Novel Combination Therapy Against Pancreatic Cancer

针对胰腺癌的新型联合疗法

• 批准号: 8114931
• 负责人: MANEESH JAIN
• 金额: $ 16.09万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8114931
• 关键词: Affect; Angiotensin II; Antibodies; Antigens; Applications Grants; Biodistribution; Blood Vessels; Blood flow; Cancer Patient; Clinical Trials; Combined Modality Therapy; Data; Diagnosis; Disease; Disseminated Malignant Neoplasm; Distant Metastasis; Dose; Drug Kinetics; Endothelin A Receptor; Engineering; Future; Goals; Immunoglobulin Fragments; Intercellular Fluid; Label; Learning; Magic; Malignant neoplasm of pancreas; Metastatic Lesion; Mus; Nature; Operative Surgical Procedures; Outcome; Perfusion; Pharmaceutical Preparations; Physiological; Property; Radiation; Radioimmunotherapy; Radiolabeled; Radiopharmaceuticals; Regimen; Relative (related person); Research; SHH gene; Schedule; Signal Pathway; Signal Transduction; Solid Neoplasm; Stromal Neoplasm; Testing; Therapeutic; Time; Toxic effect; Translating; Treatment Efficacy; Tumor Antibodies; Tumor Antigens; antibody engineering; base; cancer cell; chemotherapy; cyclopamine; human subject; improved; inhibitor/antagonist; lymph nodes; macromolecule; meetings; molecular size; neoplastic cell; novel; pancreatic neoplasm; penetratin; pharmacokinetic model; pre-clinical; pressure; radiotracer; receptor; remediation; residence; response; scale up; smoothened signaling pathway; success; theories; tumor; tumor xenograft; uptake; vasoactive agent; vasoconstriction

DESCRIPTION (provided by applicant): At the time of diagnosis, a majority of pancreatic cancer patients already have local lymph node or distant metastases, which may or may not be detectable, but certainly contribute to the lethality of the disease and hence should be treated effectively. Chemotherapy is the standard line of treatment for advanced pancreatic cancer but the untargeted nature of the current chemotherapeutic regimens often results in poor efficacy and high toxicity. Radioimmunotherapy (RIT) is a 'smart' way of delivering radiation to the known and occult metastatic cancer cells and can be a promising therapeutic option for treating pancreatic cancer. Our previous studies have demonstrated that scFv fragments of anti-tumor antibodies due to their improved pharmacokinetics and biodistribution hold a greater potential than intact antibodies for solid tumor RIT. However, various physiological impediments encountered by macromolecule-based drugs in solid tumors have limited the efficacy of RIT in solid tumors. The two major barriers to macromolecule delivery in solid tumors are: a) insufficient and heterogeneous tumor blood flow, and b) obstructive nature of tumor stroma. 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 signalling pathways that regulate various components of tumor stroma. The central hypothesis of this proposal is: "Selective modulation of tumor vascular flow and tumor stroma would improve the delivery and therapeutic efficacy of targeted radiopharmaceuticals for the treatment of pancreatic cancer." A combination of, Angiotensin II (ATII), BQ123 [antagonist of endothelin-1 receptor type A (ETAR)] and cyclopamine [(inhibitor of sonic hedgehog signalling)] will be evaluated for improving the tumor uptake and improve tumor distribution and retention of radiolabeled scFvs without compromising their pharmacokinetic and tumor targeting properties. To test the hypothesis two specific aims are proposed: 1) Determine the relative biodistribution, tumor retention and pharmacokinetics of scFv constructs in the presence, absence and various combinations of penetratin, ATII, BQ123 and cyclopamine in transplantable pancreatic tumor xenografts in mice; and 2) Study the therapeutic efficacy of penetratin co-administered, 131I-labeled scFvs (administered as fractionated doses) in combination with ATII, BQ123 and cyclopamine in pancreatic tumor bearing mice. The preclinical results obtained from the proposed study will immediately form the basis of clinical trial in pancreatic cancer patients. The proposed studies represent the first comprehensive effort to overcome physiological barriers in solid tumor to improve efficacy. PUBLIC HEALTH RELEVANCE: The proposal aims to develop a novel combination therapy that combines the excellent tumor targeting and pharmacokinetics of genetically engineered anti- tumor antibodies with "tumor- selective" agents to modulate tumor blood flow and stromal compartment. A combined administration of Angnitensin II, endotehlin-1 receptor antagonist and sonic hedgehod signaling inhibitor with radioiodinated antibody fragments to result in improved biodistribution, unaltered pharmacokinetics and enhanced therapeutic efficacy of antibody-based radiopharmaceuticals for lethal pancreatic cancer.

描述(申请人提供)：在诊断时，大多数胰腺癌患者已经有局部淋巴转移或远处转移，这可能会也可能不会被发现，但肯定会导致疾病的致命性，因此应该得到有效的治疗。化疗是晚期胰腺癌的标准治疗方案，但目前化疗方案的非靶向性往往导致疗效差和毒性高。放射免疫疗法(RIT)是一种将辐射传递给已知的和隐蔽的转移癌细胞的“聪明”方式，可以成为治疗胰腺癌的一种有前途的治疗选择。我们以前的研究已经证明，抗肿瘤抗体的单链抗体片段由于其改善的药代动力学和生物分布而具有比完整抗体更大的治疗实体瘤RIT的潜力。然而，基于高分子的药物在实体肿瘤中遇到的各种生理障碍限制了RIT在实体肿瘤中的疗效。实体瘤中大分子转运的两个主要障碍是：a)肿瘤血流不足和不均匀，b)肿瘤基质的阻塞性。与正常血管相比，肿瘤血管系统具有结构和功能异常的特点，当正常血管系统和肿瘤血管系统暴露于不同的血管活性物质时，这些差异导致不同的反应。肿瘤间质的调节可以通过选择性地靶向调节肿瘤间质的各种成分的信号通路来实现。这项提议的中心假设是：“选择性调节肿瘤血管和肿瘤间质将改善胰腺癌靶向放射性药物的输送和治疗效果。”将评估血管紧张素II(ATII)、BQ123[内皮素-1受体A型拮抗剂(ETAR)]和环胺[(Sonic Hedgehog信号抑制物)]的组合，以改善肿瘤摄取，改善放射性标记单链抗体的肿瘤分布和保留，同时不影响其药代动力学和肿瘤靶向性。为了验证这一假设，提出了两个特定的目标：1)确定穿透素、ATII、BQ123和环胺在小鼠可移植胰腺癌移植瘤中的相对生物分布、肿瘤滞留和单链抗体的药物动力学；2)研究穿透素、ATII、BQ123和环多巴胺联合应用(分次给药)与穿透素、ATII、BQ123和环丙胺联合应用的治疗效果。从拟议的研究中获得的临床前结果将立即成为胰腺癌患者临床试验的基础。提出的研究代表了第一个全面的努力，以克服生理障碍的实体肿瘤，以提高疗效。 与公共卫生相关：该提案旨在开发一种新的联合疗法，将基因工程抗肿瘤抗体出色的肿瘤靶向性和药代动力学与“肿瘤选择性”试剂结合起来，以调节肿瘤血流量和间质隔间。Angnitensin II、Endotehlin-1受体拮抗剂和Sonic Hedgehod信号抑制剂与放射性碘抗体片段联合应用，可改善基于抗体的放射性药物的生物分布、不改变药代动力学并提高其治疗效果。