Development of novel targeted agents in lung cancer

肺癌新型靶向药物的开发

基本信息

批准号：
8311498
负责人：
Alexander B Sigalov
金额：
$ 22.17万
依托单位：
SIGNABLOK, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-24 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8311498
关键词：
Adverse effects Affect American Amino Acids Animal Model Animal Testing Animals Award Biochemical Biological Availability Biological Models Biological Response Modifier Therapy Cancer Patient Clinical Colon Carcinoma Cytotoxic Chemotherapy Data Development Drug Formulations Drug Kinetics Future Generations Goals Growth Factor Inflammatory Inflammatory Response Injectable Interleukin-1 Lead Ligands Lipoproteins Macrophage Colony-Stimulating Factor Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Methodology Modeling Myeloid Cells Nature Non-Small-Cell Lung Carcinoma Particulate Patients Peptides Pharmaceutical Preparations Pharmacodynamics Phase Play Production Property Research Role Safety Signal Pathway Signal Transduction Site Solubility Solvents Staging Survival Analysis Survival Rate System Technology Testing Toxic effect Tumor Necrosis Factor-alpha Variant Water Xenograft procedure anti-cancer therapeutic anticancer activity base cancer cell cancer therapy cancer type comparative cytokine design drug candidate follow-up human TNF protein improved in vivo inhibitor/antagonist innovation killings lead series macrophage malignant breast neoplasm mouse model nanoparticle nanoparticulate nanosystems novel novel strategies phase 1 study programs receptor small hairpin RNA targeted delivery therapeutic target tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) affects over 222,000 Americans annually. Despite advances in therapy, the 5-year survival rate is as low as 15%. Current treatments of NSCLC include cytotoxic chemotherapy and targeted biologic therapies. They all have multiple shortcomings including only a modest increase in survival and significant toxicity to the patient. The limitations in efficacy and safety associated with availabe treatments for NSCLC highlight the need for new treatments. As found recently, triggering receptor expressed on myeloid cells (TREM-1) plays a role in NSCLC progression. Inhibition of TREM-1 by short hairpin RNA (shRNA) in macrophages is shown to suppress cancer cell invasion. In clinical setting, the 4-year survival rate in patients with low expression of TREM-1 on tumor-associated macrophages (TAMs) is 60%, compared with 20% in those with high expression. We hypothesize that TREM-1 inhibition can improve survival of NSCLC patients. The long-term objective of the proposed project is to develop a novel approach to targeted treatment of NSCLC. The major goal of the Phase I study is to demonstrate that specific inactivation of TREM-1 with novel inhibitory peptides suppresses tumor progression in animal model system and improves survival. Phase I specific aims are to: 1) generate and characterize injectable formulations of TREM-1 inhibitory peptides, and 2) test the TREM-1 inhibitory peptides in a mouse model of NSCLC. The peptides will be designed using SignaBlok's proprietary model of TREM-1 signaling. These peptides employ novel, ligand-independent mechanisms of action and are anticipated to have less severe side effects. In order to increase peptide solubility, bioavailability and targeting to TAMs, we will utilize SignaBlok's proprietary nanosystem for macrophage-targeted delivery of water insoluble and poorly water soluble drugs. We will use a NCI-H292 xenograft mouse model of NSCLC to test the ability of the peptides in free and particulate forms to inhibit cancer progression and promote survival. It is anticipated that the proposed research will identify novel anticancer lead compounds that will set the stage for the development of new targeted therapies of NSCLC, thereby leading to a higher survival rate of the patients. The Phase I data will be used to further improve this technology in a Phase II program. Importantly, TREM-1 may play a role in the progression of not only NSCLC but also other tumors. Thus, successful completion of Phase I will provide the proof of concept of the hypothesis that might be applicable to a variety of tumors. PUBLIC HEALTH RELEVANCE: Non-small cell lung cancer kills more patients than breast, colon, and prostate cancer combined, and the 5- year survival rate is 15%. Current treatment has multiple shortcomings including only a modest increase in survival and significant toxicity to the patient. The proposed research is expected to result in the development of novel anticancer therapeutics that could substantially improve treatment of this type of cancer, thereby leading to a higher survival rate of the patients.

描述（由申请人提供）：非小细胞肺癌（NSCLC）每年影响222,000多名美国人。尽管在治疗方面取得了进步，但5年的存活率高达15％。 NSCLC的当前治疗包括细胞毒性化疗和靶向生物疗法。他们都有多个缺点，包括仅适度增加生存率和对患者的显着毒性。与NSCLC的可用治疗相关的功效和安全性的局限性突出了对新治疗的需求。如最近发现，在髓样细胞上表达的受体（TREM-1）在NSCLC进展中起作用。巨噬细胞中短发夹RNA（shRNA）对TREM-1的抑制可抑制癌细胞侵袭。在临床环境中，在肿瘤相关巨噬细胞（TAMS）中，TREM-1表达低表达低表达的患者的4年生存率为60％，而高表达的患者为20％。我们假设TREM-1抑制可以改善NSCLC患者的存活率。拟议项目的长期目标是开发一种新型的NSCLC治疗方法。第一阶段研究的主要目的是证明具有新型抑制性肽对TREM-1的特异性失活会抑制动物模型系统中的肿瘤进展并提高生存率。第一阶段的特定目的是：1）生成和表征TREM-1抑制性肽的可注射式配方，以及2）在NSCLC小鼠模型中测试TREM-1抑制性肽。肽将使用Signablok的TREM-1信号传导的专有模型设计。这些肽采用了新型的，独立于配体的作用机理，预计副作用较少。为了提高肽溶解度，生物利用度和对TAM的靶向，我们将利用Signablok的专有纳米系统来实现巨噬细胞靶向的不溶性水和水溶性差的水。我们将使用NSCLC的NCI-H292异种移植小鼠模型来测试自由和颗粒形式中肽抑制癌症进展并促进生存的能力。预计拟议的研究将确定新型的抗癌铅化合物，为开发NSCLC的新靶向疗法奠定基础，从而导致患者的存活率更高。 I期数据将用于进一步改善II阶段计划。重要的是，TREM-1不仅在NSCLC的进展中和其他肿瘤的进展中起作用。因此，成功完成I期将提供可能适用于各种肿瘤的假设的概念证明。公共卫生相关性：非小细胞肺癌比乳腺癌，结肠癌和前列腺癌杀死的患者更多，而5年生存率为15％。当前治疗有多个缺点，包括仅适度增加生存率和对患者的显着毒性。预计拟议的研究将导致新型抗癌治疗剂的发展，这些抗癌治疗剂可以大大改善这种类型的癌症的治疗，从而导致患者的存活率更高。