade during turbot metamorphosis. The fact that TH regulates metamorphosis in amphibian and teleost fishes suggests that TH-regulated metamorphosis is a post-embryonic process conserved in most vertebrates.