Dana Bovbjerg - US grants

[unreadable] DESCRIPTION (provided by applicant): ErbB-2 (Her2/neu) is an oncogene encoding a 185 kDA (p185neu) tyrosine kinase receptor involved in cell differentiation, adhesion and motility. Mice made transgenic for the unactivated form of rat neu/erbB-2 [FVB/N-Tg(MMTVneu)202Mul/J] display a high incidence and aggressive progression of mammary carcinogenesis. In this model, focal mammary tumors are first apparent at 4 months of age in >50% of the mice, with a median incidence of 205 days. The tumors arise as hyperplastic/dysplastic foci in mammary glands; and ~70% of tumor-bearing mice >8 months of age develop lung metastases. Also, there is substantial evidence that cytokine gene therapy with IL12 results in regression of tumors in these mice. Therefore, this transgenic mouse is a highly useful model for studying the effects of stress on incidence and development of breast cancer and anti-tumor immunity to those tumors. We propose to use chronic stress models in combination with this spontaneous tumor model to document the effects of stress on tumor development, to evaluate the mechanisms resulting in enhanced tumor development, and to assess the negative effects of stress on tumor immunity. In addition, we will examine the effects of stress on the efficacy of tumor immunotherapy with IL12. Our specific aims include: Aim 1. Determine the effects of chronic stressors on mammary tumor development and lung metastases in Erbb-2 transgenic [FVB/N- Tg(Mmtvneu)202Mul/J] mice. Aim 2. Determine the effects of chronic stress on anti-tumor immunity in Erbb-2 transgenic [FVB/N-Tg(Mmtvneu)202Mul/J] mice. This project deals with the evaluation of the effects of stress on the progression, and possibly initiation, of breast cancer in a transgenic mouse model. In this model, breast tumors spontaneously develop in about half the mice; and we will determine whether stress increases to rapidity of tumor development and whether it increases the number of mice that develop tumors. We will also examine whether stress affects the ability of the mice to mediate anti- tumor immune responses to breast cancer. This may provide an important advance in the experimental approaches available to monitor the effects of stress on cancer. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): For the healthy daughters and sisters of the 200,000+ women diagnosed with breast cancer each year in the U.S., the threat of this disease is particularly salient. Biologically, they are at risk for carrying genes that increase their likelihood of developing breast cancer. Even after accounting for BRCA1/2, women with breast cancer in their families (FH+) have at least twice the population risk. Psychologically, they are at risk for symptoms of anxiety, depression, and posttraumatic stress, even years after the diagnosis. An understudied possibility is that these women may also have heightened hypothalamic pituitary adrenal (HPA) axis (e.g., cortisol) responses to acute stress, a major pathway by which stress can affect health. The contributions of genetic and/or psychological factors to this heightened responsivity have not been investigated. The overall goal of the proposed research is to test the hypothesis that healthy women with family histories of breast cancer have heightened HPA axis stress responsivity, and to investigate the contributions of the genetic and psychological aspects of family histories to response variability. Healthy, FH+, premenopausal, working women and a frequency matched FH- sample will be recruited. After rigorous prescreening to reduce extraneous sources of variability, HPA axis stress responsivity will be evaluated in two well-established, tightly-controlled, stress paradigms: 1) a laboratory approach, the Trier Social Stress Test (high internal validity); and, 2) a 'real world' approach, work-stress in daily life (high external validity). Combined results of these approaches will be statistically examined (n=220 with complete data) to explore a broader model of family history effects on stress responsivity. Research aims of this psychobiological study are: 1) to investigate the relationship between family history of breast cancer and women's HPA axis responses to stress under controlled laboratory conditions; 2) to examine the relationship between family history of breast cancer and women's cortisol responses to stress under naturalistic conditions; 3) to evaluate the effects of genetic risk and psychological sequelae of having a family history of breast cancer on women's cortisol responses to stress under laboratory and naturalistic conditions, using structural equation analyses of combined data. PUBLIC HEALTH RELEVANCE: If the results of the proposed research indicate a significant contribution of the genetic aspects of family history to heightened HPA axis responsivity to stress, it would raise the possibility that inherited predispositions to responsivity in these women could be a contributing mechanism for their increased risk of developing breast cancer and would open up a new area of research into the etiology of this disease that is diagnosed in more than 200,000 American women each year. If the results of the proposed research indicate a significant contribution of the psychological sequelae of having a family history of breast cancer to heightened HPA axis responsivity, it would suggest that the experience of breast cancer in a close relative may have biologically significant consequences for years after their relative was diagnosed with cancer and would open up a new area of research into the broader health consequences of this increased responsivity. [unreadable] [unreadable] [unreadable] [unreadable]

