Heather S. Jim, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): Research has highlighted the prevalence and disruptiveness of fatigue and depression during chemotherapy for ovarian cancer. Effective interventions are now needed to reduce fatigue and depression, but development of such interventions is hampered by gaps in current understanding of: 1) the factors that give rise to fatigue and depression, and 2) the best methods of assessing these symptoms. The current proposal extends previous research suggesting that fatigue and depression in ovarian cancer patients may be associated with disruptions in sleep/activity circadian patterns (i.e., disruptions in the rhythmicity of sleep and physical activity behaviors over a 24 hour period). The proposed study will model longitudinal changes and inter-relationships between fatigue, depression, and sleep/activity circadian patterns during the first three cycles of chemotherapy for ovarian cancer. Additionally, it will compare results obtained by two different assessment methods of fatigue and depression: retrospective self-report and real-time assessment. The specific aims are: 1) to examine changes in fatigue, depression, and sleep/activity circadian patterns prior to initiation of chemotherapy and across the first three infusions; 2) to examine competing models of relationships between fatigue, depression, and sleep/activity circadian patterns; 3) to examine the accuracy of retrospective self-reports of fatigue and depression. It is hypothesized that rates of change between symptoms will be correlated and will follow a cyclical pattern, increasing dramatically in the days following each chemotherapy infusion, then declining gradually. Further, it is hypothesized that symptoms follow a cascade pattern, in which disruptions in sleep/activity circadian patterns contribute to fatigue, which in turn contributes to depression. Finally, it is hypothesized that retrospective self-reports of fatigue and depression will be less accurate than real-time assessment, particularly when symptom variability is high. These hypotheses will be examined by collecting real-time and retrospective fatigue and depression data during three, two week periods surrounding each of the first three chemotherapy infusions. Sleep/activity circadian patterns will be recorded during these periods through an actigraph, a device worn on the non-dominant wrist that measures motion. The proposed study will contribute to a better understanding of the course and inter-relationships between fatigue, depression, and sleep/activity circadian patterns, which will serve as the basis for developing a behavioral intervention to reduce symptoms in ovarian cancer patients. In addition, the proposed study will examine the accuracy of retrospective self-reports, a common measure of symptoms. Accurate measurement is essential to assess the efficacy of new interventions, ensuring that patients receive the highest quality care. A better understanding of the relationships between common symptoms during chemotherapy may be helpful in developing more effective interventions to prevent or reduce these symptoms, thereby improving public health. Additionally, accurate measurement is essential to assess the efficacy of new interventions, ensuring that patients receive the highest quality care. The proposed study will model change and relationships over time between fatigue, depression, and sleep/activity circadian patterns, as well as examine the accuracy of a common method of assessing symptoms. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): As a clinical psychologist with a strong interest in the psychological and physical effects of cancer, I have substantial experience in behavioral oncology research. My long-term goal is to establish an NCI-supported independent research program dedicated to studying genetic influences on cognitive functioning, depression, and fatigue in individuals with cancer. My short-term goal is to examine these side effects in individuals treated with allogeneic hematopoietic stem cell transplantation (HSCT). HSCT is one of the most physically and emotionally stressful treatments for cancer. Sizeable subgroups of patients treated with HSCT experience long-term cognitive deficits, depression, and fatigue. The proposed research will: 1) provide a methodologically-rigorous evaluation of longitudinal change in cognitive functioning, depression, and fatigue in patients treated with allogeneic HSCT compared to individuals without cancer;and 2) explore genetic predictors of these side effects. This study is expected to yield clinically and conceptually important data which will inform my independent program of research. The study will be complemented by rigorous training in the following areas: the assessment of cognitive functioning, depression, and fatigue in individuals treated with HSCT;medical aspects of HSCT;longitudinal assessment and data analysis;medical genetics, behavioral genetics, and biological mechanisms of behavior;gene extraction, genotyping, and genome-wide association studies;and the responsible conduct of research. The proposed training plan includes formal mentorship, didactic coursework, and attendance and presentation at intramural and national research meetings. The resources of Moffitt Cancer Center are outstanding and will facilitate my proposed career development and program of research. I am confident that the training and research proposed in this grant will contribute to my continuing success and will accelerate my transition to an independent investigator.

