Treating pancreatic cancer with Listeria-32P

用 Listeria-32P 治疗胰腺癌

基本信息

批准号：
8957301
负责人：
CLAUDIA GRAVEKAMP
金额：
$ 1.97万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8957301
关键词：
A Mouse Adverse effects Aftercare Alleles Alternative Therapies Antibodies Antineoplastic Agents Applications Grants Attenuated Bacteria Beds Behavior Beta Particle Biodistribution Blood Bone Marrow Brain Cancer Etiology Cell Wall Cessation of life Clinical Trials Collaborations Coupled Culture Media Diagnosis Discipline of Nuclear Medicine Disseminated Malignant Neoplasm Evaluation Exhibits Feces Generations Goals Half-Life Heart Human Immune Infection Injection of therapeutic agent Ionizing radiation Isotopes Journals Kidney Laboratories Life Listeria Listeria monocytogenes Liver Long-Term Effects Lung Malignant Neoplasms Malignant neoplasm of pancreas Measures Medical center Medicine Methods Modeling Mus Myelogenous Nature Neoplasm Metastasis Normal Cell Normal tissue morphology Nutrient Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Pharmaceutical Preparations Phosphorus Primary Neoplasm Published Comment Publishing Radiation Radioactive Radioactivity Radioisotopes Reactive Oxygen Species Reporting Rhenium Safety Science Scintillation Counter Serum Site Spleen Suppressor-Effector T-Lymphocytes Survival Rate Testing Therapeutic Time Tissues Toxic effect Urine Work anticancer treatment base cancer therapy cell killing college cytokine imaging system immune clearance killings mouse model mutant neoplastic cell novel novel strategies pancreatic neoplasm public health relevance tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma, synonymous to pancreatic cancer, is the 4th leading cause of cancer deaths. The "silent killer" is characterized by its metastatic behavior before the primary tumor can be detected, resulting in a five-year survival rate of only 4%, underscoring the need for new alternative therapies. Listeria monocytogenes-based cancer therapy could be such an alternative therapy. Our laboratory discovered that Listeria exhibits novel pathways that are particularly useful against metastatic cancer. We found that Listeria infects metastases and primary tumors, and kills tumor cells through high levels of reactive oxygen species (ROS), and that myeloid-derived suppressor cells (MDSC) deliver Listeria selectively to the tumor site(s) through chemo/cytokines produced by the tumor cells, and by protecting them, after infection, from immune clearance through their immune suppressive character. Based on these results we now use Listeria as a platform for the delivery of anticancer agents to the tumor microenvironment (TME). One novel application is the delivery of radioisotopes, which emit cytocidal radiation such as beta-particles coupled to Listeria, selectively into the tumor cells. This leads to the synergistic destruction of tumor cell by ionizing radiation, which killed cells through beta-particles, and through ROS generation by Listeria. We were the first to demonstrate that in a highly aggressive model of pancreatic cancer (Panc-02), therapeutic treatment with Listeria reduced the number of metastases by 50%, and when coupled to radioisotope 188-Rhenium (188Re) by 90%. This correlated with a selective accumulation of radioactivity in the metastases with practically no side effects. This work was published in PNAS last year and its potential for human clinical trials was extensively discussed in a PNAS commentary, as well as in Science, Nature and lay magazines like The Economist and Forbes. Most recently, we explored a completely new method to RL generation using 32Phosphorus (32P), by incorporating 32P into the cell wall of Listeria (Listeria-32P) during culturing of Listeria. The Listeria-32P proved to be not only more effective against pancreatic cancer than Listeria-188Re (most likely as a result of the 32P longer half-life of 14 days vs 188Re of 17 hrs), but also much easier to generate. This novel approach avoids the need for antibodies and is much cheaper and faster than the generation of Listeria-188Re. Treatment with Listeria-32P completely eliminated the metastatic cancer in 80% of the mice. Most importantly, the incorporation of 32P delivered through Listeria into normal tissues including bone marrow (BM) was hardly detectable, in contrast to 32P alone, which strongly incorporated into the BM. Also, side effects of Listeria-32P were hardly detectable. In this grant application, our main goal is to explore the efficacy and safety of Listeria-32P for treatment of pancreatic cancer through evaluation in a humanized mouse model of pancreatic ductal adenocarcinoma (KPC mice, which conditionally express endogenous Kras-G12D and p53-R172H mutant alleles). The specific aims are as follows: (1) Evaluate function, stability, biodistribution, and safety of Listeria- 32P in KPC mice, and (2) Evaluate the effect of Listeria-32P on efficacy and survival in KPC mice.

描述（申请人提供）：胰腺导管腺癌与胰腺癌同义，是癌症死亡的第四大原因，其特点是在原发肿瘤被发现之前就发生转移，导致五年后死亡。存活率仅为 4%，这凸显了对基于单核细胞增生李斯特菌的癌症疗法的需求，我们的实验室发现李斯特菌具有新颖性。我们发现李斯特菌感染转移瘤和原发性肿瘤，并通过高水平的活性氧（ROS）杀死肿瘤细胞，并且骨髓源性抑制细胞（MDSC）选择性地将李斯特菌递送至肿瘤。通过肿瘤细胞产生的化学/细胞因子来攻击位点，并在感染后通过其免疫抑制特性保护它们免受免疫清除。基于这些结果，我们现在使用李斯特菌作为抗癌药物的平台。一种新颖的应用是将放射性同位素（例如与李斯特菌偶联的β粒子）递送到肿瘤细胞中，从而通过电离辐射协同破坏肿瘤细胞。它通过 β 粒子和李斯特菌产生的 ROS 杀死细胞，我们是第一个证明在高度侵袭性的胰腺癌模型 (Panc-02) 中，李斯特菌的治疗可减少癌症的发生。转移瘤数量减少 50%，与放射性同位素 188-铼 (188Re) 结合时，转移瘤数量减少 90%，这与转移瘤中放射性的选择性积累相关，而且几乎没有副作用。这项工作去年发表在《美国国家科学院院刊》及其潜力上。 PNAS 评论以及《科学》、《自然》以及《经济学人》和《福布斯》等非专业杂志最近讨论了一种使用 RL 生成的全新方法。 32磷 (32P)，在李斯特菌培养过程中将 32P 掺入李斯特菌 (Listeria-32P) 细胞壁中。事实证明，Listeria-32P 不仅比 Listeria-188Re 更有效地对抗胰腺癌（很可能是由于32P 的半衰期更长，为 14 天，而 188Re 的半衰期为 17 小时），而且这种新颖的方法也更容易生成。需要抗体，并且比李斯特菌 188Re 的产生便宜得多，速度更快，用李斯特菌 32P 治疗完全消除了 80% 的小鼠的转移性癌症。最重要的是，通过李斯特菌将 32P 掺入包括骨髓在内的正常组织。 (BM) 几乎检测不到，与单独的 32P 相比，Listeria-32P 的副作用几乎检测不到。在本次资助申请中，我们的主要目标是探索。通过在胰腺导管腺癌人源化小鼠模型（KPC小鼠，条件性表达内源性Kras-G12D和p53-R172H突变等位基因）中评估Listeria-32P治疗胰腺癌的有效性和安全性具体目标如下： (1)评估Listeria-32P在KPC小鼠中的功能、稳定性、生物分布和安全性，以及(2)评估效果Listeria-32P 对 KPC 小鼠的功效和存活率的影响。