Preclinical Evaluation of PK2 Antagonists for Pancreatic Cancer

描述（由申请人提供）：胰腺癌是人类最致命的癌症之一。每年有超过33，000名美国人被诊断出患有这种疾病，五年生存率仅为5%。胰腺癌通常在晚期发现，对常规癌症治疗无反应，因此必须开发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点，使它很难治疗：肿瘤块通常是由一个大的基质成分，充满了纤维化组织和浸润的免疫细胞，特别是那些骨髓谱系，如巨噬细胞和中性粒细胞。尽管这些免疫细胞在肿瘤微环境中的精确功能仍有待完全确定，但它们可能通过提供细胞因子和趋化因子而促进胰腺肿瘤发生，这些细胞因子和趋化因子反过来改变微环境以促进肿瘤生长和进展。因此，重要的是通过功能性抑制这些免疫细胞来开发胰腺癌的新疗法，包括它们响应于生长的胰腺肿瘤释放的信号而从骨髓动员。在这方面，近年来发现称为PK 2/Bv 8的趋化因子在调节肿瘤微环境中发挥作用。CD 11b + Gr 1+骨髓细胞是响应于细胞因子GCSF刺激的PK 2产生的主要来源。PK 2进而通过两个G蛋白偶联受体调节骨髓动员和可能的骨髓细胞功能。基于这一认识，我们进行了初步实验，以测试PK 2的小分子拮抗剂抑制人胰腺癌细胞裸鼠移植瘤生长的能力，并获得了有希望的初步结果。为了进一步探索PK 2拮抗剂开发为胰腺癌治疗药物的可能性，我们提出以下两个具体目的：1.采用异种移植瘤模型，将PK 2拮抗剂的抗肿瘤作用试验扩展至广谱的人胰腺癌细胞; 2.在K-Ras/p53转基因小鼠模型中测定PK 2拮抗剂对自发性胰腺肿瘤形成和进展的抑制功效。这两种互补的模型将使我们能够充分测试抗PK 2拮抗剂单独或与吉西他滨组合在抑制胰腺肿瘤发生中的功效。这两个目标的成功将为可能的临床试验奠定临床前基础。 公共卫生相关性：胰腺癌仍然是缺乏有效治疗的最致命的癌症之一。本研究旨在为PK 2拮抗剂开发为胰腺癌治疗药物的可能临床试验奠定临床前基础。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Pancreatic cancer remains one of the most deadly cancers that lack effective therapies. This study aims to lay the preclinical groundwork for the possible clinical trial for the development of PK2 antagonists into a therapeutic agent for the treatment of pancreatic cancer.