Donald M. Lamkin, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): The proposed project has the primary goal of testing the hypothesis that ovarian tumors cause behavioral signs of depression. The secondary goal is to assess whether ovarian tumors mediate this depressive effect via tumor-secreted proinflammatory cytokines. Depression is commonly comorbid with cancer, with about one third of cancer patients reporting depression around the time of diagnosis and up to one fourth suffering from Major Depression. Additionally, several studies suggest that depression predisposes cancer patients to a worsened clinical outcome. It has been assumed that cancer patients become depressed in reaction to the psychological stress of cancer diagnosis. However, recent research suggests that the tumor itself may also be a cause of depression. Elevations in the proinflammatory cytokine cascade of tumor necrosis factor alpha (TNF-a), interleukin 1 (IL-1), and interleukin 6 (IL-6) are causally related to "sickness behaviors," which overlap with the signs and symptoms of depression, and these cytokines are produced by ovarian tumor microenvironments. Because limitations inherent in correlational research with human cancer patients preclude thorough investigation of a causal pathway between ovarian tumor and depression, we have defined two specific aims to test this pathway using a well- characterized, animal model of ovarian cancer. Specific Aim 1: Experimentally determine the extent to which depressive behaviors are a result of tumor burden. Specific Aim 2: Experimentally identify the proinflammatory cytokines that may account for depressive behaviors in the model. C57BL6 mice will be injected intraperitoneally with ID8 ovarian carcinoma cells or vehicle only and allowed to develop clinical tumor. Major Depression requires that a person demonstrate loss of interest in pleasure or depressed mood, which includes a sense of hopelessness. These criteria, referred to as anhedonia and behavioral despair in animal models of depression, will be assayed in mice using reliable and validated measures including sucrose preference tests, self-stimulation of reward areas in the brain, and the tail suspension test both before and after injection with carcinoma cells. The findings of this study will have great potential for translational application in pharmacological and behavioral interventions that treat the comorbidity of depression in patients with ovarian cancer. News of a cancer diagnosis can be traumatic to the patient and lead to depression, including the core symptoms of feeling hopeless and losing interest in activities the patient once found pleasurable. This research plans to examine another scenario, however, that the tumor itself is a contributor to these depressive symptoms, and that it accomplishes these effects by secreting certain physiological factors that are known to cause depression. [unreadable] [unreadable] [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): The K07 Career Development Award will enable Dr. Donald Lamkin to achieve his career goal of becoming an independent investigator and future leader in translational biobehavioral cancer research. This proposal builds upon Dr. Lamkin's previous training in basic laboratory science, utilizing animal models of cancer and behavior to address biobehavioral questions in the area of cancer control. Training: The award will facilitate training specifically in (1) learning the cancer treatment regimens and research protocols that characterize clinical investigation at a comprehensive cancer center, (2) mastering functional genomics strategies and related technologies to study global gene expression in distinct cell populations within tumors, and (3) learning fluorescence microscopy and laser capture microdissection to visualize and retrieve cells in tumor microenvironments. The proposed training will allow Dr. Lamkin to acquire new skills that are essential for a translational scientit who wants to work at the boundaries of basic laboratory discovery and clinical investigation. Mentors & Collaborators: Dr. Patricia Ganz, a medical oncologist and Director of Cancer Prevention and Control Research at the UCLA Jonsson Comprehensive Cancer Center; Dr. Julie Bower, a clinical psychologist with expertise in immune, endocrine, and psychological factors in breast cancer patients and survivors; Dr. Steve Cole, a translational scientist and Director of the Social Genomics Core Laboratory at UCLA; Dr. Shimon Weiss, Director of the Advanced Light Microscopy-Spectroscopy Core Laboratory at UCLA; and Dr. Erica Sloan, a cancer biologist with expertise in preclinical models of breast cancer and neural- mediated metastasis. Research Plan: The Research Plan for this project builds upon two emerging findings in breast cancer research: First, preclinical evidence indicates that chronic stress induces a high buildup of alternatively activated (M2) vs. classically activated (M1) macrophages in tumors. This is significant because macrophages with M2 properties are increasingly becoming associated with poor outcomes in breast cancer. Thus, Aim 1 will examine the relationship between stress-related psychosocial factors and M2-related gene expression by macrophages in tumors of breast cancer patients. Second, preclinical research suggests that M2 macrophage buildup does not derive from blood stream monocytes that infiltrate the tumor but instead results from enhanced proliferation of macrophages that are already residing in the tumor microenvironment. Establishing such a finding in humans would challenge current ideas about how to target macrophages in cancer and open up new therapeutic opportunities. Thus, Aim 2 will investigate the extent to which M2 macrophages in primary tumor of breast cancer patients are locally established proliferating tissue macrophages. Aim 3 will experimentally determine whether chronic stress increases M2 macrophage proliferation in mammary tumors of mice. This plan will facilitate Dr. Lamkin's career training objectives and position him for a future R01 submission.