Abstract: Biobehavioral Oncology Program (BOP) The overarching goal of the Biobehavioral Oncology Program (BOP) is to increase understanding of the reciprocal interactions between the central nervous system (CNS) and cancer, with the long-term objective of contributing to reduced risk of cancer development, improved cancer treatment response, reduced symptom burden, and enhanced survival. Grounded in the behavioral sciences, Program investigators conduct basic, preclinical, clinical, and translational research that is largely focused within two central themes: 1) biobehavioral analysis of patients? responses to cancer, cancer treatment and survivorship, with a particular focus on symptom experience; and 2) biobehavioral analysis of cancer development and progression with a particular focus on smoking. Both include crosscutting research on psychological stress. The specific aims of BOP are to: 1) Promote and support transdisciplinary research on the role of psychological, biological and behavioral aspects of CNS activity in patients? responses to cancer, cancer treatment and survivorship with a particular focus on symptoms, using animal models, clinical investigations, and randomized clinical trials of novel intervention strategies; 2) Promote and support transdisciplinary research on the role of psychological, behavioral, and biological aspects of CNS activity in the development and progression of cancer with a particular focus on smoking, using animal models, human experimental investigations, community-based studies, and randomized trials of biobehavioral interventions, and 3) Promote and support transdisciplinary research examining effects of psychological stress on cancer development and progression, as well as on patients? responses to cancer, cancer treatment and survivorship. The BOP has 39 members representing 14 departments and 4 schools across the University of Pittsburgh including dedicated academic researchers focused on biobehavioral oncology and clinician-researchers who combine research with patient care responsibilities, as well as members devoted to clinical activities. BOP members currently receive $11 M annually in direct funding, including $1.8 M from the NCI and $9.1 M in other peer-reviewed support. Between January 2010 and April 2014, BOP members authored 503 cancer-related publications, of which 25% resulted from intra-programmatic and 14% resulted from inter-programmatic collaborations and approximately 60% represent collaborations with external investigators. UPCI support, including Clinical Protocol and Data Management and shared resources, specifically the Animal Facility, Biostatistics Facility, Cancer Bioinformatics Services, Cancer Pharmacokinetics and Pharmacodynamics Facility, Cell and Tissue Imaging Facility, Chemical Biology Facility, Cytometry Facility, Immunological Monitoring and Cellular Products Laboratory, In Vivo Imaging Facility, and Tissue and Research Pathology Services facilitates and enhances BOP research.

? DESCRIPTION (provided by applicant): The mechanisms by which mutations in BRCA1 result in increased risk of breast cancer are not yet fully understood, but are thought to revolve around deficits in cellular machinery responsible for the maintenance of DNA integrity, including DNA repair functions. In addition to well-known effects on repair of double-strand breaks, mutations in BRCA1 are now recognized to impact multiple processes involved in maintaining DNA integrity. Emerging evidence indicates that psychological stress can also negatively impact DNA integrity through molecular pathways leading to increased ROS levels, as well as reductions in DNA repair capacity. These considerations suggest the central hypothesis of our planned program of research: women with BRCA1 mutations may be particularly susceptible to negative effects of psychological stress on DNA integrity. As a first critical test of that hypothesis we will explore the relationships between psychological stress and DNA damage in two conceptually and logistically interrelated pilot studies (final n=50; 25 BRCA1+, 25 age-, race-matched BRCA1-) to confirm feasibility and explore effect sizes for hypothesized relationships. The first pilot study (Aim 1) will use a cross-sectional correlational study design with one primary outcome: baseline DNA damage levels in peripheral blood mononuclear cells (PBMCs) assessed using an innovative CometChip technology under alkaline conditions, (with damage secondarily characterized by assay of: ?-H2AX, pATM, and DNA 8-OHdG). Statistical analyses will explore the strength of relationships between DNA damage levels and participants' responses on validated measures of psychological stress and related constructs, as well as the contribution of DNA repair capacity assessed by recovery from damage induced by ex vivo gamma radiation. The second pilot study (Aim 2) will use an experimental study design with a primary outcome of DNA damage levels in PBMCs isolated from blood samples collected: before (Baseline, T1), immediately after (Stress, T2), and 75 minutes after (Recovery, T3) exposure of participants to the Trier Social Stress Test (TSST), the most well validated experimental stress paradigm in the psychobiological literature. The concurrent use of both research designs with the same study sample and shared blood samples (Baseline) provides a cost effective way to test our overarching hypothesis with approaches having high internal validity (experimental study) and strong external validity (association study), while also allowing direct comparisons between the results from the two approaches. Aim 1: To statistically examine the relationships between psychological stress levels and DNA damage levels in women with (BRCA1+ Group) and without (BRCA1- Group) BRCA1 mutations. Aim 2: To experimentally investigate the impact of acute psychological stress on levels of DNA damage in women with and without BRCA1 mutations. This R03-supported pilot work will document feasibility and provide effect sizes for study hypotheses that will be used as preliminary data for a comprehensive R01 application. Results have methodological, theoretical, and public health significance for reducing breast cancer risk in BRCA1+ women.

