Chemotherapy-induced circadian master clock disruptions and fatigue

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 SCN function leading to fatigue. The rationale for this work is that circadian circuitry disruption is an under- studied, relevant pathway in psycho-oncology research that could elucidate mechanisms and new, rhythm-fo- cused interventions. Three specific aims are proposed to test the central hypothesis using our novel breast cancer “survivor” mouse model. Aim 1 will determine the ability of the master clock to entrain after chemother- apy. Behavioral SCN rhythm adaptations to environmental challenges will be assessed. Aim 2 will identify the role of central inflammation in master clock disruptions after chemotherapy. The role of chemotherapy-induced neuroinflammation on SCN molecular and behavioral rhythms will be quantified. The potential resolution of fa- tigue will also be assessed. Aim 3 will determine the role of circadian disruption in chemotherapy-induced fa- tigue. Genetic and pharmacological SCN timing manipulations will precede a battery of behavioral assess- ments of the physical, motivation, and cognitive components of fatigue. In vivo and ex vivo circadian timing ap- proaches combined with systems-, cellular-, and molecular-level analyses will pinpoint the effects of two regi- mens of chemotherapy on master oscillator circadian circuitry relevant to cancer-related behavioral comorbidi- ties. 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 translational model and the circadian genetic and pharmacological techniques planned. This research will result in essential new knowledge about how com- mon cancer treatments affect the pacemaker, which is crucial to extensive downstream physiology and behav- ior (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 pharmacological 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).