Behavioral Influences on Ovarian Cancer Progression: Role of Chemoresistance

 描述（由申请人提供）：上皮性卵巢癌是第二常见的妇科癌症。由于大多数卵巢癌患者的生存率很低，因此确定导致疾病进展的因素至关重要。虽然有相当比例的卵巢癌患者对初始化疗反应良好，但治疗的成功受到化疗耐药性发展的限制，大多数患者复发并死于复发性疾病。我们以前的工作已经显示了多种机制，通过这些机制，生物行为因素（统称为行为，社会和/或心理因素以及伴随的生物过程）可以直接影响关键的生物信号传导机制，以增强肿瘤生长并损害卵巢癌的免疫反应。虽然神经内分泌应激激素去甲肾上腺素（NE）和皮质醇已被证明在临床前增加化疗耐药性，但对心理和社会过程在卵巢癌临床环境中对化疗耐药性的贡献知之甚少。基于令人信服的初步临床前数据卵巢癌，我们提出，心理和社会过程和神经内分泌应激反应将有助于损害卵巢癌患者的化疗反应。因此，该基金将重点研究心理、社会和神经内分泌对178名高级别浆液性上皮性卵巢癌患者疾病进展的影响，特别关注化疗耐药性作为一种机制。这项研究具有高度创新性，因为1）尚未研究临床环境中生物行为过程对人类上皮细胞癌化疗耐药性的贡献，2）这是第一项使用外泌体（外周循环中的肿瘤衍生囊泡）来研究生物行为因素与肿瘤动力学之间关系的转化研究。外泌体生物标志物方法的使用将提供在没有重复手术的情况下不可用的肿瘤特征的纵向窗口。如果对化疗的初始反应可以增强或维持更长的时间，它可能具有实质性的生存益处。因此，生物行为应激相关过程改变化疗反应的研究结果将对卵巢癌患者的临床管理具有重要意义，特别是辅助使用行为或药物干预来延缓化疗耐药性的发展。由于化疗反应与卵巢癌生存率密切相关，因此了解生物行为障碍对最大化疗反应具有重要的公共卫生意义。

 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.