Clinical and Translational Approaches to Cognitive Impairments in Cancer

描述(申请人提供)：虽然化疗有助于提高癌症患者的存活率，但其副作用会对生活质量造成实质性的不利影响，可能会使人虚弱；这些副作用，包括认知障碍，已成为研究的主要重点。化疗相关认知障碍(CRCI)以记忆力、注意力、注意力和执行功能障碍为特征。CRCI在化疗期间最为明显和严重(在高达80%的患者中)，然而，在高达35%的幸存者接受治疗后，它可以持续数年。美国有超过1300万癌症幸存者，据估计，多达400万幸存者可能生活在CRCI的长期影响中。CRCI 这一点特别重要，因为CRCI可能会发展为长期的认知障碍，CRCI会对生活质量产生负面影响，CRCI会影响治疗的依从性。我目前正在进行一项面向患者的NCI K奖研究，调查针对炎症的干预措施，以缓解接受化疗的乳腺癌患者的认知困难；我的实验室仅专注于CRCI研究。我们领域的主要假设之一是炎症可能会导致这些患者的认知障碍。虽然这在我们的领域得到了很好的接受，但由于大多数临床研究对CRCI的生物学相关性的了解有限，因此对这种炎症反应的性质的理解还存在差距。也缺乏能够仔细评估基础科学模型中和人体中的神经免疫因素的研究人员。我建议将我在基础免疫学、神经免疫学和神经科学方面的知识与我在认知科学、神经心理学和临床癌症控制方面的行为研究培训结合起来，以填补该领域的这些空白。虽然本研究的重点是CRCI，但它 对癌症控制和生存的许多领域具有广泛的影响。本应用程序的第一部分涉及在化疗动物模型中仔细评估和了解炎症对脑功能和神经炎症的作用(使用乳腺癌化疗范例；第IA部分)，以及在正在接受相同化疗方案治疗的乳腺癌患者队列中分析可能的病因(第IB部分)。在这项应用的第二部分，我们将利用动物模型来开发和测试癌症相关认知障碍的干预措施(这在癌症控制研究中并不常见)，这将使我们能够推进临床研究中最成功的测试干预措施。总体而言，这项建议将使我们能够更好地了解CRCI的免疫和神经毒性影响，开发CRCI的干预措施，并改善这种麻烦的副作用造成的整体公共卫生负担。

DESCRIPTION (provided by applicant): While chemotherapy has helped to improve survival for cancer patients, the side effects lead to substantial detrimental effects on quality of life tht can be debilitating; these side effects, including cognitive impairments, have become a major focus of research. Chemotherapy-related cognitive impairment (CRCI) is characterized by difficulty in memory, attention, concentration and executive function. CRCI is most pronounced and severe during chemotherapy (in up to 80% of patients), however, it can last for years following treatment in up to 35% of survivors. With over 13 million cancer survivors in the US, it is estimated that up to 4 million survivors could be living with long-lasting effects of CRCI. CRCI is particularly significant because long-term cognitive impairment can develop, CRCI negatively impacts quality of life, and CRCI can affect treatment adherence. I'm currently conducting a NCI K Award in patient-oriented research investigating interventions targeting inflammation to alleviate cognitive difficulties in breast cancer patients receiving chemotherapy; my laboratory focuses solely on CRCI research. One of the main hypotheses in our field is that inflammation may drive cognitive impairment in these patients. While this is becoming well-accepted in our field, there is a gap in understanding the nature of this inflammatory response as most clinical research studies have limited access to biological correlates of CRCI. There is also a lack of investigators that can carefully assess neuro-immune factors in basic science models as well as in people. I am proposing to use my knowledge in basic immunology, neuroimmunology, and neuroscience with my behavioral research training in cognitive science, neuropsychology and clinical cancer control to address these gaps in the field. While this research focuses on CRCI, it has broad implications for many areas of cancer control and survivorship. Part I of this application involves careful assessment and understanding of the role of inflammation on brain function and neuroinflammation in chemotherapy animal models (using a breast cancer chemotherapy paradigm; Part IA) and following up with analyzing possible etiological factors in a breast cancer patient cohort that is being treated with the same chemotherapy regimen (Part IB). In Part II of this application, we will utilize animal models to develop and test intervention for cancer-related cognitive impairment (this is not commonly done in cancer control research) which will allow us to move forward with the most successful interventions for testing in clinical research. Overall, this proposal will allow us to better understand immunologic and neurotoxic effects of CRCI, develop interventions for CRCI, and improve the overall public health burden of this troublesome side effect.