Publications

Locomotion in mammals relies on a central pattern-generating circuitry of spinal interneurons established during development that coordinates limb movement. These networks produce left-right alternation of limbs as well as coordinated activation of flexor and extensor muscles. Here we show that a premature stop codon in the DMRT3 gene has a major effect on the pattern of locomotion in horses. The mutation is permissive for the ability to perform alternate gaits and has a favourable effect on harness racing performance. Examination of wild-type and Dmrt3-null mice demonstrates that Dmrt3 is expressed in the dI6 subdivision of spinal cord neurons, takes part in neuronal specification within this subdivision, and is critical for the normal development of a coordinated locomotor network controlling limb movements. Our discovery positions Dmrt3 in a pivotal role for configuring the spinal circuits controlling stride in vertebrates. The DMRT3 mutation has had a major effect on the diversification of the domestic horse, as the altered gait characteristics of a number of breeds apparently require this mutation.

UNLABELLED

Study Type--Therapy (cohort) Level of Evidence 2a. What's known on the subject? and What does the study add? Despite expanding treatment options for castration-resistant prostate cancer (CRPC), therapies with long response duration remain intangible due to prostate cancer cells' natural ability to develop iterative resistance. Androgen receptor (AR) signaling has been shown to play a critical role in CRPC and its expression is regulated by the PI3K-Akt pathway. Thus inhibition of AR signalling and PI3K-Akt-mTOR (a downstream mediator of the PI3K-Akt pathway) pathway is a logical combination in CRPC and we report a phase II trial of RAD001 and bicalutamide. Our study is the first clinical trial report of an AR inhibitor of PI3K-Akt-mTOR. The AR pathway and the PI3K-Akt-mTOR pathway are two of the most relevant growth pathway for CRPC. Despite low efficacy results from our trial there will be significant interest in the field for these data (dose, schedule, response, toxicity, trial design) as newer generations of both AR inhibitors and PI3K-Akt-mTOR inhibitors are in development and likely will be tested in combination in CRPC.

OBJECTIVES

• To determine best overall response and duration of response of RAD001, a selective inhibitor of mammalian target of rapamycin, in combination with bicalutamide in castration-resistant prostate cancer (CRPC). • To characterize the toxicity profile of RAD001 in combination with bicalutamide in patients with CRPC.

PATIENTS AND METHODS

• A phase II study was conducted to explore the efficacy and tolerability of RAD001 (10 mg daily) in combination with bicalutamide (50 mg daily) in men with progressive CRPC. • The primary endpoint was a composite of prostate-specific antigen (PSA) level and measurable disease response by standard criteria. • This single-stage trial with a sample size of 38 eligible patients provided 90% power to differentiate a response rate of ≥ 40% from a response rate of ≤ 20%, as expected for bicalutamide alone (α= 0.10, power = 0.90).

RESULTS

• In total, 36 men were enrolled, with a median (range) age of 68 (60-72) years and median (range) baseline PSA level of 22.2 (8.4-121.3) ng/mL, and 89% had metastatic disease. • There were 31 (86%) patients had previously used bicalutamide for a median duration of 7.4 months. • There were two patients with a confirmed PSA level decline ≥ 50%. • The median (interquartile range) time to progression was 8.7 (7.9-15.9) weeks. • The most common toxicity was grade 1/2 mucositis, which was observed in 20 (56%) patients.

CONCLUSION

• The combination of RAD001 and bicalutamide in men with CRPC was well tolerated but had low activity and failed to achieve the primary endpoint of improved response compared to the results previously achieved for bicalutamide alone in this population.