Susan M. Lutgendorf, PhD - US grants

This study is designed to examine immunological and neuroendocrine correlates of relaxation and mental stress in healthy premenopausal women.

This study is designed to examine the relationships between psychological distress, natural killer cell cytotoxicity, and disease progression in women with gynecological cancer.

This study is comparing the effect of experimentally induced stress on inflammatory mediators and neuroendocrine responses of patients with interstitial cystitis and healthy controls.

The goal of this study is to provide descriptive information on psychological morbidity and predictors of well-being, and critical data on the relationship of stress with symptom exacerbation, which will be utilized in treatment models for subjects with interstitial cystitis.

DESCRIPTION: (Applicant's Description) Ovarian cancer is the second most common gynecologic cancer. Because of low rates of survival for the majority of women with ovarian cancer, identification of potential factors contributing to compromised or enhanced host resistance at the earliest possible stage (pre-treatment) can increase understanding of factors that may influence disease progression and survival. The proposed project is designed to examine the relationship of stress, depression, social support, and coping in 112 women at the time of surgical diagnosis for ovarian cancer. This project is innovative in several ways. 1) We will investigate whether the behavioral-immune relationships reported in other cancers are present among women with ovarian cancers. 2) We will be using a surgery model that will allow us to examine activity of lymphocytes from peripheral blood against autologous tumor cells, as well as cytolytic activity of cells from within the tumor itself and from the ascites (fluid around the tumor). This will allow us not only to examine relationships of psychosocial variables with peripheral blood cells which likely are important in surveillance against tumor cells, but will also allow us to examine whether these relationships are present in the local environment of the tumor where inter-cell communication and cytotoxic activity is of primary importance. 3) We will be using a very sensitive and quantitative flow cytometric method to identify tumor antigen-specific CD4+ and CDS+ cells. We will look at non-specific and specific aspects of the immune response, as both are relevant to ovarian cancer. 4) We will also examine whether these behavioral-immune relationships are mediated by dysregulation in the neuroendocrine hormone cortisol. The significance of the project is that a clearer understanding of behavioral-immune mechanisms in ovarian cancer may enable the identification of biobehavioral risk factors for cancer progression that will be useful in cancer control and as targets of future intervention strategies.

DESCRIPTION (provided by applicant): Although a large percent of the US population reports use of alternative therapies, there is little substantive empirical research examining effectiveness of many alternative modalities, nor is there a clear understanding of putative mechanisms whereby such treatments may have their effects. Healing touch is a therapy classified by NIH as a "biofield" therapy as its effects are proposed to be secondary to manipulation of hypothesized "energy fields" around the body of a patient. Although HT is frequently used as a complementary treatment by cancer patients undergoing chemotherapy and radiation to reduce toxic side effects of the treatments and to maintain immune competency, effects of this treatment during cancer treatment have not been investigated. Additionally, little is known about physiological mechanisms by which HT may work. This study is designed to examine effects of HT versus standard care on cellular immune function and short-term side effects of treatment among 44 women with advanced cervical cancer receiving a standard protocol of chemotherapy and radiation. Although combined chemotherapy and radiation treatment is potentially curative in 70 percent of cases, many patients experience acute side effects and late radiation effects have also been reported as much as 4 years following treatment. Severe immune compromise has also been reported following intensive radiation. Identification of interventions that could reduce side effects and help maintain resistance in advanced cervical cancer patients undergoing treatment is an important health problem. There are no data on the effects of healing touch on immune function or treatment side effects among cervical cancer patients, or among cancer patients receiving chemotherapy and radiation. Therefore this study is designed as an exploratory study to determine whether such immune effects exist, and if so, whether specific immune parameters associated with cervical cancer are affected. Effects of healing touch on mood and treatment-specific side effects will also be examined. The significance of this study is that it will provide preliminary data on the impact, if any, of HT on various parameters of cellular immune function and whether the magnitude of that impact is large enough to be of sufficient clinical significance to be examined in future trials.

