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，这些转移可能被发现，也可能没有被发现，但肯定会导致疾病的致命，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高毒性。放射免疫疗法（RIT）是一种“智能”的方式，将辐射传递给已知和隐匿的转移癌细胞，可能是治疗胰腺癌的一种有前途的治疗选择。我们之前的研究表明，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，比完整的抗体在实体肿瘤RIT中具有更大的潜力。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在实体瘤中的疗效。实体肿瘤中大分子递送的两个主要障碍是：a)肿瘤血流不足且不均匀，b)肿瘤基质的梗阻性。与正常血管相比，肿瘤血管的特点是结构和功能异常，当正常血管和肿瘤血管暴露于各种血管活性药物时，这些差异导致不同的反应。肿瘤间质室的调节可以通过选择性靶向调节肿瘤间质各种成分的信号通路来实现。该提案的中心假设是：“选择性调节肿瘤血管流动和肿瘤基质将改善靶向放射性药物治疗胰腺癌的递送和治疗效果。”将评估血管紧张素II （ATII）、BQ123（内皮素-1受体A型（ETAR）拮抗剂）和环巴胺（sonic hedgehog信号传导抑制剂）的组合在不影响其药代动力学和肿瘤靶向特性的情况下改善肿瘤摄取、改善肿瘤分布和保留的效果。为了验证这一假设，提出了两个具体目标：1)确定在存在、不存在以及不同组合的穿透素、ATII、BQ123和环巴胺的情况下，scFv构建体在小鼠可移植胰腺肿瘤中的相对生物分布、肿瘤保留和药代动力学；2)研究穿透素、131i标记scFvs（分次给药）与ATII、BQ123和环巴胺联合给药对荷瘤胰腺小鼠的治疗效果。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。提出的研究代表了克服实体瘤生理障碍以提高疗效的首次综合努力。

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.