Targeted Radiation Therapy for Pancreatic Cancer

胰腺癌的靶向放射治疗

• 批准号: 9305768
• 负责人: Surinder K. Batra
• 金额: $ 43.59万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-17 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9305768
• 关键词: 90Y; Abraxane; Animal Model; Antibodies; Antigens; Applications Grants; Biodistribution; Blood flow; Cancer Patient; Cell surface; Cells; Clinic; Clinical Trials; Combined Modality Therapy; Complex; Cytotoxic agent; Data; Diagnosis; Disease; Disease Progression; Disseminated Malignant Neoplasm; Distant Metastasis; Drug Kinetics; Endothelial Cells; Epitopes; Evaluation; FDA approved; Future; Heterogeneity; Human; Individual; Intercellular Fluid; Lung; Malignant Neoplasms; Malignant neoplasm of pancreas; Molecular Target; Monoclonal Antibodies; Mucins; Nature; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Pathogenesis; Patients; Peptides; Performance; Pharmaceutical Preparations; Physiological; Radiation; Radiation therapy; Radioimmunoconjugate; Radioisotopes; Radiolabeled; Radionuclide therapy; Radiopharmaceuticals; Radioresistance; Regimen; Research; Signal Pathway; Solid Neoplasm; Specificity; Stromal Neoplasm; Tandem Repeat Sequences; Testing; Therapeutic; Time; Toxic effect; Transgenic Animals; Transgenic Mice; Translating; Treatment Efficacy; Tumor Antigens; Xenograft procedure; base; cancer cell; cancer therapy; chemotherapy; clinical predictors; clinically relevant; cytotoxic; gemcitabine; improved; in vivo; lymph nodes; macromolecule; mouse model; neoplastic cell; novel; outcome forecast; overexpression; pancreatic neoplasm; penetratin; pre-clinical; preclinical evaluation; pressure; public health relevance; residence; response; subcutaneous; success; targeted agent; targeted treatment; theories; therapeutic target; therapy resistant; tumor; tumor microenvironment; uptake; vasoactive agent

 DESCRIPTION (provided by applicant): Pancreatic cancer (PC) is a highly metastatic and therapy-resistant malignancy with patients presenting with local and distant metastases at the time of diagnosis. The metastatic lesions while still undetectable contribute to the lethality of te disease and hence should be treated effectively. Antibodies directed against tumor antigens are ideal vehicles for delivering cytotoxic agents including therapeutic radionuclides to the known and occult metastatic cancer cells and can be a promising therapeutic option for treating PC. However, pancreatic tumors present a complex and highly obstructive microenvironment that is characterized by insufficient and heterogeneous tumor blood flow and extensive desmoplasia. Cell surface mucin, MUC4, is promising target for PC therapy due to its specific overexpression in tumor that correlates positively with disease progression and negatively with patient survival. Monoclonal antibody MAb 8G7, due to its reactivity to a repetitive epitope on MUC4, can potentially serve as a highly efficient targeting agent for PC. The central hypothesis of this proposal is: "MUC4 is a novel molecular target for targeted radionuclide therapy (TRT) of lethal pancreatic cancer and selective modulation of tumor microenvironment can improve the delivery and enhance the therapeutic efficacy of MUC4-targeted radiopharmaceuticals". The overall objective of the proposed studies is to determine the utility of targeting pancreatic cancer with novel radiolabeled anti-MUC4 antibodies in combination with rationally-selected specific modulators of tumor microenvironment (TME). Tumor vasculature is characterized by structural and functional anomalies as compared to normal vasculature and these differences result in differential responses when the normal and tumor vasculature are exposed to various vasoactive agents. Modulation of tumor stromal compartment can be achieved by selectively targeting the signaling pathways that regulate various components of tumor stroma. Three specific aims are proposed: 1) Evaluation of MUC4 as a target for TRT of PC; 2) Selective Modulation of tumor microenvironment for improved delivery of radiopharmaceuticals; and 3) Determine the therapeutic efficacy of MUC4 and TME targeted combination therapy. Aim 1 will provide information about the efficiency of anti-MUC4 MAb for targeting PC in vivo and characterize the MAb in terms of biodistribution and pharmacokinetics. Further, the studies will allow us to determine which therapeutic radionuclide is compatible with anti-MUC4 MAb. Aim 2 will evaluate a combination of "tumor-selective" agents for their ability to improve TME in xenograft and autochthonous tumors for enhanced delivery of radiopharmaceuticals. Aim 3 will allow us to determine if the improved delivery, distribution and retention of radiolabeled antibodies translates to improved therapeutic efficacy. The proposed studies represent the first comprehensive effort to overcome physiological barriers for macromolecular radiopharmaceuticals and utilize clinically relevant transgenic mouse models of PC. The preclinical results obtained from the proposed study will form the basis of clinical trial in PC patients.

 描述（由申请人提供）：胰腺癌（PC）是一种高度转移且难治性的恶性肿瘤，患者在诊断时已出现局部和远处转移，但转移性病灶仍无法检测到，从而导致疾病的致死率。针对抗原的抗体是将包括治疗性放射性核素在内的细胞毒性剂递送至已知和隐匿性转移性癌细胞的理想载体，并且可能是一种有前途的治疗选择。然而，胰腺肿瘤呈现出复杂且高度阻塞的微环境，其特点是肿瘤血流不足且不均匀，细胞表面粘蛋白 MUC4 是 PC 治疗的有希望的靶点，因为它在肿瘤中特异性过度表达，与肿瘤呈正相关。单克隆抗体 MAb 8G7 由于其对 MUC4 上的重复表位的反应性，可能成为 PC 的高效靶向剂。该提案的总体目标是：“MUC4是致命性胰腺癌靶向放射性核素治疗（TRT）的新型分子靶点，选择性调节肿瘤微环境可以改善MUC4靶向放射性药物的递送并增强治疗效果”。目的是确定新型放射性标记抗 MUC4 抗体与合理选择的肿瘤微环境 (TME) 特异性调节剂联合治疗胰腺癌的效用。与正常脉管系统相比，其特征在于结构和功能异常，并且当正常脉管系统和肿瘤脉管系统暴露于各种血管活性剂时，这些差异导致不同的反应，可以通过选择性地靶向调节各种成分的信号通路来实现对肿瘤基质隔室的调节。提出了三个具体目标：1）评估 MUC4 作为 PC 的 TRT 靶标；2）选择性调节肿瘤微环境以改善放射性药物的递送； 3) 确定 MUC4 和 TME 靶向联合疗法的治疗效果，目标 1 将提供有关抗 MUC4 MAb 在体内靶向 PC 的效率的信息，并在生物分布和药代动力学方面表征 MAb。确定哪种治疗放射性核素与抗 MUC4 MAb 相容，目标 2 将评估“肿瘤选择性”药物组合改善异种移植物中 TME 的能力。目标 3 将使我们能够确定放射性标记抗体的递送、分布和保留的改善是否会转化为提高治疗效果。相关的 PC 转基因小鼠模型。从拟议研究中获得的临床前结果将构成 PC 患者临床试验的基础。