Both exogenous (e.g., ionizing radiation) and endogenous (e.g., metabolic processes) factors are known to cause considerable DNA damage on a daily basis. Robust DNA repair mechanisms normally repair damage within minutes, but repair is not perfect. With each repair comes the risk of an error that could result in introduction of a DNA mutation contributing to increased risk of carcinogenesis. The overarching hypothesis of our program of research is that repeated exposures to daily psychological stresses may contribute to increased risk of cancer by repeatedly causing DNA damage. Support for a link between psychological stress and DNA damage comes from: 1) correlational studies in humans; 2) experimental stress studies in animals; and, 3) tissue culture studies demonstrating increased DNA damage after brief exposure to stress hormones, and prevention by specific neuroendocrine receptor blocking (e.g., with the beta-adrenergic antagonist, propranolol). Critically lacking are experimental studies to establish that increases in DNA damage in humans can be caused by psychological stress and reduced by propranolol. The goal of the research described here is to address those gaps in our knowledge. A diverse sample of participants (50% women, 50% African American) will be exposed to a controlled laboratory social stress challenge (Trier Social Stress Test, TSST), which is the most highly validated, broadly effective, and widely used stressor in human biobehavioral research. Total DNA damage (primary study outcome) in peripheral blood mononuclear cells (PBMCs) collected before and after exposure to the TSST will be assessed by single cell gel electrophoresis under alkaline conditions (the highly validated Comet assay) using a newly developed CometChip system. The involvement of beta- adrenergic pathways will be tested using an innovative ?Combined Propranolol/TSST Paradigm?, with one study group randomly assigned (double blind) to receive a single dose of a safe and effective beta-adrenergic receptor antagonist 60 minutes prior to the TSST (Propranolol Group, n=80), while another will receive matching placebo (Placebo Group, n=120). Aim 1: To experimentally test the hypothesis that exposure to an acute psychological stress causes increased DNA damage in humans (Aim 1.1), while concurrently testing the hypothesis that these effects can be reduced by pharmacological blockade of beta-adrenergic receptors (Aim 1.2). Aim 2: To investigate increases in blood levels of catecholamines as mediators of the effects of acute stress on DNA damage (primary hypothesis), as well as explore other potential mediators (e.g., cortisol). Aim 3: To examine key demographic (race, sex, age) and baseline biological variables (anti-oxidant activity, DNA repair capacity) as susceptibility/resiliency factors (moderators) of stress-induced DNA damage. The planned research will establish psychological stress as a cause of DNA damage in humans, providing critical support for new areas of research to explore: 1) effects of stress-induced DNA damage on cancer risk; 2) specific molecular mechanisms responsible; 3) more selective novel interventions to prevent such effects.

