Chemotherapy-induced circadian master clock disruptions and fatigue

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Project Summary/Abstract Understanding the causes and mechanisms underlying circadian rhythm disruptions that are associated with fatigue during cancer treatment remains unclear. This current deficiency means that successful cancer treat- ment falls short of its potential and prior quality-of-life remains elusive for patients. Our long-term goal is to im- prove debilitating behavioral sequelae in cancer patients, thus improving quality-of-life, other comorbidities, and mortality. Thus, the overall objective here is to establish the potential role of circadian disruption as a fun- damental pathway by which chemotherapy promotes cancer-associated fatigue. Indeed, robust circadian rhyth- micity of virtually all physiology is extremely well-conserved; desynchrony of these rhythms leads to negative health and behavioral consequences. The central hypothesis is that chemotherapy-induced inflammation inhib- its peripheral (adrenal) clock function contributing to fatigue. The rationale for this work is that circadian cir- cuitry disruption is an understudied, relevant pathway in psycho-oncology research that could elucidate mecha- nisms and new, rhythm-focused interventions. One specific aim is proposed to test the central hypothesis us- ing our novel breast cancer “survivor” mouse model: What is the relationship between peripheral (supplement) and master (parent) circadian clocks after chemotherapy? Three hypotheses will be tested to answer this questions. H1: Attenuated glucocorticoid responses to light challenges are correlated with longer SCN re-en- trainment duration in chemotherapy-treated mice. Corticosterone and melatonin will be quantified during the light-pulse and jet lag challenges in the parent grant. The rhythmicity of these hormones and their relationships to wheel running re-entrainment will be assessed. H2: Chemotherapy disruption of clock genes rhythms and circulating GCs are independent of the HPA axis. Plasma ACTH and corticosterone and clock genes in the PVN, adrenals, and pituitary will be assessed every 2 h over 24 h. H3: Neuroinflammation drives chemother- apy-induced GC arrhythmia. Corticosterone rhythms will be analyzed during anti-inflammatory SCN treatment and cytokines will be quantified in plasma. The proposed research is conceptually innovative because using circadian approaches is new to psycho-oncology. It is also technically innovative by way of the superior trans- lational model and the circadian genetic and pharmacological techniques planned. This research will result in essential new knowledge about how common cancer treatments affect auxiliary clocks, which modulates physi- ology and behavior (i.e., beyond fatigue). Results will provide much needed evidence to make circadian-based approaches standard in clinical practice, as well as inform the design of novel circadian-directed pharmacologi- cal and non-pharmacological interventions. This research is applicable to other cancers and in non-oncological populations treated with chemotherapy (e.g., stem cell transplant, lupus).