DESCRIPTION (provided by applicant): Ovarian cancer is the second most common gynecologic cancer. Because of low rates of survival for the majority of ovarian cancer patients, identification of factors contributing to tumor growth and progression is of paramount importance. Although relationships between psychosocial factors and immunity have been extensively documented, there has been little investigation of relationships between psychosocial factors and cytokines involved in angiogenesis, the formation of new blood vessels that enhance tumor growth. These cytokines include Interleukin-8 (IL-8), Interleukin-12 (IL-12), Interleukin-6 (IL-6), and Vascular Endothelial Growth Factor (VEGF). VEGF, one of the key promoters of tumor angiogenesis, is associated with poorer ovarian cancer survival. VEGF is influenced by a variety of cytokines, hormones including cortisol, and by sympathetic activation. We have reported that ovarian cancer patients reporting greater social support had significantly lower serum VEGF pre-surgery, whereas those reporting greater feelings of distress had higher VEGF. Additionally, in an in vitro model, we have observed that stress hormones, such as norepinephrine, induce production of VEGF from an ovarian tumor cell line and that these tumor cells also express beta-adrenergic receptors. These effects are further augmented by cortisol. These novel findings, coupled with known hormonal modulation of other angiogenic cytokines, highlight the possibility that psychosocial factors may directly influence angiogenesis, and thus tumor progression in ovarian cancer. This 5-year prospective longitudinal study will investigate relationships among psychosocial factors and 4 angiogenic cytokines: VEGF, IL-6, IL-8, and IL-12, among 154 ovarian cancer patients in a clinical setting. We have selected these cytokines because of their critical role in ovarian cancer growth and progression. Measurements of cytokines and psychosocial factors will be taken pre-surgery and at intervals up to 9 months post-surgery; disease progression will be assessed until 18 months post-surgery. The significance of these findings is that they will investigate a novel mechanism by which biobehavioral factors in ovarian cancer patients may contribute to tumor growth and disease progression. Findings will have implications for innovative behavioral and pharmacological intervention strategies for ovarian cancer patients.

DESCRIPTION (provided by applicant): Breast cancer patients use Complementary and Alternative Medicine (CAM) in greater proportions than any other group of cancer patients. The primary reason breast cancer patients cite for use of CAM is strengthening the immune system. Healing touch (HT) is a CAM treatment frequently used by cancer patients to reduce adverse side effects of chemotherapy and radiation and to enhance immunity. HT is classified by NIH as a "biofield" therapy as its effects are proposed to be secondary to manipulation of "energy fields" around the body of a patient. A recent meta-analysis has demonstrated relatively large effects of HT on well being and on physiological parameters, even from brief treatments. However, to date, there are no data on the effects of HT on immune function among breast cancer patients during treatment. This is particularly important as several immune parameters show long-term suppression or alteration, particularly after combined adjuvant chemotherapy and radiation among breast cancer patients. Additionally, there are no data on the effects of HT on the common side effects of breast cancer treatment which can include profound fatigue and radiation-induced skin damage. Physiological mechanisms underlying possible effects of HT are also poorly understood. This study is designed to reduce this knowledge gap by examining how HT affects cellular immune function and biomarkers related to two of the most problematic side effects of breast cancer treatment, fatigue and radiation-induced tissue damage. Effects on the subjective experience of fatigue and clinician rated skin damage will also be noted. Participants will be 42 early stage breast cancer patients who are receiving a standard course of radiotherapy following breast conservation surgery and chemotherapy. The significance of this study is that it will provide preliminary data on a) feasibility of this intervention in a breast cancer population, b) the impact, if any, or HT on these intermediate outcome measures, c) information on mechanisms of action, and d) whether the magnitude of the impact is large enough to be sufficient clinical significance to be examined in future Phase II and III dose and efficacy trials.