The overarching goal of the research described in this R21 grant application is to provide a first critical test of the novel scientific idea that a combined diet and exercise intervention may ameliorate leukocyte telomere length (LTL) in cancer survivors with nonmuscle-invasive bladder cancer (NMIBC). In this understudied population of cancer survivors, who are at high risk of recurrence and progression to life-threatening muscle- invasive bladder cancer, shorter LTL is a significant predictor of decreased survival independent of traditional prognostic variables including age, tumor grade and stage. The research is consistent with PA-15-310 ?Physical Activity and Weight Control Interventions Among Cancer Survivors: Effects on Biomarkers (R21).? The research described here will be the first to test the hypothesis that significant amelioration of LTL can be achieved by adding 250 min/wk physical activity to dietary reductions as part of a theory-based behavioral intervention in NMIBC survivors. This randomized clinical trial (RCT) will also be the first to concurrently explore biomarkers in two systemic biological pathways that contribute to telomere shortening: oxidative DNA damage and inflammatory biomarkers. The research has strong conceptual/empirical grounding and will build directly upon prior extensive diet and physical activity intervention trials by Dr. Jakicic (co-PI). Aim 1: To conduct a RCT with survivors of NMIBC to test the effects of a behavioral intervention program targeting physical activity and diet on: 1) LTL (primary [1o] outcome,) [H1.1]; and, 2) systemic biomarkers of oxidative stress and inflammatory processes (secondary [2o] outcomes) [H1.2], using a randomized design with two groups: 1) Diet only [DIET], final n=40; 2) Diet plus physical activity [DIET-PA], final n=40), stratified by classic prognostic risk phenotypes and assessed three times (baseline, 3mo, 6mo). Aim 2: To concurrently investigate three health behavior-related pathways hypothesized to underlie intervention effects on LTL in NMIBC survivors: 1) obesity; 2) physical activity; and 3) cardiorespiratory fitness to explore relationships between those variables and the 1o [H2.1] and 2o outcomes [H2.2]. This aim is not dependent on Aim 1 results; here relationships are examined independent of the intervention. Aim 3: To explore hypothesized relationships between the 1o and 2o outcomes independently [H3.1], and as part of mediational analyses of results found in Aim 1 [H3.2] and Aim 2 [H3.3]. Impact: With a focus on an understudied cancer survivor population at high risk for recurrence and progression, the planned research will have a ?sustained powerful influence on the research fields involved? (PA-15-310). Anticipated results will support a subsequent fully powered multisite trial to confirm generalizability, and open new areas of research into the underlying molecular mechanisms and into the clinical consequences of behavioral interventions targeting BMI and physical activity to ameliorate LTL in survivors of NMIBC and potentially, other cancers as well.

Abstract Persistent pain following breast cancer surgery is increasingly recognized as an important clinical and public health issue due to the large number of women affected, the powerful negative impact that persistent pain has on emotional and physical functioning and its financial costs. Most of the more than a quarter of a million women newly diagnosed with breast cancer in the U.S. this year will undergo surgery as a part of curative treatment. The prevalence of persistent pain following surgical removal of the affected breast (mastectomy) or more limited surgeries (lumpectomy) is high, ranging from 25-60% across studies. Unlike acute post-operative pain, which is a normal response to surgical trauma, persistent pain at or near the surgical site has an uncertain multifaceted etiology, and no satisfactory pharmacological treatment. A critical question is whether key pain-related psychosocial factors are drivers of the continuing burden of persistent pain, and whether they could be ameliorated by non-pharmacological intervention. The research planned under this award will provide a first critical test of the hypothesized driving role of pain catastrophizing in persistent pain after breast cancer surgery. It also will explore the role of two other key psychosocial variables that may contribute to the burden associated with persistent pain after breast cancer surgery: self-efficacy for engaging in valued activities and psychological inflexibility. We have developed, manualized, and pilot tested a pain coping skills training intervention that specifically targets the needs of women with persistent pain following breast cancer surgery (Targeted PCST) and aims to reduce pain catastrophizing, increase self-efficacy for engaging in valued activities, and decrease psychological inflexibility. We propose a multiple-site, randomized clinical trial to evaluate the efficacy of the Targeted-PCST intervention. The study will be conducted in 9 diverse oncology clinics: 5 affiliated with Duke University/Duke Cancer Network and 4 affiliated with the University of Pittsburgh/UPMC Hillman Cancer Center. Participants (N=564) will be randomized to either receive: 1) Targeted-PCST, 2) a general health education intervention (control), or 3) usual care (control). Participants will complete assessments pre-intervention and at 3 months (post-intervention), 6 months follow-up, and 12 months follow-up. Study aims are: Aim1: Examine the impact of Targeted-PCST on persistent post-surgical pain severity and interference (i.e., PEG score), emotional distress (anxiety and depression), and cancer- specific distress. Aim 2: Investigate the impact of Targeted-PCST on pain catastrophizing, pain self-efficacy, and psychological inflexibility, and evaluate these variables as possible mediators of the benefits of Targeted- PCST. Aim 3: Evaluate the impact of Targeted-PCST on pain sensitivity and central sensitization, and explore whether changes in these variables mediate group differences in pain severity and interference.