Radiation-induced signaling and treatment resistance

描述(申请人提供)：直肠癌对放射治疗的抵抗表现为局部复发，这是一个常见但知之甚少的问题。辐射通过不同的信号通路诱导细胞凋亡，但这些死亡诱导刺激可以被强大的细胞生存机制所覆盖，称为可诱导耐药通路。诱导耐药通路在某些癌症中可能异常活跃，但到目前为止，这些机制尚未在临床放射治疗的背景下进行研究。该项目的长期目标是更好地了解治疗诱导的抗细胞凋亡信号在接受直肠癌放射治疗的患者中的重要性。这一目标将通过检查接受术前治疗的患者在接受单次放射治疗后很早就进行的肿瘤活检来实现。我们将使用能够区分分子活动状态的抗体来分析信号通路。然后，我们将首先在动物模型中，然后在患者中，使用专门拮抗上述信号通路的药物来扰乱这些通路。然后，我们将在活检样本中确定这种扰动的分子和临床影响。我们的中心假设是，放射治疗上调了一条或多条生存途径，导致临床上显著的放射抵抗，通过使用靶向药物消除这些信号反应，治疗反应将得到改善。所描述的研究项目构成了血液科/肿瘤科助理教授伯特·奥尼尔博士5年职业发展计划的核心。他的导师乔尔·泰珀博士、阿尔伯特·鲍德温博士和理查德·戈德伯格博士是G1恶性肿瘤临床研究以及细胞凋亡和转录调控基础科学领域的领导者。他们提出了一种教学和翻译相结合的研究经验，以促进奥尼尔博士发展成为一名独立的临床医生研究员，在抗癌治疗和细胞凋亡信号的分子机制方面拥有专业知识。他们召集了一个精心挑选的合作者小组，协助这项研究和奥尼尔博士的职业发展。直肠癌是一个主要的健康问题，其治疗可能导致改变生活的发病率，例如要求永久结肠造口作为治疗的一部分。这在一定程度上是因为与其他癌症类型相比，放射治疗直肠癌相对无效，我们正试图通过这一提议更好地理解这一现象。我们研究的长期目标是除了放射治疗外，还应用针对肿瘤而不是正常组织的药物来提高直肠癌的放射治疗效果。

DESCRIPTION (provided by applicant): Resistance of rectal cancer to radiotherapy manifests as local recurrence, and represents a common but poorly understood problem. Radiation exposure induces apoptosis through diverse signaling pathways, but these death-inducing stimuli can be overriden by powerful cell survival mechanisms termed inducible resistance pathways. Inducible resistance pathways may be abnormally active in some cancers, but these mechanisms have not been studied in the setting of clinical radiotherapy to date. The long-term goal of this project is to better understand the importance of treatment-induced anti-apoptotic signaling in patients being treated with radiation for rectal cancer. This goal will be realized by examining tumor biopsies taken very early after a single fraction of radiation in patients undergoing preoperative therapy. We will analyze signaling pathways with antibodies that are capable of distinguishing the active state of the molecules. We will then perturb these pathways, first in animal models and then in patients, using agents that specifically antagonize the signaling pathways in question. We will then determine the molecular and clinical effects of this perturbation in biopsy samples. Our central hypothesis is that radiation therapy upregulates one or more prosurvival pathways resulting in clinically significant radioresistance and that therapeutic response will be improved by abrogating these signaling responses using targeted drugs. The research projects described form the core of a 5-year career development plan for Dr. Bert O'Neil, an Assistant Professor in the Division of Hematology/Oncology. His mentors, Drs. Joel Tepper, Albert Baldwin, and Richard Goldberg are leaders in the fields of clinical research on Gl malignancies and the basic science of apoptosis and transcriptional regulation. They propose a combined didactic and translational research experience to foster Dr. O'Neil's development into an independent clinician investigator with expertise in the molecular mechanisms of resistance to cancer therapy and apoptosis signaling. They have assembled a carefully selected group of collaborators to assist in the research and in Dr. O'Neil's career development. Rectal cancer is a major health problem whose treatment can result in life-changing morbidity such as the requirement for permanent colostomy as part of therapy. This is partly due to the relative ineffectiveness of radiation on rectal cancer compared with other cancer types, a phenomenon we are trying to better understand via this proposal. The long-term goal of our research is to apply drugs that target tumor but not normal tissue in addition to radiation to improve the effectiveness of radiation on rectal cancer.