[unreadable] DESCRIPTION (provided by applicant): The primary objective of this methodological supplement is to relate psychosocial self-reports to measurements of catecholamines extracted from ovarian tumor tissue, to enable examination of norepineprine (NE) and epinephrine (E) that is biologically available to these tumor cells and would likely contribute to their production of pro-angiogenic cytokines. The rationale for this is as follows. We have documented that ovarian cancer patients with low levels of social support have higher levels of vascular endothelial growth factor (VEGF), a cytokine that promotes angiogenesis (blood vessel growth in tumors). We have also experimentally demonstrated that both NE and E can induce increases in VEGF in ovarian cancer cell lines and that NE increases the invasive potential of ovarian cancer cells. We have documented the presence of beta-adrenergic receptors on ovarian tumor cell lines. These findings suggest that ovarian cancer would be a highly relevant model to study stress-catecholamine-angiogenesis relationships. Our working hypothesis is that stress hormones such as catecholamines can promote blood vessel growth in tumors by increasing the levels of proangiogenic cytokines. Dr. Lutgendorf is Principal Investigator on a 5 year RO1 grant entitled "Biobehavioral Cytokine Interactions in Ovarian Cancer" (10/1/03-9/30/08) that prospectively examines relationships of psychosocial factors such as stress and social support to angiogenic cytokines and time to recurrence among ovarian cancer patients. It would be ideal in a project such as this to be able to measure stress hormones as possible mediators of the hypothesized effects on angiogenic cytokines of the psychosocial factors being measured by self-report. Pre-surgery, when subjects complete psychosocial surveys, there is no feasible way to measure peripheral catecholamines without inducing excessive patient burden. Furthermore it is not known what the catecholamine concentrations are in the microenvironment of the tumor. This proposal enables direct measurement within the tumor environment of the proposed endocrine mediators of the psychosocial factors measured by self-report. We will also measure these angiogenic mediators within the tumor. Thus with very little additional effort or expense, understanding of mechanisms underlying the hypothesized relationships between stress and tumor growth can be achieved, thus vastly enhancing the understanding that can be drawn from the parent grant. This proposal is responsive to the measurement aspect of the RFA in that it examines the assessment of the relationship of self-report measures to an innovative biological measure. To our knowledge, self-report psychosocial data has never been related to levels of catecholamines that are biologically available to tumor cells. Thus the measurement model we are proposing is highly innovative and could enhance methodology in biobehavioral studies in cancer control. [unreadable] [unreadable]

immune response; therapy adverse effect; human therapy evaluation; touch; alternative medicine; cellular immunity; cervix neoplasms; clinical trial phase II; combination cancer therapy; neoplasm /cancer chemotherapy; neoplasm /cancer radiation therapy; women's health; patient oriented research; human subject; female; clinical research;

immune response; therapy adverse effect; human therapy evaluation; touch; quality of life; breast surgery; neoplasm /cancer chemotherapy; breast neoplasms; cellular immunity; alternative medicine; neoplasm /cancer immunology; neoplasm /cancer surgery; neoplasm /cancer radiation therapy; women's health; biomarker; fatigue; patient oriented research; behavioral /social science research tag; human subject; clinical research;

