Novel Combination Therapy Against Pancreatic Cancer

描述（由申请人提供）：在诊断时，大多数胰腺癌患者已经有局部淋巴结或远处转移，这些转移可能是或可能不是可检测的，但肯定有助于疾病的致死性，因此应该得到有效治疗。化疗是晚期胰腺癌的标准治疗线，但目前化疗方案的非靶向性质往往导致疗效差和毒性高。放射免疫治疗（RIT）是一种“聪明”的方式，可以将放射线传递到已知的和隐藏的转移性癌细胞，并且可以成为治疗胰腺癌的一种有前途的治疗选择。我们先前的研究已经证明，抗肿瘤抗体的scFv片段由于其改善的药代动力学和生物分布而比完整抗体具有更大的用于实体瘤RIT的潜力。然而，基于大分子的药物在实体瘤中遇到的各种生理障碍限制了RIT在实体瘤中的功效。实体瘤中大分子递送的两个主要障碍是：a）肿瘤血流不足和不均匀，和B）肿瘤基质的阻塞性质。肿瘤血管系统的特征在于与正常血管系统相比的结构和功能异常，并且当正常和肿瘤血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。肿瘤间质区室的调节可以通过选择性靶向调节肿瘤间质的各种组分的信号传导途径来实现。该提案的中心假设是：“选择性调节肿瘤血管流动和肿瘤间质将改善靶向放射性药物治疗胰腺癌的递送和疗效。“血管紧张素II（ATII），BQ 123 [内皮素-1受体A型（ETAR）拮抗剂]和环巴胺[（音刺猬信号抑制剂）]的组合将被评估用于改善肿瘤摄取，改善肿瘤分布和放射性标记的scFv的保留，而不影响其药代动力学和肿瘤靶向特性。为了检验该假设，提出了两个具体的目的：1）确定在存在、不存在穿透素、ATII、BQ 123和环巴胺以及它们的各种组合的情况下，scFv构建体在小鼠中的可移植胰腺肿瘤异种移植物中的相对生物分布、肿瘤保留和药代动力学;和2）研究共施用的穿透素、131 I标记的scFv的治疗功效在胰腺肿瘤荷瘤小鼠中，将其与ATII、BQ 123和环巴胺组合（作为分次剂量施用）。从拟议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。拟议的研究代表了克服实体瘤生理障碍以提高疗效的第一次全面努力。 公共卫生相关性：该提案旨在开发一种新型联合治疗，将基因工程抗肿瘤抗体的优异肿瘤靶向和药代动力学与“肿瘤选择性”药物结合起来，以调节肿瘤血流和基质隔室。一种血管紧张素II、内皮素-1受体拮抗剂和音刺猬信号传导抑制剂与放射性碘标记的抗体片段的联合给药，以导致基于抗体的放射性药物对致死性胰腺癌的改善的生物分布、不变的药代动力学和增强的治疗功效。

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.