Switching from a gonadotropin-releasing hormone (GnRH) agonist to a GnRH antagonist in prostate cancer patients: A systematic review and meta-analysis.

INTRODUCTION: We sought to address whether there are clinical responses when patients who are failing gonadotropin-releasing hormone (GnRH) agonist therapy are switched to degarelix. Androgen-deprivation therapy remains the backbone of treatment for disseminated prostate cancer and may be achieved with orchiectomy, GnRH agonists, or degarelix, a GnRH antagonist. METHODS: We conducted a systematic review and meta-analysis with a search of the BIOSIS Previews, Embase, International Pharmaceutical Abstracts, MEDLINE, and Google Scholar databases using key terms. Quantitative meta-analysis was performed to provide a pooled estimate of prostate specific antigen (PSA) response at three months. RESULTS: Thirteen studies were identified, eight of which were included in the qualitative and quantitative analyses. Patient characteristics were broadly similar between the studies. Out of 155 patients across all included studies, 20 had stable PSA after the switch (12.9%), 14 had a 10-30% decrease in PSA (9.0%), three had a 30-50% decrease (1.9%), and 13 had a more than 50% decrease (8.4%). Random effects meta-analysis of these data demonstrated a pooled response rate of 27.75% (95% confidence interval 18.9-36.5%; I2=7.9%). Changes in testosterone levels following the switch could not be quantitatively assessed due to lack of sufficient data. CONCLUSIONS: Our results suggest that a switch to GnRH antagonist following progression on a GnRH agonist may result in a stable or decreased PSA at three months in about 30% of patients. This information should be considered among the potential options to discuss with patients with a rising PSA on GnRH agonist therapy.

Structural maintenance of chromosome (SMC) proteins link microtubule stability to genome integrity.

Structural maintenance of chromosome (SMC) proteins are key organizers of chromosome architecture and are essential for genome integrity. They act by binding to chromatin and connecting distinct parts of chromosomes together. Interestingly, their potential role in providing connections between chromatin and the mitotic spindle has not been explored. Here, we show that yeast SMC proteins bind directly to microtubules and can provide a functional link between microtubules and DNA. We mapped the microtubule-binding region of Smc5 and generated a mutant with impaired microtubule binding activity. This mutant is viable in yeast but exhibited a cold-specific conditional lethality associated with mitotic arrest, aberrant spindle structures, and chromosome segregation defects. In an in vitro reconstitution assay, this Smc5 mutant also showed a compromised ability to protect microtubules from cold-induced depolymerization. Collectively, these findings demonstrate that SMC proteins can bind to and stabilize microtubules and that SMC-microtubule interactions are essential to establish a robust system to maintain genome integrity.

KIF14 binds tightly to microtubules and adopts a rigor-like conformation.

The mitotic kinesin motor protein KIF14 is essential for cytokinesis during cell division and has been implicated in cerebral development and a variety of human cancers. Here we show that the mouse KIF14 motor domain binds tightly to microtubules and does not display typical nucleotide-dependent changes in this affinity. It also has robust ATPase activity but very slow motility. A crystal structure of the ADP-bound form of the KIF14 motor domain reveals a dramatically opened ATP-binding pocket, as if ready to exchange its bound ADP for Mg·ATP. In this state, the central ß-sheet is twisted ~10° beyond the maximal amount observed in other kinesins. This configuration has only been seen in the nucleotide-free states of myosins-known as the "rigor-like" state. Fitting of this atomic model to electron density maps from cryo-electron microscopy indicates a distinct binding configuration of the motor domain to microtubules. We postulate that these properties of KIF14 are well suited for stabilizing midbody microtubules during cytokinesis.

DHTP is an allosteric inhibitor of the kinesin-13 family of microtubule depolymerases.

The kinesin-13 family of microtubule depolymerases is a major regulator of microtubule dynamics. RNA interference-induced knockdown studies have highlighted their importance in many cell division processes including spindle assembly and chromosome segregation. Since microtubule turnovers and most mitotic events are relatively rapid (in minutes or seconds), developing tools that offer faster control over protein functions is therefore essential to more effectively interrogate kinesin-13 activities in living cells. Here, we report the identification and characterization of a selective allosteric kinesin-13 inhibitor, DHTP. Using high resolution microscopy, we show that DHTP is cell permeable and can modulate microtubule dynamics in cells.