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic bladder condition characterized by urinary frequency, urgency, and pelvic pain. The etiology and pathogenesis of IC/PBS are still unclear despite extensive investigation. Whereas local bladder-related factors contributing to this illness have been examined, little is known regarding underlying systemic conditions that might permit a state of chronic inflammation and pain to be established and maintained in IC/PBS. Findings from animal models indicate that the responses of the hypothalamic pituitary adrenal (HPA) axis to inflammatory mediators influence susceptibility to inflammatory illnesses. Abnormalities of the HPA feedback system result in poorer regulation of the inflammatory response and are present in many chronic inflammatory and pain conditions, some of which some have high comorbidity with IC/PBS. These include irritable bowel syndrome (IBS) and fibromyalgia (FM). The high levels of comorbidity between these conditions and IC/PBS suggest that similar pathophysiological mechanisms may be operating in IC/PBS. HPA abnormalities, however, have not been systematically investigated in IC/PBS. The main objectives of this project are to: 1) investigate the characteristics of subgroups of IC/PBS patients based on presence/absence of comorbid diagnoses such as IBS and FM, 2) examine dysregulations of the HPA axis and inflammation in IC/PBS patients with and without comorbid diagnoses, and 3) examine the relationship of the HPA axis and inflammation to symptoms in IC/PBS patients. We hypothesize that the HPA axis is involved in the pathophysiology of the chronic inflammation observed in IC/PBS and that there are subgroups of IC/PBS patients with different patterns of HPA dysfunction. We also hypothesize that interactions between cortisol and bladder mast cells and other inflammatory mediators may contribute to IC/PBS symptomatology. To test these hypotheses, the integrity of the HPA axis and levels of inflammatory mediators will be assessed at rest and when challenged in a standardized laboratory stress reactivity protocol. We plan to use a 4-group design: IC/PBS patients with no comorbid conditions;2) IC/PBS patients with comorbid fibromyalgia (FM) or irritable bowel syndrome (IBS); 3) patients with functional somatic syndromes (patients with FM or IBS with no IC/PBS);and healthy controls.

DESCRIPTION (provided by applicant): Ovarian cancer is the second most common gynecologic cancer. Because of low rates of survival for the majority of ovarian cancer patients, identification of factors contributing to tumor progression is of paramount importance. Epidemiologic studies have suggested an association between biobehavioral factors such as life stress, depression, and social support and cancer progression. This study examines a novel pathway that may underlie these links in ovarian cancer, specifically, the relationship of biobehavioral factors with resident macrophages within the tumor microenvironment. It is now acknowledged that the tumor microenvironment is critical in supporting or inhibiting tumor progression. We have previously reported associations of depression and low social support with a poorer cellular immune response in ovarian cancer patients in the tumor microenvironment. We have also demonstrated direct links between biobehavioral factors and cytokines supporting angiogenesis, the formation of new blood vessels that enhance tumor growth and progression. Macrophages are major components of the tumor microenvironment where they are predominantly converted from an anti-tumor phenotype to a pro-tumor phenotype and play a key role in supporting inflammation and tumor progression. However, little is known regarding whether biobehavioral factors influence tumor associated macrophages (TAM) and interactions between TAM and tumor cells in a way that favors tumor growth. Based on compelling preliminary data, we propose that biobehavioral influences on both TAM and tumor cells in the tumor microenvironment have significant effects on production of factors supporting tumor growth and progression. We focus on TAM because of their key role in the tumor microenvironment, and because of indications of macrophage sensitivity to stress factors in the cardiovascular literature and in our preliminary data. Thus, the overarching goal of this proposal is to examine pathways by which biobehavioral factors contribute to a permissive local environment for interactions between resident cells (TAM) and tumor cells that favor tumor growth in ovarian cancer. The proposed project will prospectively examine the relationship of biobehavioral factors (life stress, depression, and social support) and TAM products (inflammatory cytokines and tumor growth factors) in the tumor microenvironment in 206 ovarian cancer patients. Association of biobehavioral factors with upregulation of gene transcripts related to inflammation and proliferation in tumor cells will also be examined. Based on preliminary data we will examine the role of adrenergic signaling as a mediator in these relationships. To determine the clinical significance of these biological alterations, the investigation will assess progression-free and overall survival during the 24 months following diagnosis. Findings will have implications for innovative behavioral and pharmacological intervention strategies for ovarian cancer patients. PUBLIC HEALTH RELEVANCE: There has been very little research examining systemic effects on the tumor microenvironment. This research examines a novel pathway by which biobehavioral factors may contribute to a permissive milieu for tumor growth and disease progression in the tumor microenvironment among ovarian cancer patients. A clearer understanding of biobehavioral risk factors and pathways by which they operate is critical for identifying targets for psychosocial and pharmacological intervention for ovarian cancer patients who may be at risk.

