Preclinical Evaluation of PK2 Antagonists for Pancreatic Cancer

胰腺癌是人类最致命的癌症之一。它被诊断在超过 每年有33,000名美国人五年生存率只有5%。胰腺癌是指 通常是晚期，对传统的癌症治疗没有反应，所以必须 开发了新的治疗策略来对抗这种毁灭性疾病。胰腺癌 具有一些独特的特征，使其很难治疗：肿瘤块通常 由充满纤维化组织和浸润免疫细胞的大基质成分组成 细胞，特别是骨髓谱系的细胞，如巨噬细胞和嗜中性粒细胞。虽然 这些免疫细胞在肿瘤微环境中的确切功能仍有待进一步研究。 完全确定，它们可能通过提供 细胞因子和趋化因子，其反过来改变微环境以增强肿瘤生长， 进展因此，重要的是开发新的治疗胰腺癌的功能， 抑制这些免疫细胞，包括它们响应于免疫应答而从骨髓动员。 胰腺肿瘤生长释放的信号在这方面，称为PK 2/Bv 8的趋化因子 近年来发现它在调节肿瘤微环境中发挥作用。 CD 11b + Gr 1+骨髓细胞是PK 2产生的主要来源， 细胞因子GCSF。PK 2反过来调节骨髓动员，并可能发挥作用， 通过两个G蛋白偶联受体来控制骨髓细胞。基于这些知识，我们有 进行中试实验以测试PK 2的基于小分子的拮抗剂的能力， 抑制人胰腺癌细胞在裸小鼠体内的异种移植生长，并取得了有希望的成果 初步结果。进一步探索开发PK 2拮抗剂的可能性 转化为胰腺癌的治疗剂，我们提出以下两个具体目的：1. 将PK 2拮抗剂的抗肿瘤作用试验扩展至广谱人类 使用异种移植肿瘤模型的胰腺癌细胞; 2.确定PK 2的功效 拮抗剂抑制自发性胰腺肿瘤的形成和发展， Ras/p53转基因小鼠模型。这两种互补的模式将使我们能够 充分测试抗PK 2拮抗剂单独或与吉西他滨联合治疗 抑制胰腺肿瘤发生。这两个目标的成功将奠定临床前 可能的临床试验的基础。

Pancreatic cancer is among the most deadly cancers in humans. It is diagnosed in more than 33,000 Americans a year with a five-year survival rate of only 5%. Pancreatic cancer is found often in late stage that is unresponsive to conventional cancer therapy, so it is imperative that new therapeutic strategies are developed to combat this devastating disease. Pancreatic cancer has some unique characteristics that make it so difficult to treat: The tumor mass is often composed of a large stromal component that is filled with fibrotic tissues and infiltrated immune cells, particularly those of myeloid lineages, such as macrophages and neutrophils. Although the precise functions of those immune cells within the tumor microenvironment remain to be fully determined, it is likely that they contribute to pancreatic tumorigenesis by providing cytokines and chemokines that in turn alter the microenvironment to enhance tumor growth and progression. Thus, it is important to develop new therapies for pancreatic cancer by functionally inhibiting those immune cells, including their mobilization from the bone marrow in response to signals released by the growing pancreatic tumor. In this regard, a chemokine termed PK2/Bv8 has been found in recent years to play a role in regulating the tumor microenvironment. CD11b+Gr1+ myeloid cells are the main source of PK2 production in response to stimulation by the cytokine GCSF. PK2 in turn regulates the bone marrow mobilization and possibly functions of myeloid cells via two G protein-coupled receptors. Based on this knowledge, we have conducted pilot experiments to test the ability of small molecule-based antagonists for PK2 to inhibit xenograft growth of human pancreatic cancer cells in nude mice and obtained promising preliminary results. To further explore the possibility that the PK2 antagonists can be developed into therapeutic agents for pancreatic cancer, we propose the following two Specific Aims: 1. Expand the test of anti-tumor effect of PK2 antagonists to a broad spectrum of human pancreatic cancer cells using xenograft tumor model; 2. Determine the efficacy of PK2 antagonists on the inhibition of spontaneous pancreatic tumor formation and progression in a K- Ras/p53 mouse transgenic model. Together these two complementary models will allow us to fully test the efficacy of anti-PK2 antagonists, alone or in combination with Gemcitabine, in inhibiting pancreatic tumorigenesis. Success of these two aims would lay the preclinical foundation for a possible clinical trial.