DESCRIPTION (provided by applicant): Research has highlighted the prevalence and disruptiveness of fatigue, depression, and disruptions in sleep and physical activity (i.e., sickness behaviors) during chemotherapy. Biological mechanisms of sickness behaviors secondary to chemotherapy remain unknown, however. One potential biological mechanism of sickness behaviors is increased pro-inflammatory cytokines. Cross-sectional observational studies suggest that circulating pro-inflammatory cytokines are higher in post-treatment breast cancer survivors who experience chronic cancer-related fatigue. Despite these data, no studies have longitudinally examined the relationship between sickness behaviors and pro-inflammatory cytokines during and after chemotherapy. The trajectory and timing of pro-inflammatory cytokines relative to sickness behaviors is therefore unknown. Moreover, the components through which behavioral interventions exert beneficial effects on cytokines and sickness behaviors is unclear; one possibility is by increasing relaxed mood. The proposed project will assess fatigue, depression, sleep, activity, and circulating pro-inflammatory cytokines via self-report, actigraphy, and venipuncture in 150 gynecologic cancer patients receiving platinum- and taxane-based chemotherapy, one of the most arduous treatment regimens for cancer. Patients will be assessed the week before and the week after their first, third, and sixth chemotherapy infusions, as well as six and twelve months after chemotherapy ends. This study design will capture changes in sickness behaviors and cytokines on-treatment as well as in the early survivorship period. Patient participants who report clinically significant fatigue or depression a the twelve month assessment will participate in an experimental induction of relaxed mood to test the short-term effects of relaxation on cytokines and sickness behaviors. Because women without cancer also experience fatigue, depression, poor sleep, and reduced physical activity, and because data are sparse regarding normal fluctuations in circulating pro-inflammatory cytokines, the study will also assess sickness behaviors, and pro-inflammatory cytokines over a comparable time period in a sample of 150 women without cancer matched individually to patients based on age and zip code. The study will provide valuable information regarding the natural course of sickness behaviors and circulating pro-inflammatory cytokines in cancer patients treated with chemotherapy, including rates of change, temporal interrelationships, variation compared to women without cancer. In addition, it will determine whether induction of relaxation is an effective component of behavioral interventions to reduce sickness behaviors. These data will form the basis for future studies examining biobehavioral mechanisms of sickness behaviors and interventions to ameliorate them.

DESCRIPTION (provided by applicant): Targeted therapies are a new generation of drugs designed to interfere with molecular targets critical for tumor growth and progression. One of the first and most successful examples is the oral medication imatinib developed for chronic myelogenous leukemia (CML). Although imatinib and similar medications are much better tolerated than regimens they replaced, they still possess side effects that are bothersome to patients, interfere with quality of life, and contribute to problems with adherence. Since treatment typically continues on a daily basis for many years and may be life-long, effective management of side effects is critically important. Recent studies show that fatigue is the most common and bothersome symptom identified by CML patients being treated with oral targeted therapy. The proposed research represents the first systematic attempt to address the problem of targeted therapy-related fatigue (TTF). Toward this end, it builds on previous research showing that a form of cognitive behavior therapy (CBT) based on a precipitating-perpetuating model of symptom evolution is highly effective against fatigue in cancer patients with no clinical evidence of disease who have completed treatment (i.e., post-cancer fatigue or PCF). Accordingly, in collaboration with its developers, we will adapt CBT-PCF, an intervention based on the precipitating-perpetuating model for fatigued patients who completed treatment, to develop CBT-TTF, an intervention based on a revised precipitating-exacerbating model for fatigued patients on maintenance targeted therapy. Adopting the tailored modular approach of the original intervention, we will first conduct iterative qualitative research with fatigued CML patients and CML care providers to determine which CBT-PCF modules to retain and adapt and to identify potential new modules to develop based on the conceptual model. The adaptation also involves moving from clinic-based delivery to Internet-assisted delivery using video telephony and tablet computer technology (FaceTime using iPads) in order to minimize travel burden, maximize convenience, and foster greater dissemination potential. Once developed, CBT-TTF will be evaluated with fatigued CML patients on oral targeted therapy for feasibility, acceptability and potential efficacy relative to usual care only in a small-scale randomized controlled trial. The specific aims are to: 1) develop an Internet-assisted form of CBT for TTF (CBT-TTF) using as a foundation an empirically-supported form of CBT effective against post-treatment cancer-related fatigue; 2) evaluate CBT-TTF and related methods for feasibility and acceptability; 3) explore the efficacy of CBT-TTF in reducing fatigue (primary outcome); and 4) explore the efficacy of CBT-TTF in improving quality of life and oral medication adherence (secondary outcomes). Successful completion of this research will provide a strong foundation for a larger multi-center clinical trial expected to yield a highly effective and readily disseminale intervention that addresses a major treatment consequence in the growing population of patients for whom target therapies are transforming cancer from a life-threatening illness to a chronic illness.