Abstract The interface of behavioral and biomedical sciences is one of the most vibrant frontiers of science today. The overarching objective of our NIGMS-funded predoctoral Training Program, Mechanisms of Health and Disease at the Behavioral-Biomedical Interface, is to train the next generation of diverse behavioral science researchers to utilize rigorous biomedical methodologies and conceptual frameworks that stretch the boundaries of their thinking and research to position them to make transformative breakthroughs in addressing issues of health and disease. The program provides predoctoral behavioral science students in the University of Iowa Department of Psychological and Brain Sciences with an integrated program of coursework and laboratory experiences. These include (1) broad-based training in the fundamentals of behavioral science including rigor and transparency, quantitative methodology and experimental design, responsible conduct of research, and key issues in health psychology, clinical psychology, and neuroscience; (2) In-depth training in pathophysiology and specific biomedical research areas (including conceptual framework, driving hypotheses, and laboratory techniques); and (3) guidance and mentoring for development and implementation of an innovative independent research program that spans both behavioral and biomedical science. The Training Program focuses on two themes: Lifespan Brain Health and Psychobiology of Chronic Disease and Women's Health. Behavioral mentors are from Psychological and Brain Sciences; Biomedical mentors come from the Colleges of Medicine, Public Health, and Nursing. Over the first 3 years of NIGMS support, we have developed a highly successful Training Program that has had far-reaching and lasting influences on a group of committed and enthusiastic students. We have used the support slots provided by the T32 grant and the two matching slots provided by the Graduate College of the U. of Iowa to recruit outstanding diverse students and to provide a catalyst for this program, which has matured into a vibrant setting for scientific exchange between behavioral science students and biomedical mentors and their labs. Since the start of the program, in addition to our 8 T32 funded students, we have had 25 additional trainees take advantage of the Training Program, including 7 diverse students. We have developed a program of seminars and retreats, featuring professional development, science communication, manuscript and grant writing, and discussions of cutting-edge research at the Behavioral-Biomedical interface. In sum, the NIGMS support for 4 students/year has returned large dividends on the investment. This renewal application requests the continuation of 4 slots per year so that we can build upon our strong foundation to continue this innovative program for another funding cycle. The program is highly relevant to public health because training at the behavioral-biomedical interface will enable these scientists to innovatively address mechanisms that influence health and disease.

? DESCRIPTION (provided by applicant): Ovarian cancer is the second most common gynecologic cancer; however, more women die annually from ovarian cancer than from cancers of all other gynecologic sites combined. Ovarian cancer survivors often experience high levels of distress, sleep disturbances, fatigue, neuropathies, multiple symptoms and side effects, and existential concerns, along with a generally poor prognosis. Additionally, we have documented strong links between psychosocial factors and physiological pathways related to disease progression in ovarian cancer. Because of compromises to many aspects of quality of life (QOL) combined with low rates of survival for the majority of these patients, development of innovative approaches for improving QOL is of paramount importance, but research examining the potential efficacy of psychosocial interventions in ovarian cancer survivors has been extremely limited. Barriers to development of an in-person intervention have included low populations of ovarian cancer survivors at any one site and debility of patients. Based on focus interview feedback from ovarian cancer survivors, we have been developing an intervention targeted to ovarian cancer survivors, drawing from key elements of Cognitive Behavioral Stress Management (CBSM) and Mindfulness-Based Stress Reduction (MBSR) along with some of the value-based content of Acceptance and Commitment Therapy (ACT). Over the last year we have developed a mobile responsive web platform to deliver a live web-based conferencing psychosocial intervention that ovarian cancer patients can access from their homes. The primary goal of this application is further development, web deployment, field usability, and field testing of this intervention among ovarian cancer survivors. The ultimate goal of this program of research will be to conduct a larger scale randomized clinical trial of this intervention using web delivery, with examination of mood, symptoms, and QOL along with clinically relevant endpoints and biomarkers. The significance of the application is that this intervention has the potential to improve quality of life of ovarian cancer survivors and may have the ability to lengthen the period of recurrence free survival.

