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（由适用提供）：胰腺导管腺癌，胰腺癌的代名词，是癌症死亡的第四个主要原因。 “沉默的杀手”的特征是在检测原发性肿瘤之前的转移性行为，导致五年生存率仅为4％，强调了对新的替代疗法的需求。基于单核细胞增生李斯特菌的癌症治疗可能是一种替代疗法。我们的实验室发现，李斯特菌展示了针对转移性癌症特别有用的新型途径。我们发现李斯特菌感染了转移酶和原发性肿瘤，并通过高水平的活性氧（ROS）杀死肿瘤细胞，并且髓样衍生的抑制细胞（MDSC）通过肿瘤细胞和通过免疫感染的性能通过肿瘤细胞产生的化学/细胞因子选择性地将李斯特菌通过化学/细胞因子选择性地传递到肿瘤部位（S）。基于这些结果，我们现在使用李斯特菌作为将抗癌剂传递到肿瘤微环境（TME）的平台。一种新颖的应用是放射性同位素的递送，它会散发出胞质辐射，例如与李斯特菌耦合的β粒子，有选择地进入肿瘤细胞。这通过电离辐射导致肿瘤细胞的协同破坏，从而通过β粒子杀死细胞，并通过李斯特菌通过ROS产生。我们是第一个证明，在高度侵略性的胰腺癌模型（PANC-02）中，李斯特菌治疗治疗将转移数量降低了50％，当与放射性同位素耦合188-Rhenium（188RE）时，则减少了90％。这项工作于去年发表在PNA中，其人类临床试验的潜力在PNAS评论以及科学，自然和外行杂志（如经济学家和福布斯）中进行了广泛讨论。最近，我们通过在李斯特菌培养期间将32p编码32p在李斯特菌（李斯特菌-32p）的细胞壁中探索了一种全新的RL生成方法。事实证明，李斯特菌-32p不仅比李斯特菌188RE更有效（最有可能是由于32p更长的半衰期14天，而17小时的188re更有效），而且更容易产生。这种新颖的方法避免了对抗体的需求，并且比Listeria-188RE的产生更便宜，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，与仅32P相比，几乎无法检测到通过李斯特菌递送到包括骨髓（BM）在内的正常组织中的32p掺入，而32p强烈掺入了BM中。同样，李斯特菌-32p的副作用几乎无法检测到。在此赠款应用中，我们的主要目标是通过在人源化的胰腺导管腺癌（KPC小鼠）中评估李斯特菌32p治疗胰腺癌的有效性和安全性，该模型有条件地表达内源性KRAS-G12D和p53-R172H突变型弹药）。具体目的如下：（1）评估KPC小鼠中李斯特菌-32p的功能，稳定性，生物分布和安全性，以及（2）评估李斯特菌-32p对KPC小鼠有效性和存活的影响。