PROJECT SUMMARY Moderate to severe nausea is reported by up to 38% of cancer patients receiving moderately- or highly- emetogenic chemotherapy despite international antiemetic guidelines. Chemotherapy-induced nausea is associated with worse quality of life, increased healthcare utilization, and greater costs of care. Previous research has identified clinical and personal risk factors for nausea (e.g., disease stage, emetogenicity of chemotherapy, age, sex, history of motion sickness, anxiety, alcohol use), but risk-prediction algorithms based on these factors demonstrate room for improvement. Recent methodologies for studying the human genome and microbiome enable us for the first time to develop a more comprehensive understanding of the pathophysiology of chemotherapy-induced nausea and develop better algorithms. The goal of the current study is to improve understanding of risk of chemotherapy-induced nausea through integrated examination of genetic and microbiome variables with well-established clinical and personal risk factors. We will conduct the first GWAS of chemotherapy-induced nausea, then use pathway analysis to place results into functional context. Significant variants will be incorporated with clinical and personal factors into a clinical risk prediction algorithm. This study will also be among the first to examine the association of the gut microbiome with chemotherapy-induced nausea. Importantly, this study is one of the first to truly integrate biological, clinical, and patient-reported data to predict risk of treatment toxicity. This groundbreaking study will be a model for similar efforts in other side effects of chemotherapy such as cognitive impairment, fatigue, and peripheral neuropathy. Updated risk algorithms from the current study will be made publicly available and will inform a future randomized trial of risk-based antiemetic cancer care delivery. Positive results will spur integration of the risk algorithms into the electronic medical record with provider alerts to identify patients at risk of chemotherapy-induced nausea. Microbiome analyses conducted in the first two years of the study will provide rapid knowledge about its contributions to chemotherapy-induced nausea. Positive results will generate additional studies to determine whether microbial manipulation can prevent chemotherapy-induced nausea. Microbiome data are particularly exciting because they focus on an entirely new mechanism in chemotherapy-related toxicity. In summary, this rigorous, comprehensive study provides an integrated new approach to chemotherapy-induced nausea that is expected to significantly advance our understanding of pathophysiology and risk of this important clinical problem.

PROJECT SUMMARY Fatigue is one of the most prevalent and distressing symptoms experienced by cancer patients. Treatment options for cancer-related fatigue are limited; additional therapies are a high priority for research. Bupropion has been identified as a potential therapy for cancer-related fatigue since 1999. Bupropion has diverse actions that target pathways associated with cancer-related fatigue, including inflammation and hypothalamic pituitary adrenal (HPA) axis functioning. Metabolism of bupropion by cytochrome P 450 B6 (CYP2B6) has been extensively characterized. Two pilot studies of bupropion have shown promise in reducing cancer-related fatigue but to date no adequately-powered, randomized controlled trials have been conducted. The goal of the current study is to conduct the first adequately-powered, randomized, double-blinded, placebo-controlled trial of bupropion for cancer-related fatigue. Because fatigue is well-characterized in women with breast cancer, the study will focus on this population. A sample of 422 disease-free breast cancer patients who completed chemotherapy and/or radiotherapy 12-60 months previously and report significant fatigue will be recruited through the University of Rochester Cancer Center (URCC) National Cancer Institute Community Oncology Research Program (NCORP). Participants will be randomized 1:1 to receive generic bupropion XL or placebo. Fatigue will be assessed prior to randomization and 12 weeks later. Blood and saliva will be collected to measure bupropion metabolites, inflammation, CYP2B6 genotype, and cortisol (a marker for HPA axis functioning). Data will be used to address the following aims: 1) to determine the efficacy of bupropion versus placebo in reducing fatigue in a double-blinded, placebo-controlled, randomized clinical trial of breast cancer survivors with fatigue; 2) to assess the tolerability of bupropion in breast cancer survivors with fatigue, 3) to explore the effects of bupropion on putative mechanisms of cancer-related fatigue, and 4) to explore associations of CYP2B6 genotype with bupropion metabolism and changes in fatigue. Positive results from the current study could revolutionize the treatment of cancer-related fatigue, as bupropion is safe, inexpensive, widely-available, and may be more tolerable and acceptable for many patients than current, limited treatment options. Exploration of the effects of bupropion on putative mechanisms of cancer-related fatigue could open new avenues for additional efficacious treatments. Exploration of genetic moderators of efficacy could help identify which patients are most likely to benefit and tailor dosage.