Radiation-induced signaling and treatment resistance

描述（由申请人提供）：直肠癌对放疗的抵抗表现为局部复发，是一个常见但知之甚少的问题。辐射暴露通过不同的信号传导途径诱导细胞凋亡，但这些诱导死亡的刺激可以被称为诱导抗性途径的强大细胞存活机制所取代。诱导耐药途径可能在某些癌症中异常活跃，但迄今为止尚未在临床放射治疗的背景下研究这些机制。该项目的长期目标是更好地了解治疗诱导的抗凋亡信号在直肠癌放射治疗患者中的重要性。这一目标将通过检查接受术前治疗的患者在单次放疗后早期进行的肿瘤活检来实现。我们将用能够区分分子活性状态的抗体分析信号通路。然后，我们将干扰这些途径，首先在动物模型中，然后在患者中，使用特异性拮抗所讨论的信号通路的试剂。然后，我们将确定这种扰动在活检样本中的分子和临床影响。我们的中心假设是，放射治疗上调一个或多个促生存途径，导致临床上显着的放射抗性，治疗反应将改善废除这些信号反应使用靶向药物。所描述的研究项目形成了血液学/肿瘤学系助理教授Bert O 'Neil博士5年职业发展计划的核心。他的导师Joel Tepper、Albert Baldwin和Richard Goldberg博士是GI恶性肿瘤临床研究领域以及细胞凋亡和转录调控基础科学领域的领导者。他们提出了一个结合教学和转化研究经验，以促进奥尼尔博士发展成为一个独立的临床研究人员，在耐药的分子机制癌症治疗和细胞凋亡信号。他们已经召集了一个精心挑选的合作者小组，以协助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，如需要永久性结肠造口术作为治疗的一部分。这在一定程度上是由于与其他癌症类型相比，直肠癌的辐射相对无效，我们正试图通过这一建议更好地了解这一现象。我们研究的长期目标是在放射治疗的基础上应用靶向肿瘤而非正常组织的药物，以提高放射治疗直肠癌的有效性。

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.