? DESCRIPTION (provided by applicant): Epithelial ovarian cancer is the second most common gynecologic cancer. Because of poor survival for the majority of ovarian cancer patients, identification of factors contributing to disease progression is of utmost importance. Although a significant percentage of ovarian cancer patients respond well to initial chemotherapy, the success of treatment is limited by the development of chemo resistance, and the majority of patients relapse and die from recurrent disease. Our previous work has shown a variety of mechanisms by which biobehavioral factors (referring collectively to behavioral, social, and/or psychological factors and concomitant biologic processes) can directly affect key biological signaling mechanisms to enhance tumor growth and impair the immune response in ovarian cancer. Although the neuroendocrine stress hormones norepinephrine (NE) and cortisol have been shown to increase chemo resistance pre-clinically, little is known about the contribution of psychological and social processes to chemo resistance in the clinical setting of ovarian cancer. Based on compelling preliminary pre-clinical data in ovarian cancer, we propose that psychological and social processes and the neuroendocrine stress response will contribute to impairment of the chemotherapeutic response in ovarian cancer patients. Thus, this grant will focus on mapping psychological and social and neuroendocrine influences on disease progression in 178 women with high grade serous epithelial ovarian cancer, with particular attention to chemo resistance as a mechanism. This study is highly innovative as 1) contributions of biobehavioral processes to chemo resistance in human epithelial cell cancers in a clinical setting have not been examined, and 2) this is the first translational study using exosomes (tumor derived vesicles in peripheral circulation) to examine relationships between biobehavioral factors and tumor dynamics. Use of the exosome biomarker approach will provide a longitudinal window on tumor characteristics not otherwise available in the absence of repeated surgery. If initial response to chemotherapy could be enhanced or maintained for a longer duration, it could have substantial survival benefits. Thus findings that biobehavioral stress-related processes alter the response to chemotherapy would have significant implications for clinical management of ovarian patients, specifically the potential for adjunct use of behavioral or pharmacological interventions to delay the development of chemo resistance. Because chemotherapeutic response is closely linked to ovarian cancer survival, understanding biobehavioral impediments to maximum chemotherapeutic response is of great public health significance.

Abstract Over the last two decades, we and others have documented the chronic and often debilitating experience of ovarian cancer survivorship which may include poor health related quality of life (HRQOL), elevated anxiety and depression, poor sleep, fatigue, multiple symptoms/side effects, existential concerns, and a generally poor prognosis. Because of compromises to many aspects of HRQOL combined with low rates of survival for the majority of these patients, development of innovative approaches for improving HRQOL and potentially improving clinical outcomes is of paramount importance. This need is particularly true in rural settings where women may have less access to clinic-based support systems. Despite the multiple challenges experienced by ovarian cancer survivors, research targeting the potential efficacy of psychosocial interventions in enhancing HRQOL has been extremely limited. Over the last several years this research team has developed and piloted a web-based group conferencing intervention entitled Living Well (Web-Enhanced Lessons for Living) targeting key concerns of ovarian cancer survivors and developed with input from survivors. The overarching goal of the present submission is to examine the efficacy of the Living Well intervention vs. a Health Promotion active control intervention in a randomized controlled trial in 256 ovarian cancer survivors who have completed primary treatment and are less than 5-years post-diagnosis. We hypothesize that the Living Well Intervention will be efficacious in improving HRQOL, decreasing perceived stress (primary outcomes) and in decreasing depressive mood, anxiety, and fatigue (secondary outcomes). This application is highly innovative because it combines elements of evidence-based psychosocial interventions in a novel way to target the needs of ovarian cancer survivors, using a state-of-the-art web and video conferencing platform that allows wide dissemination, including to rural survivors. This work is highly translational as it is a direct application of findings from mechanistic stress-related research to testing an intervention to reduce stress in ovarian cancer survivors. The significance of the application is that this intervention has the potential to overcome prior barriers to the implementation of such psychosocial interventions and improve HRQOL, thus providing public health benefits to an understudied and compromised cancer population with a high likelihood of recurrence.