Preclinical Evaluation of PK2 Antagonists for Pancreatic Cancer

胰腺癌是人类最致命的癌症之一。它被诊断出的病例不止于 每年3.3万美国人，而五年存活率只有5%。发现胰腺癌 通常是在对传统癌症治疗无效的晚期，所以当务之急是 开发了新的治疗策略来对抗这种毁灭性的疾病。胰腺癌 有一些独特的特征，使它很难治疗：肿瘤肿块通常是 由充满纤维组织和浸润性免疫的大基质成分组成 细胞，特别是髓系细胞，如巨噬细胞和中性粒细胞。虽然 这些免疫细胞在肿瘤微环境中的确切功能尚不清楚。 完全确定的是，它们很可能通过提供 细胞因子和趋化因子，进而改变微环境，促进肿瘤生长和 进步。因此，从功能上开发治疗胰腺癌的新方法具有重要意义。 抑制这些免疫细胞，包括从骨髓中动员它们以应对 不断生长的胰腺肿瘤释放的信号。在这方面，一种称为PK2/Bv8的趋化因子 近年来发现具有调节肿瘤微环境的作用。 CD11b+Gr1+髓系细胞是PK2产生的主要来源 细胞因子GCSF。PK2反过来调节骨髓动员和可能的功能 通过两个G蛋白偶联受体对髓系细胞的影响。基于这些知识，我们有 进行了中试实验以测试基于小分子的PK2拮抗剂的能力 抑制人胰腺癌细胞裸鼠移植瘤生长的研究进展 初步结果。进一步探索开发PK2拮抗剂的可能性 对于胰腺癌的治疗药物，我们提出了以下两个具体目标：1. 将PK2拮抗剂的抗肿瘤作用试验扩大到更广泛的人体 胰腺癌细胞异种移植瘤模型的建立；2.检测PK2的疗效 拮抗剂对自发性胰腺癌形成和发展的抑制作用 Ras/p53转基因小鼠模型。这两个互补的模式结合在一起将使我们能够 充分测试单独或与吉西他滨联合使用的抗PK2拮抗剂的疗效 抑制胰腺肿瘤的发生。这两个目标的成功将为临床前 为可能的临床试验奠定基础。

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.