RESUMEN
Circulating IL-6, an activator of JAK/STAT signaling, is associated with poor prognosis and aromatase inhibitor (AI) resistance in hormone-receptor positive (HR+) breast cancer. Here we report the results of a phase 2 single-arm Simon 2-stage trial combining Ruxolitinib, an oral selective inhibitor of JAK1/2, with exemestane, a steroidal AI, in patients with HR+ metastatic breast cancer (MBC) after progression on non-steroidal AI (NSAI). Safety and efficacy were primary objectives, and analysis of inflammatory markers as predictors of response was a key secondary objective. Twenty-five subjects enrolled. The combination of ruxolitinib and exemestane was safe, though anemia requiring transfusion in 5/15 (33%) at the 25 mg dose in stage 1 led to a reduction to 15 mg twice daily in stage 2 (with no additional transfusions). Clinical benefit rate (CBR) in the overall study population was 24% (95% CI 9.4-45.1); 6/25 patients demonstrated stable disease for ≥6 months. Median progression-free survival was 2.8 months (95% CI 2.6-3.9). Exploratory biomarkers revealed high levels of systemic inflammation and 60% harbored a high-risk IL-6 genotype. Pharmacodynamics demonstrated modest on-target inhibition of phosphorylated-STAT3 by ruxolitinib at a tolerable dose. Thus, ruxolitinib combined with exemestane at a tolerable dose was safe but minimally active in AI-resistant tumors of patients with high levels of systemic inflammation. These findings highlight the need for more potent and specific therapies targeting inflammation in MBC.
RESUMEN
Endocrine disrupting chemicals mimic or disrupt action of the natural hormones, adversely impacting hormonal function as well as cardiovascular, reproductive, and metabolic health. Goldfish are seasonal breeders with an annual reproductive cycle regulated by neuroendocrine signaling which involves allocation of metabolic energy to sustain growth and reproduction. We hypothesize that seasonal changes in physiology alter overall vulnerability of goldfish to metabolic perturbation induced by environmental contaminants. In this study, we assess effects of endogenous hormones, individual contaminants and their mixture on metabolism of goldfish at different reproductive stages. Exposure effects were assessed using 1H-NMR metabolomics profiling of male goldfish midbrain, gonad and liver harvested during early recrudescence (October), mid-recrudescence (February) and late recrudescence (June). Compounds assessed include bisphenol A, nonylphenol, bis(2-ethylhexyl) phthalate, fucosterol and a tertiary mixture (DEHP + NP + FS). Metabolome-level responses induced by contaminant exposure across tissues and seasons were benchmarked against responses induced by 17ß-estradiol, testosterone and thyroid hormone (T3). We observe a clear seasonal dependence to metabolome-level alteration induced by hormone or contaminant exposures, with February (mid-recrudescence) the stage at which male goldfish are most vulnerable to metabolic perturbation. Responses induced by contaminant exposures differed from those induced by the natural hormones in a season-specific manner. Exposure to the tertiary mixture induced a functional gain at the level of biochemical pathways modeling over responses induced by individual components in select tissues and seasons. We demonstrate the importance of seasonally driven changes in physiology altering overall vulnerability of goldfish to metabolic perturbation induced by environmental contaminants, the relevance of which likely extends to other seasonally-breeding species.
RESUMEN
Endocrine disrupting chemicals (EDCs) are endocrine-active chemical pollutants that disrupt reproductive, neuroendocrine, cardiovascular and metabolic health across species. The circadian clock is a transcriptional oscillator responsible for entraining 24-hour rhythms of physiology, behavior and metabolism. Extensive bidirectional cross talk exists between circadian and endocrine systems and circadian rhythmicity is present at all levels of endocrine control, from synthesis and release of hormones, to sensitivity of target tissues to hormone action. In mammals, a range of hormones directly alter clock gene expression and circadian physiology via nuclear receptor (NR) binding and subsequent genomic action, modulating physiological processes such as nutrient and energy metabolism, stress response, reproductive physiology and circadian behavioral rhythms. The potential for EDCs to perturb circadian clocks or circadian-driven physiology is not well characterized. For this reason, we explore evidence for parallel endocrine and circadian disruption following EDC exposure across species. In the reviewed studies, EDCs dysregulated core clock and circadian rhythm network gene expression in brain and peripheral organs, and altered circadian reproductive, behavioral and metabolic rhythms. Circadian impacts occurred in parallel to endocrine and metabolic alterations such as impaired fertility and dysregulated metabolic and energetic homeostasis. Further research is warranted to understand the nature of interaction between circadian and endocrine systems in mediating physiological effects of EDC exposure at environmental levels.
